Expression, Regulation, and Function of IGF-1, IGF-1R, and IGF-1 Binding Proteins in Blood Vessels
http://www.100md.com
《动脉硬化血栓血管生物学》
From the Section of Cardiology, School of Medicine, Tulane University Medical Center, New Orleans, LA.
Correspondence to Patrice Delafontaine, MD, FACC, FAHA, FACP, FESC, Tulane University Medical Center, School of Medicine, Section of Cardiology, 1430 Tulane Ave, New Orleans, LA 70112-2699. E-mail pdelafon@tulane.edu
Abstract
The vascular insulin-like growth factor (IGF)-1 system includes the IGFs, the IGF-1 receptor (IGF-1R), and multiple binding proteins. This growth factor system exerts multiple physiologic effects on the vasculature through both endocrine and autocrine/paracrine mechanisms. The effects of IGF-1 are mediated principally through the IGF-1R but are modulated by complex interactions with multiple IGF binding proteins that themselves are regulated by phosphorylation, proteolysis, polymerization, and cell or matrix association. During the last decade, a significant body of evidence has accumulated, indicating that expression of the components of the IGF system are regulated by multiple factors, including growth factors, cytokines, lipoproteins, reactive oxygen species, and hemodynamic forces. In addition, cross-talk between the IGF system and other growth factors and integrin receptors has been demonstrated. There is accumulating evidence of a role for IGF-1 in multiple vascular pathologies, including atherosclerosis, hypertension, restenosis, angiogenesis, and diabetic vascular disease. This review will discuss the regulation of expression of IGF-1, IGF-1R, and IGF binding proteins in the vasculature and summarize evidence implicating involvement of this system in vascular diseases.
Key Words: insulin-like growth factor-1 ? insulin-like growth factor binding proteins ? blood vessels ? signaling pathways ? vascular diseases
Introduction
The insulin-like growth factors (IGFs) are synthesized by almost all tissues and are important mediators of cell growth, differentiation, and transformation.1 Because of the wide range of their biologic effects and their therapeutic potential, the IGFs have become the focus of research by an increasing number of investigators. This review will focus on the expression, regulation, and function of IGF-1, IGF-1 receptors (IGF-1Rs), and IGF-1 binding proteins (IGFBPs) in blood vessels.
IGF-1 is the product of the IGF-1 gene, which has been mapped to chromosome 12 in humans and chromosome 10 in mice.2 The mammalian gene consists of at least 6 exons, and transcription results from at least 2 transcription start sites located on exon 1 and exon 2.2 Additional complexity results from the presence of distinct carboxyterminal E domains of IGF-1 (Ea and Eb variants). Exon 1 and Ea-containing transcripts are expressed ubiquitously, whereas exon 2 and Eb transcripts are expressed more specifically in the liver.2 IGF-1 has a fundamental role in both prenatal and postnatal development and exerts all of its known physiologic effects by binding to the IGF-1R,3 and its effects are modulated by multiple IGFBPs.4 Circulating IGF-1 is generated by the liver under the control of growth hormone. The binding of growth hormone with its hepatic receptor stimulates expression and release of IGF-1 peptide in the circulation, which has high affinity for IGFBPs, and represents the endocrine form of IGF-1.2,4 In addition to the liver, many other organs produce IGF-1, which has a lower affinity for IGFBPs, representing autocrine and paracrine form of IGF-1.2,4
The human IGF-1R is the product of a single-copy gene located on chromosome 15 and is ubiquitously expressed.2 The mature receptor is a tetramer consisting of 2 extracellular -chains and 2 intracellular ?-chains.1 The ?-chains include an intracellular tyrosine kinase domain that is thought to be essential for most of the receptor’s biologic effects.2 IGF-1R signaling involves autophosphorylation and subsequent tyrosine phosphorylation of Shc and insulin receptor substrate (IRS) -1, -2, -3, and -4.5 IRS serves as a docking protein and can activate multiple signaling pathways, including phosphatidyl inositol 3-kinase (PI3K), Akt, and mitogen-activated protein kinase (MAPK).3,6 The activation of these signaling pathways induces differential biologic actions of IGF-1, including cell growth, differentiation, migration, and survival7 (Figure 1). "Cross-talk" between IGF-1 and other growth factors makes the IGF-1 signaling cascade more complicated.8,9
Figure 1. IGF-1 signal transduction. Activation of the IGF-1R triggers several signaling pathways. The IGF-1R is a tyrosine kinase that undergoes autophosphorylation and catalyzes the phosphorylation of multiple cellular proteins, including members of the IRS family. On phosphorylation, IRSs interact with signaling molecules, including Akt, Ras/Raf, and Rac. Activation of the PI3K and Akt pathway prevents loss of mitochondrial membrane potential and release of cytochrome c, thereby inhibiting caspase-3 activation and apoptosis. The Ras/Raf pathway is critical for proliferative responses, whereas activation of Rac is important for cell migration. indicates mitochondrial membrane potential.
The IGFBP family has at least 6 members, which serve as transporter proteins and as storage pools for IGF-1. The expression of IGFBPs are tissue- and developmental stage–specific, and the concentrations of IGFBPs in different body compartments are different.10 The functions of IGFBPs are regulated by phosphorylation, proteolysis, polymerization, and cell or matrix association of the IGFBP.11 All 6 IGFBPs have been shown to inhibit IGF-1 action, but IGFBP-1, -3, and -5 are also shown to stimulate IGF-1 action.4 Some of IGFBPs’ effects might be IGF-1 independent.10,12 Whereas the IGFBPs consistently have extremely high affinity for IGF-1, the N-terminally truncated des-IGF-1 and a variety of IGF-1 analogues have markedly reduced affinity for IGFBPs but retain normal affinity for IGF-1R.4,13
Expression, Regulation, and Function of IGF-1, IGF-1R, and IGFBPs in Vascular Cells
IGF-1 and VSMCs
IGF-1 is synthesized and secreted by cultured vascular smooth muscle cells (VSMCs).14 There are 3 primary mRNA transcripts, 0.9 to 1.2 kb, 1.7 kb, and 7.5 kb, and IGF-1 gene expression in VSMCs is regulated by several factors (Table 1). Thrombin and serum deprivation,9 tumor necrosis factor (TNF)-,15 and estrogen16 downregulate IGF-1 mRNA and protein levels. In contrast, reactive oxygen species (ROS) increase IGF-1 mRNA and protein in rat VSMCs.17 Angiotensin II (Ang II) has been reported to both increase IGF-1 mRNA and protein17 and decrease IGF-1 transcripts in rat VSMCs.18 Platelet-derived growth factor (PDGF) also has been reported to both increase14 and decrease19,20 IGF-1 mRNA levels. Native LDL dose-dependently increases IGF-1 mRNA, but the same doses of oxidized LDL (oxLDL) significantly reduce IGF-1 mRNA and protein expression.21
TABLE 1. Regulation of IGF-1, IGF-1R, and IGFBPs in VSMCs
IGF-1 is a potent mitogen and antiapoptotic factor for VSMCs, and it also stimulates migration of VSMCs.22 Thus, potential reductions in IGF-1 effects might be beneficial in certain pathologic conditions, such as hypertension and the early stages of atherosclerotic plaque formation characterized by hypertrophy/hyperplasia of VSMCs,23,24 but detrimental in other conditions in which loss of VSMCs contributes to the disease process, such as destabilization of atherosclerotic plaques.25 The ability of IGF-1 to stimulate the G1-to-S phase progression is important for mitogenic effects of other growth factors. Thus, anti–IGF-1 antiserum inhibits Ang II and PDGF-induced VSMC growth.26 IGF-1 can reduce oxLDL-induced mitochondrial dysfunction, cytochrome c release, and apoptosis in VSMCs27 and can also inhibit TNF-–induced caspase-3 activation and apoptosis of VSMCs.15 Targeted expression of IGF-1 to smooth muscle by an -actin promoter in transgenic mice resulted in smooth muscle hyperplasia in arteries, veins, and other smooth muscle–rich tissues and corresponding organ hypertrophy and notably increased aortic medial area and thickness.28 These findings support a central role of IGF-1 in mediating VSMC growth and survival.
IGF-1R and VSMCs
The IGF-1R is expressed on VSMCs and regulated by several factors (Table 1) via multiple signaling pathways. Ang II–induced upregulation of IGF-1R mRNA and protein is mediated by the activation of a tyrosine kinase, the transcription factor nuclear factor (NF)-B, and ROS and was shown to be protein kinase C independent.29,30 Basic fibroblast growth factor–induced upregulation of IGF-1R mRNA is mediated by the transcription factors STAT1, STAT3, and the Janus kinase-2 kinase.30 The Ras-Raf–MAPK kinase pathway was shown to be required for effects of both growth factors. Thrombin-induced upregulation of IGF-1R mRNA and protein levels in VSMCs was protein tyrosine kinase and NAD(P)H oxidase dependent. In contrast, protein kinase C, epidermal growth factor receptor kinase, Janus kinase-2 kinase, and Src kinase were not involved in this process.31 Estrogen-induced downregulation of IGF-1R mRNA and protein in rat aortic VSMCs was mediated by the inhibition of SP-1 binding to the IGF-1R promoter.16 OxLDL significantly reduced IGF-1R mRNA and protein expression,21 but the mechanism was not clear.
IGF-1R density is a critical determinant of VSMC growth response. Thus, the upregulation of IGF-1R expression by Ang II, basic fibroblast growth factor, and thrombin on VSMCs is critical for their mitogenic effects.30–32 The downregulation of IGF-1R expression by oxLDL is critical for oxLDL-induced VSMC apoptosis.21 Recently, we have reported that overexpression of IGF-1R by an adenovirus prevented oxLDL-induced apoptosis of human VSMCs.27
The function of IGF-1 is also regulated by cross-talk between IGF-1R and other receptors, including integrin receptors. Ligand occupancy of the V?3 integrin influences the recruitment of the phosphatase SHP-2 to the IGF-1R receptor.33 Blocking ligand occupancy of V?3 results in premature recruitment of SHP-2 to the IGF-1R receptor and reduces IGF-1R signaling.33 Therefore, V?3 integrin antagonists block IGF-1–induced DNA synthesis, VSMC migration,34 and IGF-1R–mediated intracellular signaling.35 Cross-talk between IGF-1R and other growth factors8,9 has implications for understanding the requirement for IGF-1R signaling in mitogenic effects for other growth factors.30–32
IGFBPs and VSMCs
The expression and secretion of IGFBPs in VSMCs are species specific. Human VSMCs express mRNAs for IGFBPs -2 through -6, and corresponding proteins are detected in conditioned medium, with the exception of IGFBP-3.36,37 In addition, low-molecular-mass immunoreactive degradation products for IGFBP-2 and -4 are also found. Bovine aortic SMCs express predominantly IGFBP-3 and -4,37 rat VSMCs express predominantly IGFBP-2 and -4,38 and porcine aortic SMCs express BP-2, -4, and -5.24,39
The expression of IGFBPs in VSMCs is regulated by many factors, including platelet-derived growth factor, fibroblast growth factor, transforming growth factor-?, and IGF-1 (Table 1), and the regulation is species specific and dependent on the specific form of IGFBPs. In rat aortic VSMCs, Ang II,40 thrombin,40 and ROS17 reduce IGFBP-4 in conditioned medium, and IGF-1 and IGF-II induce IGFBP-4 proteolysis in these cells.38 Serum starvation significantly lowered the mRNA levels of IGFBP-2 to IGFBP-6 mRNA.36 In contrast, TNF- markedly increased IGFBP-3 mRNA and protein,15 and native LDL and oxLDL significantly increased IGFBP-2 and IGFBP-4 protein levels in rat VSMCs.21 Gustafsson et al18 reported that IGF-1 increases BP-2 and BP-4 mRNA in rat VSMCs, whereas Cohick et al39 reported that IGF-1 affected neither BP-2 nor BP-4 mRNA levels in porcine VSMCs but decreased IGFBP-4 protein in conditioned medium of these cells. IGF-1 transcriptionally regulated IGFBP-5 in porcine aortic VSMCs.24 Targeted overexpression of IGF-1 in smooth muscle was not associated with changes in BP-4 and BP-5 mRNA or protein levels, indicating that long-term overexpression of IGF-1 in vivo cannot further increase BP-5 gene expression, contrary to short-term in vitro effects.28 Studies indicate that local IGFBPs are important determinants of VSMC responses to IGF-1. IGFBP-2 and IGFBP-4 were found to inhibit IGF-1–stimulated DNA synthesis and VSMC migration.41 IGFBP-5 had an inhibitory effect on IGF-1–stimulated DNA synthesis, but it strongly potentiated IGF-1–induced VSMC migration.41 Duan and Clemmons42 also demonstrated that BP-4 inhibits IGF-1–stimulated DNA synthesis, whereas BP-5 has potentiating effects in VSMCs.
The functions of IGFBPs in VSMCs are also regulated by phosphorylation, proteolysis, polymerization,11 and by cell or matrix association of the IGFBP.43 Posttranslational phosphorylation of IGFBPs significantly increases their affinity for IGF-1 and can therefore suppress the function of IGF-1 at the cellular level.44,45 However, proteolysis or polymerization of IGFBPs or binding to extracellular matrix results in reduction or loss of IGF-1 binding to IGFBPs, thus increasing the binding of IGF-1 to IGF-1R and the activity of IGF-1.46 The polymerization of IGFBP-1, through a reduction in binding affinity, leads to loss of IGFBP-1’s ability to inhibit IGF-1–stimulated protein synthesis in VSMCs.11 Imai et al47 have shown that a protease-resistant form of IGFBP-5 is an inhibitor of IGF-1 actions on porcine SMCs in culture. Parker et al48 have shown that binding of IGFBP-5 to porcine SMC extracellular matrix increases the cellular response to IGF-1. BP-5 is cleaved by physiologic concentrations of thrombin, leading to increased free IGF-1 levels, which contribute to thrombin’s mitogenic effects.49 Targeted expression of a protease-resistant BP-4 mutant in smooth muscle of transgenic mice results in BP-4 stabilization and smooth muscle hypotrophy,50 suggesting that IGF-1–induced hypertrophy is regulated by BP-4 proteolysis. The zinc-binding metalloproteinase pregnancy-associated plasma protein A (PAPP-A) has been identified as a major IGFBP-4 protease51–53 and is expressed in VSMCs.54,55
All 6 IGFBPs have been shown to regulate IGF-1 actions; however, the mechanisms are different. IGFBP-3 is unique in combining with the acid-labile subunit and is the primary stabilizer of circulating IGF-1. IGFBP-1, IGFBP-2, and IGFBP-4, also found in the bloodstream, can across endothelial barriers and might transport IGF-1 from blood to peripheral tissue. BP-4 is the most abundant IGFBP expressed in the rat artery wall in vivo and is the dominant IGFBP secreted by rat VSMCs in vitro.54
IGFBPs also mediate IGF-independent biologic effects. IGFBP-1 stimulates Chinese hamster ovary cell migration via an IGF-independent mechanism involving binding to integrin receptors,12 whereas IGFBP-3 and IGFBP-5 might have specific cell-surface receptors with serine kinase activity.56 Using a non–IGF-binding IGFBP-5 mutant and an IGF-1 neutralizing antibody, Hsieh et al41 demonstrated that IGFBP-5 stimulates VSMC migration by interacting with cell-surface heparan sulfate proteoglycans, which is an IGF-independent effect. Interestingly, the decrease of SMC mass in BP-4 transgenic mice occurred without changes in IGF-1 abundance or gene expression, suggesting that the inhibitory action of BP-4 on SMC mass might occur through an IGF-independent mechanism.10,57
IGF-1, IGF-1R, and IGFBPs in ECs
The expression of IGF-1 in endothelial cells (ECs) is low,58 which might reflect to a significant extent IGF-1 sequestered from serum.59 Both macrovessel and microvessel ECs express IGF-1R.60,61 Similarly, macrovessel and microvessel bovine ECs express IGFBP-2 through BP-6 mRNA,62–64 although microvessel cells secrete predominantly BP-2 and BP-3, whereas macrovessel ECs secrete mainly IGFBP-3 and BP-4.62–64 The expression of components of the IGF system in ECs is regulated by various conditions and growth factors, including vascular origin,65 cell density,66 hypoxia,65 transforming growth factor-?1, vascular endothelial growth factor,67 and IGF-168 (Table 2). Stimulation of cAMP increases IGFBP-4 mRNA levels in a clonal EC line.69 IGF-1 stimulates the expression of BP-3 in ECs.68 Interestingly, EC confluence and postconfluence markedly increases gene expression and secretion of IGFBP-3 in bovine aortic ECs.66
TABLE 2. Regulation of IGF-1, IGF-1R, and IGFBPs in Macrovascular ECs
The effects of IGF-1 on microvascular and macrovascular ECs are different.70,71 IGF-1 stimulates neutral amino acid and glucose uptake and DNA synthesis in microvessel ECs but not in macrovascular bovine ECs.61 IGF-1 also regulates migration and angiogenesis72,73 and enhances inflammatory and vasodilatory responses in ECs.74
The effects of IGF-1 on ECs are mediated by the activation of differential IGF-1 signaling pathways. IGF-1–induced nuclear factor-B translocation requires both PI3K and extracellular-regulated kinase, whereas IGF-1–stimulated EC migration requires only PI3K activation.75 The effects of IGF-1 on ECs are also mediated via regulation of endothelial nitric oxide synthase (eNOS) expression and vascular endothelial growth factor signaling.76 It has been reported that IGF-1 increases aortic eNOS expression and stimulates vascular NO production.77 Moreover, other factors that regulate the function of ECs might be dependent on the activation of IGF-1 signaling pathways. Thus, the vasodilatory effect of estrogen is modulated by IGF-1 through PI3K/Akt-related pathways with a subsequent increase in eNOS activity.78,79
Regulation and Role of IGF-1, IGF-1R, and IGFBPs in Vascular Pathologic States
Atherosclerosis
Atherosclerosis, the leading cause of mortality in the Western world, is a complex disease involving multiple cell type, including circulating, inflammatory, and progenitor cells,80 and multiple cell types within the arterial wall.25 SMC proliferation and migration contribute to the development of atherosclerotic plaque; however, SMC apoptosis is a hallmark of advanced atherosclerotic plaque and particularly unstable plaque that is predisposed to rupture and/or erosion, leading to acute coronary events. Thus, the IGF-1 system might contribute to the balance between the death and survival of VSMCs in atherosclerotic lesions (Figure 2, Table 3).
Figure 2. Dual role of IGF-1 axis in atherosclerosis. IGF-1 stimulates VSMC proliferation and migration, contributing to plaque development. However, decreased expression of IGF-1/IGF-1R leads to VSMC apoptosis and contributes to plaque destabilization.
TABLE 3. Alterations of the IGF-1 System and Pathophysiology of Vascular Diseases
Grant et al81 have reported that IGF-1, IGF-1R, and IGFBP-1 through IGFBP-5 were not detected in SMCs of normal coronary arteries but were markedly increased in atherectomy specimens. However, IGF-1 and IGF-1R expression is reduced in advanced plaque,82,83 and this is consistent with the increased apoptotic rates of VSMCs from atherosclerotic plaques, which also secrete higher levels of IGFBPs.83,84 OxLDL is crucially important in the pathogenesis of atherosclerosis and potentially in the depletion of VSMCs, contributing to plaque destabilization,85 and its ability to decrease IGF-1/IGF-1R expression in VSMC might be an important mechanism leading to VSMC loss.21 The ability of TNF- to reduce IGF-1 and to increase IGFBP-3 could also be important for plaque destabilization.15 An V?3 integrin antagonist reduces atherosclerotic lesion size in pigs and inhibits IGF-1 signaling.23 It is important to note that PAPP-A, an IGFBP-4 protease,51 has been reported to be present in unstable but not stable plaques,52 and its circulating levels are elevated in acute coronary syndromes. A potential proinflammatory effect of IGF-1 that could promote early atherosclerosis has been suggested by Che et al,74 who demonstrated that IGF-1 enhanced TNF-–induced adhesion molecule expression in cultured, bovine ECs.
Although reported changes of circulating IGF-1 and IGFBPs in atherosclerotic vascular disease are not consistent,52,55,86–92 of particular interest is the recent report that individuals with low circulating IGF-1 levels and high IGFBP-3 levels had a significantly increased risk of developing atherosclerosis and ischemic heart disease during a 15-year follow-up period.86 Janssen et al90 have reported that high fasting serum free IGF-1 levels are associated with a decreased prevalence of coronary artery disease, whereas high fasting IGFBP-1 levels are associated with a more favorable cardiovascular profile. Furthermore, a polymorphism of the IGF-1 gene associated with lower circulating IGF-1 levels has been demonstrated to be related to 2 early markers of atherosclerosis, namely, carotid intima-media thickness and aortic pulse wave velocity.94
Restenosis
Restenosis remains a major clinical problem after percutaneous coronary interventions95 and results from vessel recoil, neointimal proliferation, and early thrombus formation.96 Neointimal proliferation is the critical determinant of in-stent restenosis. Multiple growth factors and cytokines are involved in the restenotic process, including IGF-1. Thus, IGF-1 and IGF-1R mRNA levels are reported to be increased in synthetic VSMCs from de novo and restenotic coronary plaques compared with normal coronary arteries.81 Moreover, IGF-1 is upregulated in rat aortas after balloon denudation, whereas IGF-1R is downregulated.97 Transgenic mice with IGF-1 overexpression show VSM hyperplasia,98 and mice with paracrine overproduction of IGFBP-4 developed smooth muscle hypoplasia consistent with growth-inhibitory effects of IGFBP-4.50 IGFBP-4 protease (ie, PAPP-A) expression and proteolytic activity are reportedly increased in VSMCs after injury, suggesting a role for this protease in mediating increases in bioactive IGF-1.99 Thus, IGF-1 likely contributes to the proliferation and migration of VSMCs that are characteristic of restenosis.
Animal studies show that IGF-1 inhibitors, including angiopeptin and octreotide, prevent VSMC proliferation and neointimal formation.100 However, clinical trials show that octreotide has no benefit,101 and the effects of angiopeptin on restenosis are equivocal.102–104 This discrepancy could be due to different doses and treatment regimes. It is important to note that an inhibitory stable D-peptide analogue of IGF-1 inhibits VSMC proliferation after rat carotid artery balloon injury, consistent with a role for IGF-1 in the restenotic process.105
Angiogenesis
Angiogenesis occurs during normal wound healing and atherosclerosis106–108 and is regulated by many growth factors, including IGF-1. IGF-1 stimulates vascular EC migration and tube formation109 and promotes rat aortic angiogenesis in vitro.110 IGF-1 is important for promoting retinal angiogenesis, and an IGF-1R antagonist suppresses retinal neovascularization in vivo by inhibiting vascular endothelial growth factor signaling.76 Recombinant IGF, as well as the local delivery of an IGF-1 adenoviral vector, stimulates angiogenesis and neovascularization.111 Increased monocyte expression of IGF-1 in ischemic tissue could contribute to the angiogenic process.112
Diabetes and Hyperinsulinemia
Studies indicate that IGF-1 might be a potential mediator of vascular growth responses in insulin-deficient diabetes and in hyperinsulinemic states.113,114 The actions of the IGF-1 system in local tissues might be modified when glucose concentrations are increased.115 Insulin increases IGF-1 expression in rat aorta,116 indicating that hyperinsulinism might favor atherogenesis via enhanced expression of IGF-1 in the vessel wall. In the insulin-deficient diabetic rat, IGF-1 mRNA levels are markedly decreased in the heart, skeletal muscle, and aorta,117 which might explain the observation that DNA synthesis after balloon-injury of the aorta is either decreased118 or unchanged in diabetes.119
Hyperinsulinemia coupled with physiologic concentrations of IGF-1 stimulate plasminogen activator inhibitor type 1 synthesis,114 which decreases local fibrinolysis, and through increased thrombogenicity could be a mechanism contributing to accelerated atherosclerosis. Indeed, plasminogen activator inhibitor type 1 is increased in the arterial wall from diabetic patients.120
One consequence of long-term hyperglycemia is the formation of advanced glycation end-products (AGEs); the accumulation of AGEs in the vessel wall could play an important role in the pathogenesis of diabetic vascular complications, including atherosclerosis.121122 AGEs enhance proinflammatory pathways and atherosclerotic lesion development in diabetic apolipoprotein E–null mice.123 AGE induction of IGF-1 synthesis in human monocytes could play a role in hyperglycemia-induced vascular proliferative changes.124
Although VSMCs and ECs express both the insulin receptor and IGF-1R,71 the vasodilation induced by insulin might be mediated primarily via its stimulatory effects on the IGF-1R.118,125 In streptozotocin-diabetic rats, aortic IGF-1 mRNA expression was unaffected; in contrast, aortic IGF-1 receptor mRNA was increased, and relaxation caused by IGF-1 was significantly greater in aortic strips from streptozotocin-induced diabetic rats than in age-matched, control rats.126 Insulin treatment ameliorated endothelial dysfunction in these rats and further increased IGF-1R expression.126
The role of the IGF-1 system in diabetic retinopathy is unclear.127 IGF-1 mRNA levels are substantially lower in the human and rat diabetic retina, whereas IGF-1R activation and signaling are not affected after 5 months of streptozotocin-induced diabetes in rats.128 In human retina ECs, long-term exposure to high concentrations of glucose was able to reduce IGF-1–induced mitogenesis by decreasing the stimulatory IGFBP-2, -3, and -5 levels, leaving the concentration of the inhibitory IGFBP-4 constant.129
It is of note that hepatic IGF-1 gene deletion induces insulin resistance in mice,130 and low circulating IGF-1 is associated with an increased risk for developing insulin resistance in humans.131 IGF-1 therapy can improve insulin sensitivity.132 Overexpression of IGFBP-1 in transgenic mice has been reported to induce insulin resistance and hyperglycemia.133
Hypertension
Increased IGF-1 mRNA and protein expression in hypertensive aorta and in volume-overloaded caval vein suggests that the IGF-1 axis mediates adaptive growth responses in the vasculature (Table 3).134,135 IGFBP-4 mRNA has been shown to be markedly elevated in the hypertensive rat aorta after abdominal coarctation,136 and this induction of IGFBP-4 is limited to the hypertensive blood vessel. This suggests that increases in vascular load directly stimulate IGFBP-4 expression, and this is consistent with data from Chen et al,137 showing increased IGFBP-2 and BP-4 expression in pressure-overloaded bladder after partial urethral ligation.
The vasoactive effects of IGF-1 indicate that IGF-1 can control blood pressure and regional blood flow via NO. Short-term injection of IGF-1 decreased mean arterial pressure, and this effect was inhibited by preinfusion of an NO inhibitor, indicating that the decrease in blood pressure in response to IGF-1 is mediated by NO.138 A significant elevation of arterial pressure was also observed in mice homozygous for a site-specific insertional mutation in exon 3 of IGF-1.139 Peripheral resistance and systolic blood pressure were increased in liver-specific IGF-1 knockout mice.140 In spontaneously hypertensive rats, IGF-1–induced vasorelaxant effects were impaired before the onset of hypertension, indicating that this effect could play a causative role in the development of hypertension.141 It is of note that smooth muscle–targeted overexpression of IGF-1 results in enhanced vascular contractility, possibly via regulation of contractile protein expression.142
The role of circulating IGF-1 and IGFBPs in human hypertension is unclear. Increased free IGF-1, increased IGF-1 to IGFBP-3 ratio, and increased BP-1 to BP-3 ratio have been reported in patients with hypertension.143 Interestingly, low levels of IGFBP-1 and particularly, of highly phosphorylated BP-1 are associated with the presence of macrovascular disease and hypertension in type 2 diabetes.144
Summary and Perspectives for Future Research
IGF-1 exerts multiple physiologic effects on the vasculature, including proliferative, hypertrophic, survival, vasomotor, and metabolic effects. The expression of IGF-1, IGF-1R, and IGFBPs in blood vessels is regulated by multiple factors, including growth factors, cytokines, lipoproteins, ROS, and hemodynamic forces. Cross-talk between the IGF-1 system and other growth factors at the level of the ligand receptor and at the level of postreceptor signaling pathways has important implications for understanding potential involvement of the IGF system in vascular diseases. Despite the technical challenges in successfully using the Cre-lox and transgenic approaches with cell type–specific promoters, the overexpression or downregulation of IGF-1, IGF-1R, and IGFBPs in selected tissues of transgenic or knockout models will be a promising strategy to reveal the endocrine/paracrine function of the IGF-1 axis in different pathophysiologic conditions. Future directions for research include addressing the mechanisms whereby IGF-1 interacts with specific form of IGFBPs, cross-talk between the IGF-1 system and other growth factor systems, identification of distinct receptors for IGFBPs, elucidation of the IGF-1–independent function of IGFBPs, and the physiologic role of specific IGFBP proteases. Undoubtedly, insights gained from basic research will lead to novel and pertinent clinical research targeted at prevention and therapy of vascular diseases.
Acknowledgments
Supported by NIH Grant HL-70241 (P.D.).
References
Le Roith D. Seminars in medicine of the Beth Israel Deaconess Medical Center. Insulin-like growth factors. N Engl J Med. 1997; 336: 633–640.
Delafontaine P. Insulin-like growth factor I and its binding proteins in the cardiovascular system. Cardiovasc Res. 1995; 30: 825–834.
LeRoith D, Werner H, Beitner-Johnson D, Roberts CT Jr. Molecular and cellular aspects of the insulin-like growth factor I receptor. Endocr Rev. 1995; 16: 143–163.
Jones JI, Clemmons DR. Insulin-like growth factors and their binding proteins: biological actions. Endocr Rev. 1995; 16: 3–34.
Tsuruzoe K, Emkey R, Kriauciunas KM, Ueki K, Kahn CR. Insulin receptor substrate 3 (IRS-3) and IRS-4 impair IRS-1- and IRS-2-mediated signaling. Mol Cell Biol. 2001; 21: 26–38.
Saltiel AR, Kahn CR. Insulin signalling and the regulation of glucose and lipid metabolism. Nature. 2001; 414: 799–806.
Stewart CE, Rotwein P. Growth, differentiation, and survival: multiple physiological functions for insulin-like growth factors. Physiol Rev. 1996; 76: 1005–1026.
Du J, Sperling LS, Marrero MB, Phillips L, Delafontaine P. G-protein and tyrosine kinase receptor cross-talk in rat aortic smooth muscle cells: thrombin- and angiotensin II-induced tyrosine phosphorylation of insulin receptor substrate-1 and insulin-like growth factor 1 receptor. Biochem Biophys Res Commun. 1996; 218: 934–939.
Rao GN, Delafontaine P, Runge MS. Thrombin stimulates phosphorylation of insulin-like growth factor-1 receptor, insulin receptor substrate-1, and phospholipase C-?1 in rat aortic smooth muscle cells. J Biol Chem. 1995; 270: 27871–27875.
Schneider MR, Lahm H, Wu M, Hoeflich A, Wolf E. Transgenic mouse models for studying the functions of insulin-like growth factor-binding proteins. FASEB J. 2000; 14: 629–640.
Sakai K, Busby WH Jr, Clarke JB, Clemmons DR. Tissue transglutaminase facilitates the polymerization of insulin-like growth factor-binding protein-1 (IGFBP-1) and leads to loss of IGFBP-1’s ability to inhibit insulin-like growth factor-I-stimulated protein synthesis. J Biol Chem. 2001; 276: 8740–8745.
Jones JI, Gockerman A, Busby WH Jr, Wright G, Clemmons DR. Insulin-like growth factor binding protein 1 stimulates cell migration and binds to the á5a1 integrin by means of its Arg-Gly-Asp sequence. Proc Natl Acad Sci U S A. 1993; 90: 10553–10557.
Cascieri MA, Chicchi GG, Applebaum J, Hayes NS, Green BG, Bayne ML. Mutants of human insulin-like growth factor I with reduced affinity for the type 1 insulin-like growth factor receptor. Biochemistry. 1988; 27: 3229–3233.
Delafontaine P, Lou H, Alexander RW. Regulation of insulin-like growth factor I messenger RNA levels in vascular smooth muscle cells. Hypertension. 1991; 18: 742–747.
Anwar A, Zahid AA, Scheidegger KJ, Brink M, Delafontaine P. Tumor necrosis factor-á regulates insulin-like growth factor-1 and insulin-like growth factor binding protein-3 expression in vascular smooth muscle. Circulation. 2002; 105: 1220–1225.
Scheidegger KJ, Cenni B, Picard D, Delafontaine P. Estradiol decreases IGF-1 and IGF-1 receptor expression in rat aortic smooth muscle cells: mechanisms for its atheroprotective effects. J Biol Chem. 2000; 275: 38921–38928.
Delafontaine P, Ku L. Reactive oxygen species stimulate insulin-like growth factor I synthesis in vascular smooth muscle cells. Cardiovasc Res. 1997; 33: 216–222.
Gustafsson T, Andersson P, Chen Y, Magnusson JO, Arnqvist HJ. Interaction of angiotensin II and the insulin-like growth factor system in vascular smooth muscle cells. Am J Physiol. 1999; 277: H499–H507.
Giannella-Neto D, Kamyar A, Sharifi B, Pirola CJ, Kupfer J, Rosenfeld RG, Forrester JS, Fagin JA. Platelet-derived growth factor isoforms decrease insulin-like growth factor I gene expression in rat vascular smooth muscle cells and selectively stimulate the biosynthesis of insulin-like growth factor binding protein 4. Circ Res. 1992; 71: 646–656.
Bornfeldt KE, Arnqvist HJ, Norstedt G. Regulation of insulin-like growth factor-I gene expression by growth factors in cultured vascular smooth muscle cells. J Endocrinol. 1990; 125: 381–386.
Scheidegger KJ, James RW, Delafontaine P. Differential effects of low density lipoproteins on insulin-like growth factor-1 (IGF-1) and IGF-1 receptor expression in vascular smooth muscle cells. J Biol Chem. 2000; 275: 26864–26869.
Arnqvist HJ, Bornfeldt KE, Chen Y, Lindstrom T. The insulin-like growth factor system in vascular smooth muscle: interaction with insulin and growth factors. Metabolism. 1995; 44: 58–66.
Nichols TC, du Laney T, Zheng B, Bellinger DA, Nickols GA, Engleman W, Clemmons DR. Reduction in atherosclerotic lesion size in pigs by áVa3 inhibitors is associated with inhibition of insulin-like growth factor-I-mediated signaling. Circ Res. 1999; 85: 1040–1045.
Duan C, Hawes SB, Prevette T, Clemmons DR. Insulin-like growth factor-I (IGF-I) regulates IGF-binding protein-5 synthesis through transcriptional activation of the gene in aortic smooth muscle cells. J Biol Chem. 1996; 271: 4280–4288.
Libby P, Aikawa M. Stabilization of atherosclerotic plaques: new mechanisms and clinical targets. Nat Med. 2002; 8: 1257–1262.
Delafontaine P, Lou H. Angiotensin II regulates insulin-like growth factor I gene expression in vascular smooth muscle cells. J Biol Chem. 1993; 268: 16866–16870.
Li Y, Higashi Y, Itabe H, Song YH, Du J, Delafontaine P. Insulin-like growth factor-1 receptor activation inhibits oxLDL-induced cytochrome c release and apoptosis via the phosphatidylinositol 3-kinase/Akt signaling pathway. Arterioscler Thromb Vasc Biol. 2003; 23: 2178–2184.
Wang J, Niu W, Nikiforov Y, Naito S, Chernausek S, Witte D, LeRoith D, Strauch A, Fagin JA. Targeted overexpression of IGF-I evokes distinct patterns of organ remodeling in smooth muscle cell tissue beds of transgenic mice. J Clin Invest. 1997; 100: 1425–1439.
Du J, Meng XP, Delafontaine P. Transcriptional regulation of the insulin-like growth factor-I receptor gene: evidence for protein kinase C-dependent and -independent pathways. Endocrinology. 1996; 137: 1378–1384.
Scheidegger KJ, Du J, Delafontaine P. Distinct and common pathways in the regulation of insulin-like growth factor-1 receptor gene expression by angiotensin II and basic fibroblast growth factor. J Biol Chem. 1999; 274: 3522–3530.
Du J, Brink M, Peng T, Mottironi B, Delafontaine P. Thrombin regulates insulin-like growth factor-1 receptor transcription in vascular smooth muscle: characterization of the signaling pathway. Circ Res. 2001; 88: 1044–1052.
Delafontaine P, Anwar A, Lou H, Ku L. G-protein coupled and tyrosine kinase receptors: evidence that activation of the insulin-like growth factor I receptor is required for thrombin-induced mitogenesis of rat aortic smooth muscle cells. J Clin Invest. 1996; 97: 139–145.
Maile LA, Clemmons DR. Regulation of insulin-like growth factor I receptor dephosphorylation by SHPS-1 and the tyrosine phosphatase SHP-2. J Biol Chem. 2002; 277: 8955–8960.
Clemmons DR, Horvitz G, Engleman W, Nichols T, Moralez A, Nickols GA. Synthetic áVa3 antagonists inhibit insulin-like growth factor-I-stimulated smooth muscle cell migration and replication. Endocrinology. 1999; 140: 4616–4621.
Zheng B, Clemmons DR. Blocking ligand occupancy of the áVa3 integrin inhibits insulin-like growth factor I signaling in vascular smooth muscle cells. Proc Natl Acad Sci U S A. 1998; 95: 11217–11222.
Andersson P, Gustafsson T, Arnqvist HJ. Insulin-like growth factor binding proteins-2 to -6 are expressed by human vascular smooth muscle cells. J Endocrinol. 1999; 163: 281–288.
Boes M, Booth BA, Dake BL, Moser DR, Bar RS. Insulin-like growth factor binding protein production by bovine and human vascular smooth muscle cells: production of insulin-like growth factor binding protein-6 by human smooth muscle. Endocrinology. 1996; 137: 5357–5363.
Kamyar A, Pirola CJ, Wang HM, Sharifi B, Mohan S, Forrester JS, Fagin JA. Expression and insulin-like growth factor-dependent proteolysis of insulin-like growth factor-binding protein-4 are regulated by cell confluence in vascular smooth muscle cells. Circ Res. 1994; 74: 576–585.
Cohick WS, Gockerman A, Clemmons DR. Vascular smooth muscle cells synthesize two forms of insulin-like growth factor binding proteins which are regulated differently by the insulin-like growth factors. J Cell Physiol. 1993; 157: 52–60.
Anwar A, Zahid AA, Phillips L, Delafontaine P. Insulin-like growth factor binding protein-4 expression is decreased by angiotensin II and thrombin in rat aortic vascular smooth muscle cells. Arterioscler Thromb Vasc Biol. 2000; 20: 370–376.
Hsieh T, Gordon RE, Clemmons DR, Busby WH Jr, Duan C. Regulation of vascular smooth muscle cell responses to insulin-like growth factor (IGF)-I by local IGF binding proteins. J Biol Chem. 2003; 278: 42886–42892.
Duan C, Clemmons DR. Differential expression and biological effects of insulin-like growth factor-binding protein-4 and -5 in vascular smooth muscle cells. J Biol Chem. 1998; 273: 16836–16842.
Moralez A, Busby WH Jr, Clemmons D. Control of insulin-like growth factor binding protein-5 protease synthesis and secretion by human fibroblasts and porcine aortic smooth muscle cells. Endocrinology. 2003; 144: 2489–2495.
Conover CA, Kiefer MC, Zapf J. Posttranslational regulation of insulin-like growth factor binding protein-4 in normal and transformed human fibroblasts: insulin-like growth factor dependence and biological studies. J Clin Invest. 1993; 91: 1129–1137.
Blat C, Villaudy J, Binoux M. In vivo proteolysis of serum insulin-like growth factor (IGF) binding protein-3 results in increased availability of IGF to target cells. J Clin Invest. 1994; 93: 2286–2290.
Schneider MR, Wolf E, Hoeflich A, Lahm H. IGF-binding protein-5: flexible player in the IGF system and effector on its own. J Endocrinol. 2002; 172: 423–440.
Imai Y, Busby WH Jr, Smith CE, Clarke JB, Garmong AJ, Horwitz GD, Rees C, Clemmons DR. Protease-resistant form of insulin-like growth factor-binding protein 5 is an inhibitor of insulin-like growth factor-I actions on porcine smooth muscle cells in culture. J Clin Invest. 1997; 100: 2596–2605.
Parker A, Rees C, Clarke J, Busby WH Jr, Clemmons DR. Binding of insulin-like growth factor (IGF)-binding protein-5 to smooth-muscle cell extracellular matrix is a major determinant of the cellular response to IGF-I. Mol Biol Cell. 1998; 9: 2383–2392.
Zheng B, Clarke JB, Busby WH, Duan C, Clemmons DR. Insulin-like growth factor-binding protein-5 is cleaved by physiological concentrations of thrombin. Endocrinology. 1998; 139: 1708–1714.
Zhang M, Smith EP, Kuroda H, Banach W, Chernausek SD, Fagin JA. Targeted expression of a protease-resistant IGFBP-4 mutant in smooth muscle of transgenic mice results in IGFBP-4 stabilization and smooth muscle hypotrophy. J Biol Chem. 2002; 277: 21285–21290.
Lawrence JB, Oxvig C, Overgaard MT, Sottrup-Jensen L, Gleich GJ, Hays LG, Yates JR 3rd, Conover CA. The insulin-like growth factor (IGF)-dependent IGF binding protein-4 protease secreted by human fibroblasts is pregnancy-associated plasma protein-A. Proc Natl Acad Sci U S A. 1999; 96: 3149–3153.
Bayes-Genis A, Conover CA, Overgaard MT, Bailey KR, Christiansen M, Holmes DR Jr, Virmani R, Oxvig C, Schwartz RS. Pregnancy-associated plasma protein A as a marker of acute coronary syndromes. N Engl J Med. 2001; 345: 1022–1029.
Overgaard MT, Haaning J, Boldt HB, Olsen IM, Laursen LS, Christiansen M, Gleich GJ, Sottrup-Jensen L, Conover CA, Oxvig C. Expression of recombinant human pregnancy-associated plasma protein-A and identification of the proform of eosinophil major basic protein as its physiological inhibitor. J Biol Chem. 2000; 275: 31128–31133.
Smith EP, Kamyar A, Niu W, Wang J, Cercek B, Chernausek SD, Fagin JA. IGF-binding protein-4 expression and IGF-binding protein-4 protease activity are regulated coordinately in smooth muscle during postnatal development and after vascular injury. Endocrinology. 2001; 142: 4420–4427.
Bayes-Genis A, Schwartz RS, Lewis DA, Overgaard MT, Christiansen M, Oxvig C, Ashai K, Holmes DR Jr, Conover CA. Insulin-like growth factor binding protein-4 protease produced by smooth muscle cells increases in the coronary artery after angioplasty. Arterioscler Thromb Vasc Biol. 2001; 21: 335–341.
Frost RA, Lang CH. Differential effects of insulin-like growth factor I (IGF-I) and IGF-binding protein-1 on protein metabolism in human skeletal muscle cells. Endocrinology. 1999; 140: 3962–3970.
Wang J, Niu W, Witte DP, Chernausek SD, Nikiforov YE, Clemens TL, Sharifi B, Strauch AR, Fagin JA. Overexpression of insulin-like growth factor-binding protein-4 (IGFBP-4) in smooth muscle cells of transgenic mice through a smooth muscle á-actin-IGFBP-4 fusion gene induces smooth muscle hypoplasia. Endocrinology. 1998; 139: 2605–2614.
Kern PA, Svoboda ME, Eckel RH, Van Wyk JJ. Insulinlike growth factor action and production in adipocytes and endothelial cells from human adipose tissue. Diabetes. 1989; 38: 710–717.
Gajdusek CM, Luo Z, Mayberg MR. Sequestration and secretion of insulin-like growth factor-I by bovine aortic endothelial cells. J Cell Physiol. 1993; 154: 192–198.
Bar RS, Boes M. Distinct receptors for IGF-I, IGF-II, and insulin are present on bovine capillary endothelial cells and large vessel endothelial cells. Biochem Biophys Res Commun. 1984; 124: 203–209.
Boes M, Dake BL, Bar RS. Interactions of cultured endothelial cells with TGF-a, bFGF, PDGF and IGF-I. Life Sci. 1991; 48: 811–821.
Bar RS, Harrison LC, Baxter RC, Boes M, Dake BL, Booth B, Cox A. Production of IGF-binding proteins by vascular endothelial cells. Biochem Biophys Res Commun. 1987; 148: 734–739.
Booth BA, Bar RS, Boes M, Dake BL, Bayne M, Cascieri M. Intrinsic bioactivity of insulin-like growth factor-binding proteins from vascular endothelial cells. Endocrinology. 1990; 127: 2630–2638.
Moser DR, Lowe WL Jr, Dake BL, Booth BA, Boes M, Clemmons DR, Bar RS. Endothelial cells express insulin-like growth factor-binding proteins 2 to 6. Mol Endocrinol. 1992; 6: 1805–1814.
Tucci M, Nygard K, Tanswell BV, Farber HW, Hill DJ, Han VK. Modulation of insulin-like growth factor (IGF) and IGF binding protein biosynthesis by hypoxia in cultured vascular endothelial cells. J Endocrinol. 1998; 157: 13–24.
Delafontaine P, Ku L, Anwar A, Hayzer DJ. Insulin-like growth factor 1 binding protein 3 synthesis by aortic endothelial cells is a function of cell density. Biochem Biophys Res Commun. 1996; 222: 478–482.
Dahlfors G, Arnqvist HJ. Vascular endothelial growth factor and transforming growth factor-a1 regulate the expression of insulin-like growth factor-binding protein-3, -4, and -5 in large vessel endothelial cells. Endocrinology. 2000; 141: 2062–2067.
Erondu NE, Dake BL, Moser DR, Lin M, Boes M, Bar RS. Regulation of endothelial IGFBP-3 synthesis and secretion by IGF-I and TGF-a. Growth Regul. 1996; 6: 1–9.
Yang YW, Pioli P, Fiorelli G, Brandi ML, Rechler MM. Cyclic adenosine monophosphate stimulates insulin-like growth factor binding protein-4 and its messenger ribonucleic acid in a clonal endothelial cell line. Endocrinology. 1993; 133: 343–351.
Bar RS, Dolash S, Dake BL, Boes M. Cultured capillary endothelial cells from bovine adipose tissue: a model for insulin binding and action in microvascular endothelium. Metabolism. 1986; 35: 317–322.
King GL, Goodman AD, Buzney S, Moses A, Kahn CR. Receptors and growth-promoting effects of insulin and insulinlike growth factors on cells from bovine retinal capillaries and aorta. J Clin Invest. 1985; 75: 1028–1036.
Shigematsu S, Yamauchi K, Nakajima K, Iijima S, Aizawa T, Hashizume K. IGF-1 regulates migration and angiogenesis of human endothelial cells. Endocr J. 1999; 46 (suppl): S59–S62.
Kondo T, Vicent D, Suzuma K, Yanagisawa M, King GL, Holzenberger M, Kahn CR. Knockout of insulin and IGF-1 receptors on vascular endothelial cells protects against retinal neovascularization. J Clin Invest. 2003; 111: 1835–1842.
Che W, Lerner-Marmarosh N, Huang Q, Osawa M, Ohta S, Yoshizumi M, Glassman M, Lee JD, Yan C, Berk BC, Abe J. Insulin-like growth factor-1 enhances inflammatory responses in endothelial cells: role of Gab1 and MEKK3 in TNF-á-induced c-Jun and NF-B activation and adhesion molecule expression. Circ Res. 2002; 90: 1222–1230.
Liu W, Liu Y, Lowe WL Jr. The role of phosphatidylinositol 3-kinase and the mitogen-activated protein kinases in insulin-like growth factor-I-mediated effects in vascular endothelial cells. Endocrinology. 2001; 142: 1710–1719.
Smith LE, Shen W, Perruzzi C, Soker S, Kinose F, Xu X, Robinson G, Driver S, Bischoff J, Zhang B, Schaeffer JM, Senger DR. Regulation of vascular endothelial growth factor-dependent retinal neovascularization by insulin-like growth factor-1 receptor. Nat Med. 1999; 5: 1390–1395.
Wickman A, Jonsdottir IH, Bergstrom G, Hedin L. GH and IGF-I regulate the expression of endothelial nitric oxide synthase (eNOS) in cardiovascular tissues of hypophysectomized female rats. Eur J Endocrinol. 2002; 147: 523–533.
Isenovic E, Muniyappa R, Milivojevic N, Rao Y, Sowers JR. Role of PI3-kinase in isoproterenol and IGF-1 induced ecNOS activity. Biochem Biophys Res Commun. 2001; 285: 954–958.
Isenovic ER, Divald A, Milivojevic N, Grgurevic T, Fisher SE, Sowers JR. Interactive effects of insulin-like growth factor-1 and a-estradiol on endothelial nitric oxide synthase activity in rat aortic endothelial cells. Metabolism. 2003; 52: 482–487.
Ross R. Atherosclerosis: an inflammatory disease. N Engl J Med. 1999; 340: 115–126.
Grant MB, Wargovich TJ, Ellis EA, Tarnuzzer R, Caballero S, Estes K, Rossing M, Spoerri PE, Pepine C. Expression of IGF-I, IGF-I receptor and IGF binding proteins-1, -2, -3, -4 and -5 in human atherectomy specimens. Regul Pept. 1996; 67: 137–144.
Okura Y, Brink M, Zahid AA, Anwar A, Delafontaine P. Decreased expression of insulin-like growth factor-1 and apoptosis of vascular smooth muscle cells in human atherosclerotic plaque. J Mol Cell Cardiol. 2001; 33: 1777–1789.
Patel VA, Zhang QJ, Siddle K, Soos MA, Goddard M, Weissberg PL, Bennett MR. Defect in insulin-like growth factor-1 survival mechanism in atherosclerotic plaque-derived vascular smooth muscle cells is mediated by reduced surface binding and signaling. Circ Res. 2001; 88: 895–902.
Bennett MR, Evan GI, Schwartz SM. Apoptosis of human vascular smooth muscle cells derived from normal vessels and coronary atherosclerotic plaques. J Clin Invest. 1995; 95: 2266–2274.
Okura Y, Brink M, Itabe H, Scheidegger KJ, Kalangos A, Delafontaine P. Oxidized low-density lipoprotein is associated with apoptosis of vascular smooth muscle cells in human atherosclerotic plaques. Circulation. 2000; 102: 2680–2686.
Juul A, Scheike T, Davidsen M, Gyllenborg J, Jorgensen T. Low serum insulin-like growth factor I is associated with increased risk of ischemic heart disease: a population-based case-control study. Circulation. 2002; 106: 939–944.
Ruotolo RA, Evans SR. Mesenteric ischemia in the elderly. Clin Geriatr Med. 1999; 15: 527–557.
Goodman-Gruen D, Barrett-Connor E, Rosen C. IGF-1 and ischemic heart disease in older people. J Am Geriatr Soc. 2000; 48: 860–861.
Botker HE, Skjaerbaek C, Eriksen UH, Schmitz O, Orskov H. Insulin-like growth factor-I, insulin, and angina pectoris secondary to coronary atherosclerosis, vasospasm, and syndrome X. Am J Cardiol. 1997; 79: 961–963.
Janssen JA, Stolk RP, Pols HA, Grobbee DE, Lamberts SW. Serum total IGF-I, free IGF-I, and IGFB-1 levels in an elderly population: relation to cardiovascular risk factors and disease. Arterioscler Thromb Vasc Biol. 1998; 18: 277–282.
Spallarossa P, Brunelli C, Minuto F, Caruso D, Battistini M, Caponnetto S, Cordera R. Insulin-like growth factor-I and angiographically documented coronary artery disease. Am J Cardiol. 1996; 77: 200–202.
Schuler-Luttmann S, Monnig G, Enbergs A, Schulte H, Breithardt G, Assmann G, Kerber S, von Eckardstein A. Insulin-like growth factor-binding protein-3 is associated with the presence and extent of coronary arteriosclerosis. Arterioscler Thromb Vasc Biol. 2000; 20: e10–e15.
Deleted in proof.
Schut AF, Janssen JA, Deinum J, Vergeer JM, Hofman A, Lamberts SW, Oostra BA, Pols HA, Witteman JC, van Duijn CM. Polymorphism in the promoter region of the insulin-like growth factor I gene is related to carotid intima-media thickness and aortic pulse wave velocity in subjects with hypertension. Stroke. 2003; 34: 1623–1627.
Farb A, Sangiorgi G, Carter AJ, Walley VM, Edwards WD, Schwartz RS, Virmani R. Pathology of acute and chronic coronary stenting in humans. Circulation. 1999; 99: 44–52.
Bhargava B, Karthikeyan G, Abizaid AS, Mehran R. New approaches to preventing restenosis. BMJ. 2003; 327: 274–279.
Khorsandi MJ, Fagin JA, Giannella-Neto D, Forrester JS, Cercek B. Regulation of insulin-like growth factor-I and its receptor in rat aorta after balloon denudation: evidence for local bioactivity. J Clin Invest. 1992; 90: 1926–1931.
Zhu B, Zhao G, Witte DP, Hui DY, Fagin JA. Targeted overexpression of IGF-I in smooth muscle cells of transgenic mice enhances neointimal formation through increased proliferation and cell migration after intraarterial injury. Endocrinology. 2001; 142: 3598–3606.
Bayes-Genis A, Conover CA, Schwartz RS. The insulin-like growth factor axis: a review of atherosclerosis and restenosis. Circ Res. 2000; 86: 125–130.
Yumi K, Fagin JA, Yamashita M, Fishbein MC, Shah PK, Kaul S, Niu W, Nilsson J, Cercek B. Direct effects of somatostatin analog octreotide on insulin-like growth factor-I in the arterial wall. Lab Invest. 1997; 76: 329–338.
von Essen R, Ostermaier R, Grube E, Maurer W, Tebbe U, Erbel R, Roth M, Oel W, Brom J, Weidinger G. Effects of octreotide treatment on restenosis after coronary angioplasty: results of the VERAS study. Verringerung der Restenoserate nach Angioplastie durch ein Somatostatin-analogon. Circulation. 1997; 96: 1482–1487.
Emanuelsson H, Beatt KJ, Bagger JP, Balcon R, Heikkila J, Piessens J, Schaeffer M, Suryapranata H, Foegh M. Long-term effects of angiopeptin treatment in coronary angioplasty: reduction of clinical events but not angiographic restenosis. European Angiopeptin Study Group. Circulation. 1995; 91: 1689–1696.
Eriksen UH, Amtorp O, Bagger JP, Emanuelsson H, Foegh M, Henningsen P, Saunamaki K, Schaeffer M, Thayssen P, Orskov H, et al. Randomized double-blind Scandinavian trial of angiopeptin versus placebo for the prevention of clinical events and restenosis after coronary balloon angioplasty. Am Heart J. 1995; 130: 1–8.
Santoian ED, Schneider JE, Gravanis MB, Foegh M, Tarazona N, Cipolla GD, King SB 3rd. Angiopeptin inhibits intimal hyperplasia after angioplasty in porcine coronary arteries. Circulation. 1993; 88: 11–14.
Hayry P, Myllarniemi M, Aavik E, Alatalo S, Aho P, Yilmaz S, Raisanen-Sokolowski A, Cozzone G, Jameson BA, Baserga R. Stabile D-peptide analog of insulin-like growth factor-1 inhibits smooth muscle cell proliferation after carotid ballooning injury in the rat. FASEB J. 1995; 9: 1336–1344.
Kwon HM, Sangiorgi G, Ritman EL, Lerman A, McKenna C, Virmani R, Edwards WD, Holmes DR, Schwartz RS. Adventitial vasa vasorum in balloon-injured coronary arteries: visualization and quantitation by a microscopic three-dimensional computed tomography technique. J Am Coll Cardiol. 1998; 32: 2072–2079.
Kumamoto M, Nakashima Y, Sueishi K. Intimal neovascularization in human coronary atherosclerosis: its origin and pathophysiological significance. Hum Pathol. 1995; 26: 450–456.
Sueishi K, Yonemitsu Y, Nakagawa K, Kaneda Y, Kumamoto M, Nakashima Y. Atherosclerosis and angiogenesis: its pathophysiological significance in humans as well as in an animal model induced by the gene transfer of vascular endothelial growth factor. Ann N Y Acad Sci. 1997; 811: 311–322, 322–314.
Nakao-Hayashi J, Ito H, Kanayasu T, Morita I, Murota S. Stimulatory effects of insulin and insulin-like growth factor I on migration and tube formation by vascular endothelial cells. Atherosclerosis. 1992; 92: 141–149.
Nicosia RF, Nicosia SV, Smith M. Vascular endothelial growth factor, platelet-derived growth factor, and insulin-like growth factor-1 promote rat aortic angiogenesis in vitro. Am J Pathol. 1994; 145: 1023–1029.
Su EJ, Cioffi CL, Stefansson S, Mittereder N, Garay M, Hreniuk D, Liau G. Gene therapy vector-mediated expression of insulin-like growth factors protects cardiomyocytes from apoptosis and enhances neovascularization. Am J Physiol Heart Circ Physiol. 2003; 284: H1429–H1440.
Kluge A, Zimmermann R, Weihrauch D, Mohri M, Sack S, Schaper J, Schaper W. Coordinate expression of the insulin-like growth factor system after microembolisation in porcine heart. Cardiovasc Res. 1997; 33: 324–331.
Frystyk J, Ledet T, Moller N, Flyvbjerg A, Orskov H. Cardiovascular disease and insulin-like growth factor I. Circulation. 2002; 106: 893–895.
Schneider DJ, Sobel BE. Augmentation of synthesis of plasminogen activator inhibitor type 1 by insulin and insulin-like growth factor type I: implications for vascular disease in hyperinsulinemic states. Proc Natl Acad Sci U S A. 1991; 88: 9959–9963.
Lee TS, Saltsman KA, Ohashi H, King GL. Activation of protein kinase C by elevation of glucose concentration: proposal for a mechanism in the development of diabetic vascular complications. Proc Natl Acad Sci U S A. 1989; 86: 5141–5145.
Murphy LJ, Ghahary A, Chakrabarti S. Insulin regulation of IGF-I expression in rat aorta. Diabetes. 1990; 39: 657–662.
Bornfeldt KE, Skottner A, Arnqvist HJ. In-vivo regulation of messenger RNA encoding insulin-like growth factor-I (IGF-I) and its receptor by diabetes, insulin and IGF-I in rat muscle. J Endocrinol. 1992; 135: 203–211.
Bornfeldt KE, Arnqvist HJ, Capron L. In vivo proliferation of rat vascular smooth muscle in relation to diabetes mellitus insulin-like growth factor I and insulin. Diabetologia. 1992; 35: 104–108.
Capron L, Jarnet J, Kazandjian S, Housset E. Growth-promoting effects of diabetes and insulin on arteries: an in vivo study of rat aorta. Diabetes. 1986; 35: 973–978.
Pandolfi A, Cetrullo D, Polishuck R, Alberta MM, Calafiore A, Pellegrini G, Vitacolonna E, Capani F, Consoli A. Plasminogen activator inhibitor type 1 is increased in the arterial wall of type II diabetic subjects. Arterioscler Thromb Vasc Biol. 2001; 21: 1378–1382.
Kiuchi K, Nejima J, Takano T, Ohta M, Hashimoto H. Increased serum concentrations of advanced glycation end products: a marker of coronary artery disease activity in type 2 diabetic patients. Heart. 2001; 85: 87–91.
Zhou Z, Wang K, Penn MS, Marso SP, Lauer MA, Forudi F, Zhou X, Qu W, Lu Y, Stern DM, Schmidt AM, Lincoff AM, Topol EJ. Receptor for AGE (RAGE) mediates neointimal formation in response to arterial injury. Circulation. 2003; 107: 2238–2243.
Kislinger T, Tanji N, Wendt T, Qu W, Lu Y, Ferran LJ Jr, Taguchi A, Olson K, Bucciarelli L, Goova M, Hofmann MA, Cataldegirmen G, D’Agati V, Pischetsrieder M, Stern DM, Schmidt AM. Receptor for advanced glycation end products mediates inflammation and enhanced expression of tissue factor in vasculature of diabetic apolipoprotein E-null mice. Arterioscler Thromb Vasc Biol. 2001; 21: 905–910.
Kirstein M, Aston C, Hintz R, Vlassara H. Receptor-specific induction of insulin-like growth factor I in human monocytes by advanced glycosylation end product-modified proteins. J Clin Invest. 1992; 90: 439–446.
Wu HY, Jeng YY, Yue CJ, Chyu KY, Hsueh WA, Chan TM. Endothelial-dependent vascular effects of insulin and insulin-like growth factor I in the perfused rat mesenteric artery and aortic ring. Diabetes. 1994; 43: 1027–1032.
Kobayashi T, Kamata K. Short-term insulin treatment and aortic expressions of IGF-1 receptor and VEGF mRNA in diabetic rats. Am J Physiol Heart Circ Physiol. 2002; 283: H1761–H1768.
Wang Q, Dills DG, Klein R, Klein BE, Moss SE. Does insulin-like growth factor I predict incidence and progression of diabetic retinopathy? Diabetes. 1995; 44: 161–164.
Gerhardinger C, McClure KD, Romeo G, Podesta F, Lorenzi M. IGF-I mRNA and signaling in the diabetic retina. Diabetes. 2001; 50: 175–183.
Giannini S, Cresci B, Pala L, Ciucci A, Franchini A, Manuelli C, Fujita-Yamaguchi Y, Cappugi P, Zonefrati R, Rotella CM. IGFBPs modulate IGF-I- and high glucose-controlled growth of human retinal endothelial cells. J Endocrinol. 2001; 171: 273–284.
Yakar S, Liu JL, Fernandez AM, Wu Y, Schally AV, Frystyk J, Chernausek SD, Mejia W, Le Roith D. Liver-specific igf-1 gene deletion leads to muscle insulin insensitivity. Diabetes. 2001; 50: 1110–1118.
Sandhu MS, Heald AH, Gibson JM, Cruickshank JK, Dunger DB, Wareham NJ. Circulating concentrations of insulin-like growth factor-I and development of glucose intolerance: a prospective observational study. Lancet. 2002; 359: 1740–1745.
Jabri N, Schalch DS, Schwartz SL, Fischer JS, Kipnes MS, Radnik BJ, Turman NJ, Marcsisin VS, Guler HP. Adverse effects of recombinant human insulin-like growth factor I in obese insulin-resistant type II diabetic patients. Diabetes. 1994; 43: 369–374.
Rajkumar K, Krsek M, Dheen ST, Murphy LJ. Impaired glucose homeostasis in insulin-like growth factor binding protein-1 transgenic mice. J Clin Invest. 1996; 98: 1818–1825.
Fath KA, Alexander RW, Delafontaine P. Abdominal coarctation increases insulin-like growth factor I mRNA levels in rat aorta. Circ Res. 1993; 72: 271–277.
Wickman A, Friberg P, Adams MA, Matejka GL, Brantsing C, Guron G, Isgaard J. Induction of growth hormone receptor and insulin-like growth factor-I mRNA in aorta and caval vein during hemodynamic challenge. Hypertension. 1997; 29: 123–130.
Anwar A, Delafontaine P. Hypertension increases insulin-like growth factor binding protein-4 mRNA levels in rat aorta. Hypertension. 1994; 24: 679–685.
Chen Y, Arner A, Bornfeldt KE, Uvelius B, Arnqvist HJ. Development of smooth muscle hypertrophy is closely associated with increased gene expression of insulin-like growth factor binding protein-2 and -4. Growth Regul. 1995; 5: 45–52.
Pete G, Hu Y, Walsh M, Sowers J, Dunbar JC. Insulin-like growth factor-I decreases mean blood pressure and selectively increases regional blood flow in normal rats. Proc Soc Exp Biol Med. 1996; 213: 187–192.
Lembo G, Rockman HA, Hunter JJ, Steinmetz H, Koch WJ, Ma L, Prinz MP, Ross J Jr, Chien KR, Powell-Braxton L. Elevated blood pressure and enhanced myocardial contractility in mice with severe IGF-1 deficiency. J Clin Invest. 1996; 98: 2648–2655.
Tivesten A, Bollano E, Andersson I, Fitzgerald S, Caidahl K, Sjogren K, Skott O, Liu JL, Mobini R, Isaksson OG, Jansson JO, Ohlsson C, Bergstrom G, Isgaard J. Liver-derived insulin-like growth factor-I is involved in the regulation of blood pressure in mice. Endocrinology. 2002; 143: 4235–4242.
Vecchione C, Colella S, Fratta L, Gentile MT, Selvetella G, Frati G, Trimarco B, Lembo G. Impaired insulin-like growth factor I vasorelaxant effects in hypertension. Hypertension. 2001; 37: 1480–1485.
Zhao G, Sutliff RL, Weber CS, Wang J, Lorenz J, Paul RJ, Fagin JA. Smooth muscle-targeted overexpression of insulin-like growth factor I results in enhanced vascular contractility. Endocrinology. 2001; 142: 623–632.
Diez J. Insulin-like growth factor I in essential hypertension. Kidney Int. 1999; 55: 744–759.
Heald AH, Siddals KW, Fraser W, Taylor W, Kaushal K, Morris J, Young RJ, White A, Gibson JM. Low circulating levels of insulin-like growth factor binding protein-1 (IGFBP-1) are closely associated with the presence of macrovascular disease and hypertension in type 2 diabetes. Diabetes. 2002; 51: 2629–2636.
Hayford K, Boes M, Dake BL, Bar RS. Regulations of IGF binding proteins in human aorta vascular smooth muscle cells by cAMP, dexamethasone and IGF-I. Growth Horm IGF Res. 1998; 8: 369–375.
Ververis JJ, Ku L, Delafontaine P. Regulation of insulin-like growth factor I receptors on vascular smooth muscle cells by growth factors and phorbol esters. Circ Res. 1993; 72: 1285–1292.
Ververis J, Ku L, Delafontaine P. Fibroblast growth factor regulates insulin-like growth factor-binding protein production by vascular smooth muscle cells. Am J Med Sci. 1994; 307: 77–81.
Bornfeldt KE, Raines EW, Nakano T, Graves LM, Krebs EG, Ross R. Insulin-like growth factor-I and platelet-derived growth factor-BB induce directed migration of human arterial smooth muscle cells via signaling pathways that are distinct from those of proliferation. J Clin Invest. 1994; 93: 1266–1274.
Gockerman A, Prevette T, Jones JI, Clemmons DR. Insulin-like growth factor (IGF)-binding proteins inhibit the smooth muscle cell migration responses to IGF-I and IGF-II. Endocrinology. 1995; 136: 4168–4173.
Banskota NK, Taub R, Zellner K, King GL. Insulin, insulin-like growth factor I and platelet-derived growth factor interact additively in the induction of the proto-oncogene c-myc and cellular proliferation in cultured bovine aortic smooth muscle cells. Mol Endocrinol. 1989; 3: 1183–1190.(Patrice Delafontaine; Yao)
Correspondence to Patrice Delafontaine, MD, FACC, FAHA, FACP, FESC, Tulane University Medical Center, School of Medicine, Section of Cardiology, 1430 Tulane Ave, New Orleans, LA 70112-2699. E-mail pdelafon@tulane.edu
Abstract
The vascular insulin-like growth factor (IGF)-1 system includes the IGFs, the IGF-1 receptor (IGF-1R), and multiple binding proteins. This growth factor system exerts multiple physiologic effects on the vasculature through both endocrine and autocrine/paracrine mechanisms. The effects of IGF-1 are mediated principally through the IGF-1R but are modulated by complex interactions with multiple IGF binding proteins that themselves are regulated by phosphorylation, proteolysis, polymerization, and cell or matrix association. During the last decade, a significant body of evidence has accumulated, indicating that expression of the components of the IGF system are regulated by multiple factors, including growth factors, cytokines, lipoproteins, reactive oxygen species, and hemodynamic forces. In addition, cross-talk between the IGF system and other growth factors and integrin receptors has been demonstrated. There is accumulating evidence of a role for IGF-1 in multiple vascular pathologies, including atherosclerosis, hypertension, restenosis, angiogenesis, and diabetic vascular disease. This review will discuss the regulation of expression of IGF-1, IGF-1R, and IGF binding proteins in the vasculature and summarize evidence implicating involvement of this system in vascular diseases.
Key Words: insulin-like growth factor-1 ? insulin-like growth factor binding proteins ? blood vessels ? signaling pathways ? vascular diseases
Introduction
The insulin-like growth factors (IGFs) are synthesized by almost all tissues and are important mediators of cell growth, differentiation, and transformation.1 Because of the wide range of their biologic effects and their therapeutic potential, the IGFs have become the focus of research by an increasing number of investigators. This review will focus on the expression, regulation, and function of IGF-1, IGF-1 receptors (IGF-1Rs), and IGF-1 binding proteins (IGFBPs) in blood vessels.
IGF-1 is the product of the IGF-1 gene, which has been mapped to chromosome 12 in humans and chromosome 10 in mice.2 The mammalian gene consists of at least 6 exons, and transcription results from at least 2 transcription start sites located on exon 1 and exon 2.2 Additional complexity results from the presence of distinct carboxyterminal E domains of IGF-1 (Ea and Eb variants). Exon 1 and Ea-containing transcripts are expressed ubiquitously, whereas exon 2 and Eb transcripts are expressed more specifically in the liver.2 IGF-1 has a fundamental role in both prenatal and postnatal development and exerts all of its known physiologic effects by binding to the IGF-1R,3 and its effects are modulated by multiple IGFBPs.4 Circulating IGF-1 is generated by the liver under the control of growth hormone. The binding of growth hormone with its hepatic receptor stimulates expression and release of IGF-1 peptide in the circulation, which has high affinity for IGFBPs, and represents the endocrine form of IGF-1.2,4 In addition to the liver, many other organs produce IGF-1, which has a lower affinity for IGFBPs, representing autocrine and paracrine form of IGF-1.2,4
The human IGF-1R is the product of a single-copy gene located on chromosome 15 and is ubiquitously expressed.2 The mature receptor is a tetramer consisting of 2 extracellular -chains and 2 intracellular ?-chains.1 The ?-chains include an intracellular tyrosine kinase domain that is thought to be essential for most of the receptor’s biologic effects.2 IGF-1R signaling involves autophosphorylation and subsequent tyrosine phosphorylation of Shc and insulin receptor substrate (IRS) -1, -2, -3, and -4.5 IRS serves as a docking protein and can activate multiple signaling pathways, including phosphatidyl inositol 3-kinase (PI3K), Akt, and mitogen-activated protein kinase (MAPK).3,6 The activation of these signaling pathways induces differential biologic actions of IGF-1, including cell growth, differentiation, migration, and survival7 (Figure 1). "Cross-talk" between IGF-1 and other growth factors makes the IGF-1 signaling cascade more complicated.8,9
Figure 1. IGF-1 signal transduction. Activation of the IGF-1R triggers several signaling pathways. The IGF-1R is a tyrosine kinase that undergoes autophosphorylation and catalyzes the phosphorylation of multiple cellular proteins, including members of the IRS family. On phosphorylation, IRSs interact with signaling molecules, including Akt, Ras/Raf, and Rac. Activation of the PI3K and Akt pathway prevents loss of mitochondrial membrane potential and release of cytochrome c, thereby inhibiting caspase-3 activation and apoptosis. The Ras/Raf pathway is critical for proliferative responses, whereas activation of Rac is important for cell migration. indicates mitochondrial membrane potential.
The IGFBP family has at least 6 members, which serve as transporter proteins and as storage pools for IGF-1. The expression of IGFBPs are tissue- and developmental stage–specific, and the concentrations of IGFBPs in different body compartments are different.10 The functions of IGFBPs are regulated by phosphorylation, proteolysis, polymerization, and cell or matrix association of the IGFBP.11 All 6 IGFBPs have been shown to inhibit IGF-1 action, but IGFBP-1, -3, and -5 are also shown to stimulate IGF-1 action.4 Some of IGFBPs’ effects might be IGF-1 independent.10,12 Whereas the IGFBPs consistently have extremely high affinity for IGF-1, the N-terminally truncated des-IGF-1 and a variety of IGF-1 analogues have markedly reduced affinity for IGFBPs but retain normal affinity for IGF-1R.4,13
Expression, Regulation, and Function of IGF-1, IGF-1R, and IGFBPs in Vascular Cells
IGF-1 and VSMCs
IGF-1 is synthesized and secreted by cultured vascular smooth muscle cells (VSMCs).14 There are 3 primary mRNA transcripts, 0.9 to 1.2 kb, 1.7 kb, and 7.5 kb, and IGF-1 gene expression in VSMCs is regulated by several factors (Table 1). Thrombin and serum deprivation,9 tumor necrosis factor (TNF)-,15 and estrogen16 downregulate IGF-1 mRNA and protein levels. In contrast, reactive oxygen species (ROS) increase IGF-1 mRNA and protein in rat VSMCs.17 Angiotensin II (Ang II) has been reported to both increase IGF-1 mRNA and protein17 and decrease IGF-1 transcripts in rat VSMCs.18 Platelet-derived growth factor (PDGF) also has been reported to both increase14 and decrease19,20 IGF-1 mRNA levels. Native LDL dose-dependently increases IGF-1 mRNA, but the same doses of oxidized LDL (oxLDL) significantly reduce IGF-1 mRNA and protein expression.21
TABLE 1. Regulation of IGF-1, IGF-1R, and IGFBPs in VSMCs
IGF-1 is a potent mitogen and antiapoptotic factor for VSMCs, and it also stimulates migration of VSMCs.22 Thus, potential reductions in IGF-1 effects might be beneficial in certain pathologic conditions, such as hypertension and the early stages of atherosclerotic plaque formation characterized by hypertrophy/hyperplasia of VSMCs,23,24 but detrimental in other conditions in which loss of VSMCs contributes to the disease process, such as destabilization of atherosclerotic plaques.25 The ability of IGF-1 to stimulate the G1-to-S phase progression is important for mitogenic effects of other growth factors. Thus, anti–IGF-1 antiserum inhibits Ang II and PDGF-induced VSMC growth.26 IGF-1 can reduce oxLDL-induced mitochondrial dysfunction, cytochrome c release, and apoptosis in VSMCs27 and can also inhibit TNF-–induced caspase-3 activation and apoptosis of VSMCs.15 Targeted expression of IGF-1 to smooth muscle by an -actin promoter in transgenic mice resulted in smooth muscle hyperplasia in arteries, veins, and other smooth muscle–rich tissues and corresponding organ hypertrophy and notably increased aortic medial area and thickness.28 These findings support a central role of IGF-1 in mediating VSMC growth and survival.
IGF-1R and VSMCs
The IGF-1R is expressed on VSMCs and regulated by several factors (Table 1) via multiple signaling pathways. Ang II–induced upregulation of IGF-1R mRNA and protein is mediated by the activation of a tyrosine kinase, the transcription factor nuclear factor (NF)-B, and ROS and was shown to be protein kinase C independent.29,30 Basic fibroblast growth factor–induced upregulation of IGF-1R mRNA is mediated by the transcription factors STAT1, STAT3, and the Janus kinase-2 kinase.30 The Ras-Raf–MAPK kinase pathway was shown to be required for effects of both growth factors. Thrombin-induced upregulation of IGF-1R mRNA and protein levels in VSMCs was protein tyrosine kinase and NAD(P)H oxidase dependent. In contrast, protein kinase C, epidermal growth factor receptor kinase, Janus kinase-2 kinase, and Src kinase were not involved in this process.31 Estrogen-induced downregulation of IGF-1R mRNA and protein in rat aortic VSMCs was mediated by the inhibition of SP-1 binding to the IGF-1R promoter.16 OxLDL significantly reduced IGF-1R mRNA and protein expression,21 but the mechanism was not clear.
IGF-1R density is a critical determinant of VSMC growth response. Thus, the upregulation of IGF-1R expression by Ang II, basic fibroblast growth factor, and thrombin on VSMCs is critical for their mitogenic effects.30–32 The downregulation of IGF-1R expression by oxLDL is critical for oxLDL-induced VSMC apoptosis.21 Recently, we have reported that overexpression of IGF-1R by an adenovirus prevented oxLDL-induced apoptosis of human VSMCs.27
The function of IGF-1 is also regulated by cross-talk between IGF-1R and other receptors, including integrin receptors. Ligand occupancy of the V?3 integrin influences the recruitment of the phosphatase SHP-2 to the IGF-1R receptor.33 Blocking ligand occupancy of V?3 results in premature recruitment of SHP-2 to the IGF-1R receptor and reduces IGF-1R signaling.33 Therefore, V?3 integrin antagonists block IGF-1–induced DNA synthesis, VSMC migration,34 and IGF-1R–mediated intracellular signaling.35 Cross-talk between IGF-1R and other growth factors8,9 has implications for understanding the requirement for IGF-1R signaling in mitogenic effects for other growth factors.30–32
IGFBPs and VSMCs
The expression and secretion of IGFBPs in VSMCs are species specific. Human VSMCs express mRNAs for IGFBPs -2 through -6, and corresponding proteins are detected in conditioned medium, with the exception of IGFBP-3.36,37 In addition, low-molecular-mass immunoreactive degradation products for IGFBP-2 and -4 are also found. Bovine aortic SMCs express predominantly IGFBP-3 and -4,37 rat VSMCs express predominantly IGFBP-2 and -4,38 and porcine aortic SMCs express BP-2, -4, and -5.24,39
The expression of IGFBPs in VSMCs is regulated by many factors, including platelet-derived growth factor, fibroblast growth factor, transforming growth factor-?, and IGF-1 (Table 1), and the regulation is species specific and dependent on the specific form of IGFBPs. In rat aortic VSMCs, Ang II,40 thrombin,40 and ROS17 reduce IGFBP-4 in conditioned medium, and IGF-1 and IGF-II induce IGFBP-4 proteolysis in these cells.38 Serum starvation significantly lowered the mRNA levels of IGFBP-2 to IGFBP-6 mRNA.36 In contrast, TNF- markedly increased IGFBP-3 mRNA and protein,15 and native LDL and oxLDL significantly increased IGFBP-2 and IGFBP-4 protein levels in rat VSMCs.21 Gustafsson et al18 reported that IGF-1 increases BP-2 and BP-4 mRNA in rat VSMCs, whereas Cohick et al39 reported that IGF-1 affected neither BP-2 nor BP-4 mRNA levels in porcine VSMCs but decreased IGFBP-4 protein in conditioned medium of these cells. IGF-1 transcriptionally regulated IGFBP-5 in porcine aortic VSMCs.24 Targeted overexpression of IGF-1 in smooth muscle was not associated with changes in BP-4 and BP-5 mRNA or protein levels, indicating that long-term overexpression of IGF-1 in vivo cannot further increase BP-5 gene expression, contrary to short-term in vitro effects.28 Studies indicate that local IGFBPs are important determinants of VSMC responses to IGF-1. IGFBP-2 and IGFBP-4 were found to inhibit IGF-1–stimulated DNA synthesis and VSMC migration.41 IGFBP-5 had an inhibitory effect on IGF-1–stimulated DNA synthesis, but it strongly potentiated IGF-1–induced VSMC migration.41 Duan and Clemmons42 also demonstrated that BP-4 inhibits IGF-1–stimulated DNA synthesis, whereas BP-5 has potentiating effects in VSMCs.
The functions of IGFBPs in VSMCs are also regulated by phosphorylation, proteolysis, polymerization,11 and by cell or matrix association of the IGFBP.43 Posttranslational phosphorylation of IGFBPs significantly increases their affinity for IGF-1 and can therefore suppress the function of IGF-1 at the cellular level.44,45 However, proteolysis or polymerization of IGFBPs or binding to extracellular matrix results in reduction or loss of IGF-1 binding to IGFBPs, thus increasing the binding of IGF-1 to IGF-1R and the activity of IGF-1.46 The polymerization of IGFBP-1, through a reduction in binding affinity, leads to loss of IGFBP-1’s ability to inhibit IGF-1–stimulated protein synthesis in VSMCs.11 Imai et al47 have shown that a protease-resistant form of IGFBP-5 is an inhibitor of IGF-1 actions on porcine SMCs in culture. Parker et al48 have shown that binding of IGFBP-5 to porcine SMC extracellular matrix increases the cellular response to IGF-1. BP-5 is cleaved by physiologic concentrations of thrombin, leading to increased free IGF-1 levels, which contribute to thrombin’s mitogenic effects.49 Targeted expression of a protease-resistant BP-4 mutant in smooth muscle of transgenic mice results in BP-4 stabilization and smooth muscle hypotrophy,50 suggesting that IGF-1–induced hypertrophy is regulated by BP-4 proteolysis. The zinc-binding metalloproteinase pregnancy-associated plasma protein A (PAPP-A) has been identified as a major IGFBP-4 protease51–53 and is expressed in VSMCs.54,55
All 6 IGFBPs have been shown to regulate IGF-1 actions; however, the mechanisms are different. IGFBP-3 is unique in combining with the acid-labile subunit and is the primary stabilizer of circulating IGF-1. IGFBP-1, IGFBP-2, and IGFBP-4, also found in the bloodstream, can across endothelial barriers and might transport IGF-1 from blood to peripheral tissue. BP-4 is the most abundant IGFBP expressed in the rat artery wall in vivo and is the dominant IGFBP secreted by rat VSMCs in vitro.54
IGFBPs also mediate IGF-independent biologic effects. IGFBP-1 stimulates Chinese hamster ovary cell migration via an IGF-independent mechanism involving binding to integrin receptors,12 whereas IGFBP-3 and IGFBP-5 might have specific cell-surface receptors with serine kinase activity.56 Using a non–IGF-binding IGFBP-5 mutant and an IGF-1 neutralizing antibody, Hsieh et al41 demonstrated that IGFBP-5 stimulates VSMC migration by interacting with cell-surface heparan sulfate proteoglycans, which is an IGF-independent effect. Interestingly, the decrease of SMC mass in BP-4 transgenic mice occurred without changes in IGF-1 abundance or gene expression, suggesting that the inhibitory action of BP-4 on SMC mass might occur through an IGF-independent mechanism.10,57
IGF-1, IGF-1R, and IGFBPs in ECs
The expression of IGF-1 in endothelial cells (ECs) is low,58 which might reflect to a significant extent IGF-1 sequestered from serum.59 Both macrovessel and microvessel ECs express IGF-1R.60,61 Similarly, macrovessel and microvessel bovine ECs express IGFBP-2 through BP-6 mRNA,62–64 although microvessel cells secrete predominantly BP-2 and BP-3, whereas macrovessel ECs secrete mainly IGFBP-3 and BP-4.62–64 The expression of components of the IGF system in ECs is regulated by various conditions and growth factors, including vascular origin,65 cell density,66 hypoxia,65 transforming growth factor-?1, vascular endothelial growth factor,67 and IGF-168 (Table 2). Stimulation of cAMP increases IGFBP-4 mRNA levels in a clonal EC line.69 IGF-1 stimulates the expression of BP-3 in ECs.68 Interestingly, EC confluence and postconfluence markedly increases gene expression and secretion of IGFBP-3 in bovine aortic ECs.66
TABLE 2. Regulation of IGF-1, IGF-1R, and IGFBPs in Macrovascular ECs
The effects of IGF-1 on microvascular and macrovascular ECs are different.70,71 IGF-1 stimulates neutral amino acid and glucose uptake and DNA synthesis in microvessel ECs but not in macrovascular bovine ECs.61 IGF-1 also regulates migration and angiogenesis72,73 and enhances inflammatory and vasodilatory responses in ECs.74
The effects of IGF-1 on ECs are mediated by the activation of differential IGF-1 signaling pathways. IGF-1–induced nuclear factor-B translocation requires both PI3K and extracellular-regulated kinase, whereas IGF-1–stimulated EC migration requires only PI3K activation.75 The effects of IGF-1 on ECs are also mediated via regulation of endothelial nitric oxide synthase (eNOS) expression and vascular endothelial growth factor signaling.76 It has been reported that IGF-1 increases aortic eNOS expression and stimulates vascular NO production.77 Moreover, other factors that regulate the function of ECs might be dependent on the activation of IGF-1 signaling pathways. Thus, the vasodilatory effect of estrogen is modulated by IGF-1 through PI3K/Akt-related pathways with a subsequent increase in eNOS activity.78,79
Regulation and Role of IGF-1, IGF-1R, and IGFBPs in Vascular Pathologic States
Atherosclerosis
Atherosclerosis, the leading cause of mortality in the Western world, is a complex disease involving multiple cell type, including circulating, inflammatory, and progenitor cells,80 and multiple cell types within the arterial wall.25 SMC proliferation and migration contribute to the development of atherosclerotic plaque; however, SMC apoptosis is a hallmark of advanced atherosclerotic plaque and particularly unstable plaque that is predisposed to rupture and/or erosion, leading to acute coronary events. Thus, the IGF-1 system might contribute to the balance between the death and survival of VSMCs in atherosclerotic lesions (Figure 2, Table 3).
Figure 2. Dual role of IGF-1 axis in atherosclerosis. IGF-1 stimulates VSMC proliferation and migration, contributing to plaque development. However, decreased expression of IGF-1/IGF-1R leads to VSMC apoptosis and contributes to plaque destabilization.
TABLE 3. Alterations of the IGF-1 System and Pathophysiology of Vascular Diseases
Grant et al81 have reported that IGF-1, IGF-1R, and IGFBP-1 through IGFBP-5 were not detected in SMCs of normal coronary arteries but were markedly increased in atherectomy specimens. However, IGF-1 and IGF-1R expression is reduced in advanced plaque,82,83 and this is consistent with the increased apoptotic rates of VSMCs from atherosclerotic plaques, which also secrete higher levels of IGFBPs.83,84 OxLDL is crucially important in the pathogenesis of atherosclerosis and potentially in the depletion of VSMCs, contributing to plaque destabilization,85 and its ability to decrease IGF-1/IGF-1R expression in VSMC might be an important mechanism leading to VSMC loss.21 The ability of TNF- to reduce IGF-1 and to increase IGFBP-3 could also be important for plaque destabilization.15 An V?3 integrin antagonist reduces atherosclerotic lesion size in pigs and inhibits IGF-1 signaling.23 It is important to note that PAPP-A, an IGFBP-4 protease,51 has been reported to be present in unstable but not stable plaques,52 and its circulating levels are elevated in acute coronary syndromes. A potential proinflammatory effect of IGF-1 that could promote early atherosclerosis has been suggested by Che et al,74 who demonstrated that IGF-1 enhanced TNF-–induced adhesion molecule expression in cultured, bovine ECs.
Although reported changes of circulating IGF-1 and IGFBPs in atherosclerotic vascular disease are not consistent,52,55,86–92 of particular interest is the recent report that individuals with low circulating IGF-1 levels and high IGFBP-3 levels had a significantly increased risk of developing atherosclerosis and ischemic heart disease during a 15-year follow-up period.86 Janssen et al90 have reported that high fasting serum free IGF-1 levels are associated with a decreased prevalence of coronary artery disease, whereas high fasting IGFBP-1 levels are associated with a more favorable cardiovascular profile. Furthermore, a polymorphism of the IGF-1 gene associated with lower circulating IGF-1 levels has been demonstrated to be related to 2 early markers of atherosclerosis, namely, carotid intima-media thickness and aortic pulse wave velocity.94
Restenosis
Restenosis remains a major clinical problem after percutaneous coronary interventions95 and results from vessel recoil, neointimal proliferation, and early thrombus formation.96 Neointimal proliferation is the critical determinant of in-stent restenosis. Multiple growth factors and cytokines are involved in the restenotic process, including IGF-1. Thus, IGF-1 and IGF-1R mRNA levels are reported to be increased in synthetic VSMCs from de novo and restenotic coronary plaques compared with normal coronary arteries.81 Moreover, IGF-1 is upregulated in rat aortas after balloon denudation, whereas IGF-1R is downregulated.97 Transgenic mice with IGF-1 overexpression show VSM hyperplasia,98 and mice with paracrine overproduction of IGFBP-4 developed smooth muscle hypoplasia consistent with growth-inhibitory effects of IGFBP-4.50 IGFBP-4 protease (ie, PAPP-A) expression and proteolytic activity are reportedly increased in VSMCs after injury, suggesting a role for this protease in mediating increases in bioactive IGF-1.99 Thus, IGF-1 likely contributes to the proliferation and migration of VSMCs that are characteristic of restenosis.
Animal studies show that IGF-1 inhibitors, including angiopeptin and octreotide, prevent VSMC proliferation and neointimal formation.100 However, clinical trials show that octreotide has no benefit,101 and the effects of angiopeptin on restenosis are equivocal.102–104 This discrepancy could be due to different doses and treatment regimes. It is important to note that an inhibitory stable D-peptide analogue of IGF-1 inhibits VSMC proliferation after rat carotid artery balloon injury, consistent with a role for IGF-1 in the restenotic process.105
Angiogenesis
Angiogenesis occurs during normal wound healing and atherosclerosis106–108 and is regulated by many growth factors, including IGF-1. IGF-1 stimulates vascular EC migration and tube formation109 and promotes rat aortic angiogenesis in vitro.110 IGF-1 is important for promoting retinal angiogenesis, and an IGF-1R antagonist suppresses retinal neovascularization in vivo by inhibiting vascular endothelial growth factor signaling.76 Recombinant IGF, as well as the local delivery of an IGF-1 adenoviral vector, stimulates angiogenesis and neovascularization.111 Increased monocyte expression of IGF-1 in ischemic tissue could contribute to the angiogenic process.112
Diabetes and Hyperinsulinemia
Studies indicate that IGF-1 might be a potential mediator of vascular growth responses in insulin-deficient diabetes and in hyperinsulinemic states.113,114 The actions of the IGF-1 system in local tissues might be modified when glucose concentrations are increased.115 Insulin increases IGF-1 expression in rat aorta,116 indicating that hyperinsulinism might favor atherogenesis via enhanced expression of IGF-1 in the vessel wall. In the insulin-deficient diabetic rat, IGF-1 mRNA levels are markedly decreased in the heart, skeletal muscle, and aorta,117 which might explain the observation that DNA synthesis after balloon-injury of the aorta is either decreased118 or unchanged in diabetes.119
Hyperinsulinemia coupled with physiologic concentrations of IGF-1 stimulate plasminogen activator inhibitor type 1 synthesis,114 which decreases local fibrinolysis, and through increased thrombogenicity could be a mechanism contributing to accelerated atherosclerosis. Indeed, plasminogen activator inhibitor type 1 is increased in the arterial wall from diabetic patients.120
One consequence of long-term hyperglycemia is the formation of advanced glycation end-products (AGEs); the accumulation of AGEs in the vessel wall could play an important role in the pathogenesis of diabetic vascular complications, including atherosclerosis.121122 AGEs enhance proinflammatory pathways and atherosclerotic lesion development in diabetic apolipoprotein E–null mice.123 AGE induction of IGF-1 synthesis in human monocytes could play a role in hyperglycemia-induced vascular proliferative changes.124
Although VSMCs and ECs express both the insulin receptor and IGF-1R,71 the vasodilation induced by insulin might be mediated primarily via its stimulatory effects on the IGF-1R.118,125 In streptozotocin-diabetic rats, aortic IGF-1 mRNA expression was unaffected; in contrast, aortic IGF-1 receptor mRNA was increased, and relaxation caused by IGF-1 was significantly greater in aortic strips from streptozotocin-induced diabetic rats than in age-matched, control rats.126 Insulin treatment ameliorated endothelial dysfunction in these rats and further increased IGF-1R expression.126
The role of the IGF-1 system in diabetic retinopathy is unclear.127 IGF-1 mRNA levels are substantially lower in the human and rat diabetic retina, whereas IGF-1R activation and signaling are not affected after 5 months of streptozotocin-induced diabetes in rats.128 In human retina ECs, long-term exposure to high concentrations of glucose was able to reduce IGF-1–induced mitogenesis by decreasing the stimulatory IGFBP-2, -3, and -5 levels, leaving the concentration of the inhibitory IGFBP-4 constant.129
It is of note that hepatic IGF-1 gene deletion induces insulin resistance in mice,130 and low circulating IGF-1 is associated with an increased risk for developing insulin resistance in humans.131 IGF-1 therapy can improve insulin sensitivity.132 Overexpression of IGFBP-1 in transgenic mice has been reported to induce insulin resistance and hyperglycemia.133
Hypertension
Increased IGF-1 mRNA and protein expression in hypertensive aorta and in volume-overloaded caval vein suggests that the IGF-1 axis mediates adaptive growth responses in the vasculature (Table 3).134,135 IGFBP-4 mRNA has been shown to be markedly elevated in the hypertensive rat aorta after abdominal coarctation,136 and this induction of IGFBP-4 is limited to the hypertensive blood vessel. This suggests that increases in vascular load directly stimulate IGFBP-4 expression, and this is consistent with data from Chen et al,137 showing increased IGFBP-2 and BP-4 expression in pressure-overloaded bladder after partial urethral ligation.
The vasoactive effects of IGF-1 indicate that IGF-1 can control blood pressure and regional blood flow via NO. Short-term injection of IGF-1 decreased mean arterial pressure, and this effect was inhibited by preinfusion of an NO inhibitor, indicating that the decrease in blood pressure in response to IGF-1 is mediated by NO.138 A significant elevation of arterial pressure was also observed in mice homozygous for a site-specific insertional mutation in exon 3 of IGF-1.139 Peripheral resistance and systolic blood pressure were increased in liver-specific IGF-1 knockout mice.140 In spontaneously hypertensive rats, IGF-1–induced vasorelaxant effects were impaired before the onset of hypertension, indicating that this effect could play a causative role in the development of hypertension.141 It is of note that smooth muscle–targeted overexpression of IGF-1 results in enhanced vascular contractility, possibly via regulation of contractile protein expression.142
The role of circulating IGF-1 and IGFBPs in human hypertension is unclear. Increased free IGF-1, increased IGF-1 to IGFBP-3 ratio, and increased BP-1 to BP-3 ratio have been reported in patients with hypertension.143 Interestingly, low levels of IGFBP-1 and particularly, of highly phosphorylated BP-1 are associated with the presence of macrovascular disease and hypertension in type 2 diabetes.144
Summary and Perspectives for Future Research
IGF-1 exerts multiple physiologic effects on the vasculature, including proliferative, hypertrophic, survival, vasomotor, and metabolic effects. The expression of IGF-1, IGF-1R, and IGFBPs in blood vessels is regulated by multiple factors, including growth factors, cytokines, lipoproteins, ROS, and hemodynamic forces. Cross-talk between the IGF-1 system and other growth factors at the level of the ligand receptor and at the level of postreceptor signaling pathways has important implications for understanding potential involvement of the IGF system in vascular diseases. Despite the technical challenges in successfully using the Cre-lox and transgenic approaches with cell type–specific promoters, the overexpression or downregulation of IGF-1, IGF-1R, and IGFBPs in selected tissues of transgenic or knockout models will be a promising strategy to reveal the endocrine/paracrine function of the IGF-1 axis in different pathophysiologic conditions. Future directions for research include addressing the mechanisms whereby IGF-1 interacts with specific form of IGFBPs, cross-talk between the IGF-1 system and other growth factor systems, identification of distinct receptors for IGFBPs, elucidation of the IGF-1–independent function of IGFBPs, and the physiologic role of specific IGFBP proteases. Undoubtedly, insights gained from basic research will lead to novel and pertinent clinical research targeted at prevention and therapy of vascular diseases.
Acknowledgments
Supported by NIH Grant HL-70241 (P.D.).
References
Le Roith D. Seminars in medicine of the Beth Israel Deaconess Medical Center. Insulin-like growth factors. N Engl J Med. 1997; 336: 633–640.
Delafontaine P. Insulin-like growth factor I and its binding proteins in the cardiovascular system. Cardiovasc Res. 1995; 30: 825–834.
LeRoith D, Werner H, Beitner-Johnson D, Roberts CT Jr. Molecular and cellular aspects of the insulin-like growth factor I receptor. Endocr Rev. 1995; 16: 143–163.
Jones JI, Clemmons DR. Insulin-like growth factors and their binding proteins: biological actions. Endocr Rev. 1995; 16: 3–34.
Tsuruzoe K, Emkey R, Kriauciunas KM, Ueki K, Kahn CR. Insulin receptor substrate 3 (IRS-3) and IRS-4 impair IRS-1- and IRS-2-mediated signaling. Mol Cell Biol. 2001; 21: 26–38.
Saltiel AR, Kahn CR. Insulin signalling and the regulation of glucose and lipid metabolism. Nature. 2001; 414: 799–806.
Stewart CE, Rotwein P. Growth, differentiation, and survival: multiple physiological functions for insulin-like growth factors. Physiol Rev. 1996; 76: 1005–1026.
Du J, Sperling LS, Marrero MB, Phillips L, Delafontaine P. G-protein and tyrosine kinase receptor cross-talk in rat aortic smooth muscle cells: thrombin- and angiotensin II-induced tyrosine phosphorylation of insulin receptor substrate-1 and insulin-like growth factor 1 receptor. Biochem Biophys Res Commun. 1996; 218: 934–939.
Rao GN, Delafontaine P, Runge MS. Thrombin stimulates phosphorylation of insulin-like growth factor-1 receptor, insulin receptor substrate-1, and phospholipase C-?1 in rat aortic smooth muscle cells. J Biol Chem. 1995; 270: 27871–27875.
Schneider MR, Lahm H, Wu M, Hoeflich A, Wolf E. Transgenic mouse models for studying the functions of insulin-like growth factor-binding proteins. FASEB J. 2000; 14: 629–640.
Sakai K, Busby WH Jr, Clarke JB, Clemmons DR. Tissue transglutaminase facilitates the polymerization of insulin-like growth factor-binding protein-1 (IGFBP-1) and leads to loss of IGFBP-1’s ability to inhibit insulin-like growth factor-I-stimulated protein synthesis. J Biol Chem. 2001; 276: 8740–8745.
Jones JI, Gockerman A, Busby WH Jr, Wright G, Clemmons DR. Insulin-like growth factor binding protein 1 stimulates cell migration and binds to the á5a1 integrin by means of its Arg-Gly-Asp sequence. Proc Natl Acad Sci U S A. 1993; 90: 10553–10557.
Cascieri MA, Chicchi GG, Applebaum J, Hayes NS, Green BG, Bayne ML. Mutants of human insulin-like growth factor I with reduced affinity for the type 1 insulin-like growth factor receptor. Biochemistry. 1988; 27: 3229–3233.
Delafontaine P, Lou H, Alexander RW. Regulation of insulin-like growth factor I messenger RNA levels in vascular smooth muscle cells. Hypertension. 1991; 18: 742–747.
Anwar A, Zahid AA, Scheidegger KJ, Brink M, Delafontaine P. Tumor necrosis factor-á regulates insulin-like growth factor-1 and insulin-like growth factor binding protein-3 expression in vascular smooth muscle. Circulation. 2002; 105: 1220–1225.
Scheidegger KJ, Cenni B, Picard D, Delafontaine P. Estradiol decreases IGF-1 and IGF-1 receptor expression in rat aortic smooth muscle cells: mechanisms for its atheroprotective effects. J Biol Chem. 2000; 275: 38921–38928.
Delafontaine P, Ku L. Reactive oxygen species stimulate insulin-like growth factor I synthesis in vascular smooth muscle cells. Cardiovasc Res. 1997; 33: 216–222.
Gustafsson T, Andersson P, Chen Y, Magnusson JO, Arnqvist HJ. Interaction of angiotensin II and the insulin-like growth factor system in vascular smooth muscle cells. Am J Physiol. 1999; 277: H499–H507.
Giannella-Neto D, Kamyar A, Sharifi B, Pirola CJ, Kupfer J, Rosenfeld RG, Forrester JS, Fagin JA. Platelet-derived growth factor isoforms decrease insulin-like growth factor I gene expression in rat vascular smooth muscle cells and selectively stimulate the biosynthesis of insulin-like growth factor binding protein 4. Circ Res. 1992; 71: 646–656.
Bornfeldt KE, Arnqvist HJ, Norstedt G. Regulation of insulin-like growth factor-I gene expression by growth factors in cultured vascular smooth muscle cells. J Endocrinol. 1990; 125: 381–386.
Scheidegger KJ, James RW, Delafontaine P. Differential effects of low density lipoproteins on insulin-like growth factor-1 (IGF-1) and IGF-1 receptor expression in vascular smooth muscle cells. J Biol Chem. 2000; 275: 26864–26869.
Arnqvist HJ, Bornfeldt KE, Chen Y, Lindstrom T. The insulin-like growth factor system in vascular smooth muscle: interaction with insulin and growth factors. Metabolism. 1995; 44: 58–66.
Nichols TC, du Laney T, Zheng B, Bellinger DA, Nickols GA, Engleman W, Clemmons DR. Reduction in atherosclerotic lesion size in pigs by áVa3 inhibitors is associated with inhibition of insulin-like growth factor-I-mediated signaling. Circ Res. 1999; 85: 1040–1045.
Duan C, Hawes SB, Prevette T, Clemmons DR. Insulin-like growth factor-I (IGF-I) regulates IGF-binding protein-5 synthesis through transcriptional activation of the gene in aortic smooth muscle cells. J Biol Chem. 1996; 271: 4280–4288.
Libby P, Aikawa M. Stabilization of atherosclerotic plaques: new mechanisms and clinical targets. Nat Med. 2002; 8: 1257–1262.
Delafontaine P, Lou H. Angiotensin II regulates insulin-like growth factor I gene expression in vascular smooth muscle cells. J Biol Chem. 1993; 268: 16866–16870.
Li Y, Higashi Y, Itabe H, Song YH, Du J, Delafontaine P. Insulin-like growth factor-1 receptor activation inhibits oxLDL-induced cytochrome c release and apoptosis via the phosphatidylinositol 3-kinase/Akt signaling pathway. Arterioscler Thromb Vasc Biol. 2003; 23: 2178–2184.
Wang J, Niu W, Nikiforov Y, Naito S, Chernausek S, Witte D, LeRoith D, Strauch A, Fagin JA. Targeted overexpression of IGF-I evokes distinct patterns of organ remodeling in smooth muscle cell tissue beds of transgenic mice. J Clin Invest. 1997; 100: 1425–1439.
Du J, Meng XP, Delafontaine P. Transcriptional regulation of the insulin-like growth factor-I receptor gene: evidence for protein kinase C-dependent and -independent pathways. Endocrinology. 1996; 137: 1378–1384.
Scheidegger KJ, Du J, Delafontaine P. Distinct and common pathways in the regulation of insulin-like growth factor-1 receptor gene expression by angiotensin II and basic fibroblast growth factor. J Biol Chem. 1999; 274: 3522–3530.
Du J, Brink M, Peng T, Mottironi B, Delafontaine P. Thrombin regulates insulin-like growth factor-1 receptor transcription in vascular smooth muscle: characterization of the signaling pathway. Circ Res. 2001; 88: 1044–1052.
Delafontaine P, Anwar A, Lou H, Ku L. G-protein coupled and tyrosine kinase receptors: evidence that activation of the insulin-like growth factor I receptor is required for thrombin-induced mitogenesis of rat aortic smooth muscle cells. J Clin Invest. 1996; 97: 139–145.
Maile LA, Clemmons DR. Regulation of insulin-like growth factor I receptor dephosphorylation by SHPS-1 and the tyrosine phosphatase SHP-2. J Biol Chem. 2002; 277: 8955–8960.
Clemmons DR, Horvitz G, Engleman W, Nichols T, Moralez A, Nickols GA. Synthetic áVa3 antagonists inhibit insulin-like growth factor-I-stimulated smooth muscle cell migration and replication. Endocrinology. 1999; 140: 4616–4621.
Zheng B, Clemmons DR. Blocking ligand occupancy of the áVa3 integrin inhibits insulin-like growth factor I signaling in vascular smooth muscle cells. Proc Natl Acad Sci U S A. 1998; 95: 11217–11222.
Andersson P, Gustafsson T, Arnqvist HJ. Insulin-like growth factor binding proteins-2 to -6 are expressed by human vascular smooth muscle cells. J Endocrinol. 1999; 163: 281–288.
Boes M, Booth BA, Dake BL, Moser DR, Bar RS. Insulin-like growth factor binding protein production by bovine and human vascular smooth muscle cells: production of insulin-like growth factor binding protein-6 by human smooth muscle. Endocrinology. 1996; 137: 5357–5363.
Kamyar A, Pirola CJ, Wang HM, Sharifi B, Mohan S, Forrester JS, Fagin JA. Expression and insulin-like growth factor-dependent proteolysis of insulin-like growth factor-binding protein-4 are regulated by cell confluence in vascular smooth muscle cells. Circ Res. 1994; 74: 576–585.
Cohick WS, Gockerman A, Clemmons DR. Vascular smooth muscle cells synthesize two forms of insulin-like growth factor binding proteins which are regulated differently by the insulin-like growth factors. J Cell Physiol. 1993; 157: 52–60.
Anwar A, Zahid AA, Phillips L, Delafontaine P. Insulin-like growth factor binding protein-4 expression is decreased by angiotensin II and thrombin in rat aortic vascular smooth muscle cells. Arterioscler Thromb Vasc Biol. 2000; 20: 370–376.
Hsieh T, Gordon RE, Clemmons DR, Busby WH Jr, Duan C. Regulation of vascular smooth muscle cell responses to insulin-like growth factor (IGF)-I by local IGF binding proteins. J Biol Chem. 2003; 278: 42886–42892.
Duan C, Clemmons DR. Differential expression and biological effects of insulin-like growth factor-binding protein-4 and -5 in vascular smooth muscle cells. J Biol Chem. 1998; 273: 16836–16842.
Moralez A, Busby WH Jr, Clemmons D. Control of insulin-like growth factor binding protein-5 protease synthesis and secretion by human fibroblasts and porcine aortic smooth muscle cells. Endocrinology. 2003; 144: 2489–2495.
Conover CA, Kiefer MC, Zapf J. Posttranslational regulation of insulin-like growth factor binding protein-4 in normal and transformed human fibroblasts: insulin-like growth factor dependence and biological studies. J Clin Invest. 1993; 91: 1129–1137.
Blat C, Villaudy J, Binoux M. In vivo proteolysis of serum insulin-like growth factor (IGF) binding protein-3 results in increased availability of IGF to target cells. J Clin Invest. 1994; 93: 2286–2290.
Schneider MR, Wolf E, Hoeflich A, Lahm H. IGF-binding protein-5: flexible player in the IGF system and effector on its own. J Endocrinol. 2002; 172: 423–440.
Imai Y, Busby WH Jr, Smith CE, Clarke JB, Garmong AJ, Horwitz GD, Rees C, Clemmons DR. Protease-resistant form of insulin-like growth factor-binding protein 5 is an inhibitor of insulin-like growth factor-I actions on porcine smooth muscle cells in culture. J Clin Invest. 1997; 100: 2596–2605.
Parker A, Rees C, Clarke J, Busby WH Jr, Clemmons DR. Binding of insulin-like growth factor (IGF)-binding protein-5 to smooth-muscle cell extracellular matrix is a major determinant of the cellular response to IGF-I. Mol Biol Cell. 1998; 9: 2383–2392.
Zheng B, Clarke JB, Busby WH, Duan C, Clemmons DR. Insulin-like growth factor-binding protein-5 is cleaved by physiological concentrations of thrombin. Endocrinology. 1998; 139: 1708–1714.
Zhang M, Smith EP, Kuroda H, Banach W, Chernausek SD, Fagin JA. Targeted expression of a protease-resistant IGFBP-4 mutant in smooth muscle of transgenic mice results in IGFBP-4 stabilization and smooth muscle hypotrophy. J Biol Chem. 2002; 277: 21285–21290.
Lawrence JB, Oxvig C, Overgaard MT, Sottrup-Jensen L, Gleich GJ, Hays LG, Yates JR 3rd, Conover CA. The insulin-like growth factor (IGF)-dependent IGF binding protein-4 protease secreted by human fibroblasts is pregnancy-associated plasma protein-A. Proc Natl Acad Sci U S A. 1999; 96: 3149–3153.
Bayes-Genis A, Conover CA, Overgaard MT, Bailey KR, Christiansen M, Holmes DR Jr, Virmani R, Oxvig C, Schwartz RS. Pregnancy-associated plasma protein A as a marker of acute coronary syndromes. N Engl J Med. 2001; 345: 1022–1029.
Overgaard MT, Haaning J, Boldt HB, Olsen IM, Laursen LS, Christiansen M, Gleich GJ, Sottrup-Jensen L, Conover CA, Oxvig C. Expression of recombinant human pregnancy-associated plasma protein-A and identification of the proform of eosinophil major basic protein as its physiological inhibitor. J Biol Chem. 2000; 275: 31128–31133.
Smith EP, Kamyar A, Niu W, Wang J, Cercek B, Chernausek SD, Fagin JA. IGF-binding protein-4 expression and IGF-binding protein-4 protease activity are regulated coordinately in smooth muscle during postnatal development and after vascular injury. Endocrinology. 2001; 142: 4420–4427.
Bayes-Genis A, Schwartz RS, Lewis DA, Overgaard MT, Christiansen M, Oxvig C, Ashai K, Holmes DR Jr, Conover CA. Insulin-like growth factor binding protein-4 protease produced by smooth muscle cells increases in the coronary artery after angioplasty. Arterioscler Thromb Vasc Biol. 2001; 21: 335–341.
Frost RA, Lang CH. Differential effects of insulin-like growth factor I (IGF-I) and IGF-binding protein-1 on protein metabolism in human skeletal muscle cells. Endocrinology. 1999; 140: 3962–3970.
Wang J, Niu W, Witte DP, Chernausek SD, Nikiforov YE, Clemens TL, Sharifi B, Strauch AR, Fagin JA. Overexpression of insulin-like growth factor-binding protein-4 (IGFBP-4) in smooth muscle cells of transgenic mice through a smooth muscle á-actin-IGFBP-4 fusion gene induces smooth muscle hypoplasia. Endocrinology. 1998; 139: 2605–2614.
Kern PA, Svoboda ME, Eckel RH, Van Wyk JJ. Insulinlike growth factor action and production in adipocytes and endothelial cells from human adipose tissue. Diabetes. 1989; 38: 710–717.
Gajdusek CM, Luo Z, Mayberg MR. Sequestration and secretion of insulin-like growth factor-I by bovine aortic endothelial cells. J Cell Physiol. 1993; 154: 192–198.
Bar RS, Boes M. Distinct receptors for IGF-I, IGF-II, and insulin are present on bovine capillary endothelial cells and large vessel endothelial cells. Biochem Biophys Res Commun. 1984; 124: 203–209.
Boes M, Dake BL, Bar RS. Interactions of cultured endothelial cells with TGF-a, bFGF, PDGF and IGF-I. Life Sci. 1991; 48: 811–821.
Bar RS, Harrison LC, Baxter RC, Boes M, Dake BL, Booth B, Cox A. Production of IGF-binding proteins by vascular endothelial cells. Biochem Biophys Res Commun. 1987; 148: 734–739.
Booth BA, Bar RS, Boes M, Dake BL, Bayne M, Cascieri M. Intrinsic bioactivity of insulin-like growth factor-binding proteins from vascular endothelial cells. Endocrinology. 1990; 127: 2630–2638.
Moser DR, Lowe WL Jr, Dake BL, Booth BA, Boes M, Clemmons DR, Bar RS. Endothelial cells express insulin-like growth factor-binding proteins 2 to 6. Mol Endocrinol. 1992; 6: 1805–1814.
Tucci M, Nygard K, Tanswell BV, Farber HW, Hill DJ, Han VK. Modulation of insulin-like growth factor (IGF) and IGF binding protein biosynthesis by hypoxia in cultured vascular endothelial cells. J Endocrinol. 1998; 157: 13–24.
Delafontaine P, Ku L, Anwar A, Hayzer DJ. Insulin-like growth factor 1 binding protein 3 synthesis by aortic endothelial cells is a function of cell density. Biochem Biophys Res Commun. 1996; 222: 478–482.
Dahlfors G, Arnqvist HJ. Vascular endothelial growth factor and transforming growth factor-a1 regulate the expression of insulin-like growth factor-binding protein-3, -4, and -5 in large vessel endothelial cells. Endocrinology. 2000; 141: 2062–2067.
Erondu NE, Dake BL, Moser DR, Lin M, Boes M, Bar RS. Regulation of endothelial IGFBP-3 synthesis and secretion by IGF-I and TGF-a. Growth Regul. 1996; 6: 1–9.
Yang YW, Pioli P, Fiorelli G, Brandi ML, Rechler MM. Cyclic adenosine monophosphate stimulates insulin-like growth factor binding protein-4 and its messenger ribonucleic acid in a clonal endothelial cell line. Endocrinology. 1993; 133: 343–351.
Bar RS, Dolash S, Dake BL, Boes M. Cultured capillary endothelial cells from bovine adipose tissue: a model for insulin binding and action in microvascular endothelium. Metabolism. 1986; 35: 317–322.
King GL, Goodman AD, Buzney S, Moses A, Kahn CR. Receptors and growth-promoting effects of insulin and insulinlike growth factors on cells from bovine retinal capillaries and aorta. J Clin Invest. 1985; 75: 1028–1036.
Shigematsu S, Yamauchi K, Nakajima K, Iijima S, Aizawa T, Hashizume K. IGF-1 regulates migration and angiogenesis of human endothelial cells. Endocr J. 1999; 46 (suppl): S59–S62.
Kondo T, Vicent D, Suzuma K, Yanagisawa M, King GL, Holzenberger M, Kahn CR. Knockout of insulin and IGF-1 receptors on vascular endothelial cells protects against retinal neovascularization. J Clin Invest. 2003; 111: 1835–1842.
Che W, Lerner-Marmarosh N, Huang Q, Osawa M, Ohta S, Yoshizumi M, Glassman M, Lee JD, Yan C, Berk BC, Abe J. Insulin-like growth factor-1 enhances inflammatory responses in endothelial cells: role of Gab1 and MEKK3 in TNF-á-induced c-Jun and NF-B activation and adhesion molecule expression. Circ Res. 2002; 90: 1222–1230.
Liu W, Liu Y, Lowe WL Jr. The role of phosphatidylinositol 3-kinase and the mitogen-activated protein kinases in insulin-like growth factor-I-mediated effects in vascular endothelial cells. Endocrinology. 2001; 142: 1710–1719.
Smith LE, Shen W, Perruzzi C, Soker S, Kinose F, Xu X, Robinson G, Driver S, Bischoff J, Zhang B, Schaeffer JM, Senger DR. Regulation of vascular endothelial growth factor-dependent retinal neovascularization by insulin-like growth factor-1 receptor. Nat Med. 1999; 5: 1390–1395.
Wickman A, Jonsdottir IH, Bergstrom G, Hedin L. GH and IGF-I regulate the expression of endothelial nitric oxide synthase (eNOS) in cardiovascular tissues of hypophysectomized female rats. Eur J Endocrinol. 2002; 147: 523–533.
Isenovic E, Muniyappa R, Milivojevic N, Rao Y, Sowers JR. Role of PI3-kinase in isoproterenol and IGF-1 induced ecNOS activity. Biochem Biophys Res Commun. 2001; 285: 954–958.
Isenovic ER, Divald A, Milivojevic N, Grgurevic T, Fisher SE, Sowers JR. Interactive effects of insulin-like growth factor-1 and a-estradiol on endothelial nitric oxide synthase activity in rat aortic endothelial cells. Metabolism. 2003; 52: 482–487.
Ross R. Atherosclerosis: an inflammatory disease. N Engl J Med. 1999; 340: 115–126.
Grant MB, Wargovich TJ, Ellis EA, Tarnuzzer R, Caballero S, Estes K, Rossing M, Spoerri PE, Pepine C. Expression of IGF-I, IGF-I receptor and IGF binding proteins-1, -2, -3, -4 and -5 in human atherectomy specimens. Regul Pept. 1996; 67: 137–144.
Okura Y, Brink M, Zahid AA, Anwar A, Delafontaine P. Decreased expression of insulin-like growth factor-1 and apoptosis of vascular smooth muscle cells in human atherosclerotic plaque. J Mol Cell Cardiol. 2001; 33: 1777–1789.
Patel VA, Zhang QJ, Siddle K, Soos MA, Goddard M, Weissberg PL, Bennett MR. Defect in insulin-like growth factor-1 survival mechanism in atherosclerotic plaque-derived vascular smooth muscle cells is mediated by reduced surface binding and signaling. Circ Res. 2001; 88: 895–902.
Bennett MR, Evan GI, Schwartz SM. Apoptosis of human vascular smooth muscle cells derived from normal vessels and coronary atherosclerotic plaques. J Clin Invest. 1995; 95: 2266–2274.
Okura Y, Brink M, Itabe H, Scheidegger KJ, Kalangos A, Delafontaine P. Oxidized low-density lipoprotein is associated with apoptosis of vascular smooth muscle cells in human atherosclerotic plaques. Circulation. 2000; 102: 2680–2686.
Juul A, Scheike T, Davidsen M, Gyllenborg J, Jorgensen T. Low serum insulin-like growth factor I is associated with increased risk of ischemic heart disease: a population-based case-control study. Circulation. 2002; 106: 939–944.
Ruotolo RA, Evans SR. Mesenteric ischemia in the elderly. Clin Geriatr Med. 1999; 15: 527–557.
Goodman-Gruen D, Barrett-Connor E, Rosen C. IGF-1 and ischemic heart disease in older people. J Am Geriatr Soc. 2000; 48: 860–861.
Botker HE, Skjaerbaek C, Eriksen UH, Schmitz O, Orskov H. Insulin-like growth factor-I, insulin, and angina pectoris secondary to coronary atherosclerosis, vasospasm, and syndrome X. Am J Cardiol. 1997; 79: 961–963.
Janssen JA, Stolk RP, Pols HA, Grobbee DE, Lamberts SW. Serum total IGF-I, free IGF-I, and IGFB-1 levels in an elderly population: relation to cardiovascular risk factors and disease. Arterioscler Thromb Vasc Biol. 1998; 18: 277–282.
Spallarossa P, Brunelli C, Minuto F, Caruso D, Battistini M, Caponnetto S, Cordera R. Insulin-like growth factor-I and angiographically documented coronary artery disease. Am J Cardiol. 1996; 77: 200–202.
Schuler-Luttmann S, Monnig G, Enbergs A, Schulte H, Breithardt G, Assmann G, Kerber S, von Eckardstein A. Insulin-like growth factor-binding protein-3 is associated with the presence and extent of coronary arteriosclerosis. Arterioscler Thromb Vasc Biol. 2000; 20: e10–e15.
Deleted in proof.
Schut AF, Janssen JA, Deinum J, Vergeer JM, Hofman A, Lamberts SW, Oostra BA, Pols HA, Witteman JC, van Duijn CM. Polymorphism in the promoter region of the insulin-like growth factor I gene is related to carotid intima-media thickness and aortic pulse wave velocity in subjects with hypertension. Stroke. 2003; 34: 1623–1627.
Farb A, Sangiorgi G, Carter AJ, Walley VM, Edwards WD, Schwartz RS, Virmani R. Pathology of acute and chronic coronary stenting in humans. Circulation. 1999; 99: 44–52.
Bhargava B, Karthikeyan G, Abizaid AS, Mehran R. New approaches to preventing restenosis. BMJ. 2003; 327: 274–279.
Khorsandi MJ, Fagin JA, Giannella-Neto D, Forrester JS, Cercek B. Regulation of insulin-like growth factor-I and its receptor in rat aorta after balloon denudation: evidence for local bioactivity. J Clin Invest. 1992; 90: 1926–1931.
Zhu B, Zhao G, Witte DP, Hui DY, Fagin JA. Targeted overexpression of IGF-I in smooth muscle cells of transgenic mice enhances neointimal formation through increased proliferation and cell migration after intraarterial injury. Endocrinology. 2001; 142: 3598–3606.
Bayes-Genis A, Conover CA, Schwartz RS. The insulin-like growth factor axis: a review of atherosclerosis and restenosis. Circ Res. 2000; 86: 125–130.
Yumi K, Fagin JA, Yamashita M, Fishbein MC, Shah PK, Kaul S, Niu W, Nilsson J, Cercek B. Direct effects of somatostatin analog octreotide on insulin-like growth factor-I in the arterial wall. Lab Invest. 1997; 76: 329–338.
von Essen R, Ostermaier R, Grube E, Maurer W, Tebbe U, Erbel R, Roth M, Oel W, Brom J, Weidinger G. Effects of octreotide treatment on restenosis after coronary angioplasty: results of the VERAS study. Verringerung der Restenoserate nach Angioplastie durch ein Somatostatin-analogon. Circulation. 1997; 96: 1482–1487.
Emanuelsson H, Beatt KJ, Bagger JP, Balcon R, Heikkila J, Piessens J, Schaeffer M, Suryapranata H, Foegh M. Long-term effects of angiopeptin treatment in coronary angioplasty: reduction of clinical events but not angiographic restenosis. European Angiopeptin Study Group. Circulation. 1995; 91: 1689–1696.
Eriksen UH, Amtorp O, Bagger JP, Emanuelsson H, Foegh M, Henningsen P, Saunamaki K, Schaeffer M, Thayssen P, Orskov H, et al. Randomized double-blind Scandinavian trial of angiopeptin versus placebo for the prevention of clinical events and restenosis after coronary balloon angioplasty. Am Heart J. 1995; 130: 1–8.
Santoian ED, Schneider JE, Gravanis MB, Foegh M, Tarazona N, Cipolla GD, King SB 3rd. Angiopeptin inhibits intimal hyperplasia after angioplasty in porcine coronary arteries. Circulation. 1993; 88: 11–14.
Hayry P, Myllarniemi M, Aavik E, Alatalo S, Aho P, Yilmaz S, Raisanen-Sokolowski A, Cozzone G, Jameson BA, Baserga R. Stabile D-peptide analog of insulin-like growth factor-1 inhibits smooth muscle cell proliferation after carotid ballooning injury in the rat. FASEB J. 1995; 9: 1336–1344.
Kwon HM, Sangiorgi G, Ritman EL, Lerman A, McKenna C, Virmani R, Edwards WD, Holmes DR, Schwartz RS. Adventitial vasa vasorum in balloon-injured coronary arteries: visualization and quantitation by a microscopic three-dimensional computed tomography technique. J Am Coll Cardiol. 1998; 32: 2072–2079.
Kumamoto M, Nakashima Y, Sueishi K. Intimal neovascularization in human coronary atherosclerosis: its origin and pathophysiological significance. Hum Pathol. 1995; 26: 450–456.
Sueishi K, Yonemitsu Y, Nakagawa K, Kaneda Y, Kumamoto M, Nakashima Y. Atherosclerosis and angiogenesis: its pathophysiological significance in humans as well as in an animal model induced by the gene transfer of vascular endothelial growth factor. Ann N Y Acad Sci. 1997; 811: 311–322, 322–314.
Nakao-Hayashi J, Ito H, Kanayasu T, Morita I, Murota S. Stimulatory effects of insulin and insulin-like growth factor I on migration and tube formation by vascular endothelial cells. Atherosclerosis. 1992; 92: 141–149.
Nicosia RF, Nicosia SV, Smith M. Vascular endothelial growth factor, platelet-derived growth factor, and insulin-like growth factor-1 promote rat aortic angiogenesis in vitro. Am J Pathol. 1994; 145: 1023–1029.
Su EJ, Cioffi CL, Stefansson S, Mittereder N, Garay M, Hreniuk D, Liau G. Gene therapy vector-mediated expression of insulin-like growth factors protects cardiomyocytes from apoptosis and enhances neovascularization. Am J Physiol Heart Circ Physiol. 2003; 284: H1429–H1440.
Kluge A, Zimmermann R, Weihrauch D, Mohri M, Sack S, Schaper J, Schaper W. Coordinate expression of the insulin-like growth factor system after microembolisation in porcine heart. Cardiovasc Res. 1997; 33: 324–331.
Frystyk J, Ledet T, Moller N, Flyvbjerg A, Orskov H. Cardiovascular disease and insulin-like growth factor I. Circulation. 2002; 106: 893–895.
Schneider DJ, Sobel BE. Augmentation of synthesis of plasminogen activator inhibitor type 1 by insulin and insulin-like growth factor type I: implications for vascular disease in hyperinsulinemic states. Proc Natl Acad Sci U S A. 1991; 88: 9959–9963.
Lee TS, Saltsman KA, Ohashi H, King GL. Activation of protein kinase C by elevation of glucose concentration: proposal for a mechanism in the development of diabetic vascular complications. Proc Natl Acad Sci U S A. 1989; 86: 5141–5145.
Murphy LJ, Ghahary A, Chakrabarti S. Insulin regulation of IGF-I expression in rat aorta. Diabetes. 1990; 39: 657–662.
Bornfeldt KE, Skottner A, Arnqvist HJ. In-vivo regulation of messenger RNA encoding insulin-like growth factor-I (IGF-I) and its receptor by diabetes, insulin and IGF-I in rat muscle. J Endocrinol. 1992; 135: 203–211.
Bornfeldt KE, Arnqvist HJ, Capron L. In vivo proliferation of rat vascular smooth muscle in relation to diabetes mellitus insulin-like growth factor I and insulin. Diabetologia. 1992; 35: 104–108.
Capron L, Jarnet J, Kazandjian S, Housset E. Growth-promoting effects of diabetes and insulin on arteries: an in vivo study of rat aorta. Diabetes. 1986; 35: 973–978.
Pandolfi A, Cetrullo D, Polishuck R, Alberta MM, Calafiore A, Pellegrini G, Vitacolonna E, Capani F, Consoli A. Plasminogen activator inhibitor type 1 is increased in the arterial wall of type II diabetic subjects. Arterioscler Thromb Vasc Biol. 2001; 21: 1378–1382.
Kiuchi K, Nejima J, Takano T, Ohta M, Hashimoto H. Increased serum concentrations of advanced glycation end products: a marker of coronary artery disease activity in type 2 diabetic patients. Heart. 2001; 85: 87–91.
Zhou Z, Wang K, Penn MS, Marso SP, Lauer MA, Forudi F, Zhou X, Qu W, Lu Y, Stern DM, Schmidt AM, Lincoff AM, Topol EJ. Receptor for AGE (RAGE) mediates neointimal formation in response to arterial injury. Circulation. 2003; 107: 2238–2243.
Kislinger T, Tanji N, Wendt T, Qu W, Lu Y, Ferran LJ Jr, Taguchi A, Olson K, Bucciarelli L, Goova M, Hofmann MA, Cataldegirmen G, D’Agati V, Pischetsrieder M, Stern DM, Schmidt AM. Receptor for advanced glycation end products mediates inflammation and enhanced expression of tissue factor in vasculature of diabetic apolipoprotein E-null mice. Arterioscler Thromb Vasc Biol. 2001; 21: 905–910.
Kirstein M, Aston C, Hintz R, Vlassara H. Receptor-specific induction of insulin-like growth factor I in human monocytes by advanced glycosylation end product-modified proteins. J Clin Invest. 1992; 90: 439–446.
Wu HY, Jeng YY, Yue CJ, Chyu KY, Hsueh WA, Chan TM. Endothelial-dependent vascular effects of insulin and insulin-like growth factor I in the perfused rat mesenteric artery and aortic ring. Diabetes. 1994; 43: 1027–1032.
Kobayashi T, Kamata K. Short-term insulin treatment and aortic expressions of IGF-1 receptor and VEGF mRNA in diabetic rats. Am J Physiol Heart Circ Physiol. 2002; 283: H1761–H1768.
Wang Q, Dills DG, Klein R, Klein BE, Moss SE. Does insulin-like growth factor I predict incidence and progression of diabetic retinopathy? Diabetes. 1995; 44: 161–164.
Gerhardinger C, McClure KD, Romeo G, Podesta F, Lorenzi M. IGF-I mRNA and signaling in the diabetic retina. Diabetes. 2001; 50: 175–183.
Giannini S, Cresci B, Pala L, Ciucci A, Franchini A, Manuelli C, Fujita-Yamaguchi Y, Cappugi P, Zonefrati R, Rotella CM. IGFBPs modulate IGF-I- and high glucose-controlled growth of human retinal endothelial cells. J Endocrinol. 2001; 171: 273–284.
Yakar S, Liu JL, Fernandez AM, Wu Y, Schally AV, Frystyk J, Chernausek SD, Mejia W, Le Roith D. Liver-specific igf-1 gene deletion leads to muscle insulin insensitivity. Diabetes. 2001; 50: 1110–1118.
Sandhu MS, Heald AH, Gibson JM, Cruickshank JK, Dunger DB, Wareham NJ. Circulating concentrations of insulin-like growth factor-I and development of glucose intolerance: a prospective observational study. Lancet. 2002; 359: 1740–1745.
Jabri N, Schalch DS, Schwartz SL, Fischer JS, Kipnes MS, Radnik BJ, Turman NJ, Marcsisin VS, Guler HP. Adverse effects of recombinant human insulin-like growth factor I in obese insulin-resistant type II diabetic patients. Diabetes. 1994; 43: 369–374.
Rajkumar K, Krsek M, Dheen ST, Murphy LJ. Impaired glucose homeostasis in insulin-like growth factor binding protein-1 transgenic mice. J Clin Invest. 1996; 98: 1818–1825.
Fath KA, Alexander RW, Delafontaine P. Abdominal coarctation increases insulin-like growth factor I mRNA levels in rat aorta. Circ Res. 1993; 72: 271–277.
Wickman A, Friberg P, Adams MA, Matejka GL, Brantsing C, Guron G, Isgaard J. Induction of growth hormone receptor and insulin-like growth factor-I mRNA in aorta and caval vein during hemodynamic challenge. Hypertension. 1997; 29: 123–130.
Anwar A, Delafontaine P. Hypertension increases insulin-like growth factor binding protein-4 mRNA levels in rat aorta. Hypertension. 1994; 24: 679–685.
Chen Y, Arner A, Bornfeldt KE, Uvelius B, Arnqvist HJ. Development of smooth muscle hypertrophy is closely associated with increased gene expression of insulin-like growth factor binding protein-2 and -4. Growth Regul. 1995; 5: 45–52.
Pete G, Hu Y, Walsh M, Sowers J, Dunbar JC. Insulin-like growth factor-I decreases mean blood pressure and selectively increases regional blood flow in normal rats. Proc Soc Exp Biol Med. 1996; 213: 187–192.
Lembo G, Rockman HA, Hunter JJ, Steinmetz H, Koch WJ, Ma L, Prinz MP, Ross J Jr, Chien KR, Powell-Braxton L. Elevated blood pressure and enhanced myocardial contractility in mice with severe IGF-1 deficiency. J Clin Invest. 1996; 98: 2648–2655.
Tivesten A, Bollano E, Andersson I, Fitzgerald S, Caidahl K, Sjogren K, Skott O, Liu JL, Mobini R, Isaksson OG, Jansson JO, Ohlsson C, Bergstrom G, Isgaard J. Liver-derived insulin-like growth factor-I is involved in the regulation of blood pressure in mice. Endocrinology. 2002; 143: 4235–4242.
Vecchione C, Colella S, Fratta L, Gentile MT, Selvetella G, Frati G, Trimarco B, Lembo G. Impaired insulin-like growth factor I vasorelaxant effects in hypertension. Hypertension. 2001; 37: 1480–1485.
Zhao G, Sutliff RL, Weber CS, Wang J, Lorenz J, Paul RJ, Fagin JA. Smooth muscle-targeted overexpression of insulin-like growth factor I results in enhanced vascular contractility. Endocrinology. 2001; 142: 623–632.
Diez J. Insulin-like growth factor I in essential hypertension. Kidney Int. 1999; 55: 744–759.
Heald AH, Siddals KW, Fraser W, Taylor W, Kaushal K, Morris J, Young RJ, White A, Gibson JM. Low circulating levels of insulin-like growth factor binding protein-1 (IGFBP-1) are closely associated with the presence of macrovascular disease and hypertension in type 2 diabetes. Diabetes. 2002; 51: 2629–2636.
Hayford K, Boes M, Dake BL, Bar RS. Regulations of IGF binding proteins in human aorta vascular smooth muscle cells by cAMP, dexamethasone and IGF-I. Growth Horm IGF Res. 1998; 8: 369–375.
Ververis JJ, Ku L, Delafontaine P. Regulation of insulin-like growth factor I receptors on vascular smooth muscle cells by growth factors and phorbol esters. Circ Res. 1993; 72: 1285–1292.
Ververis J, Ku L, Delafontaine P. Fibroblast growth factor regulates insulin-like growth factor-binding protein production by vascular smooth muscle cells. Am J Med Sci. 1994; 307: 77–81.
Bornfeldt KE, Raines EW, Nakano T, Graves LM, Krebs EG, Ross R. Insulin-like growth factor-I and platelet-derived growth factor-BB induce directed migration of human arterial smooth muscle cells via signaling pathways that are distinct from those of proliferation. J Clin Invest. 1994; 93: 1266–1274.
Gockerman A, Prevette T, Jones JI, Clemmons DR. Insulin-like growth factor (IGF)-binding proteins inhibit the smooth muscle cell migration responses to IGF-I and IGF-II. Endocrinology. 1995; 136: 4168–4173.
Banskota NK, Taub R, Zellner K, King GL. Insulin, insulin-like growth factor I and platelet-derived growth factor interact additively in the induction of the proto-oncogene c-myc and cellular proliferation in cultured bovine aortic smooth muscle cells. Mol Endocrinol. 1989; 3: 1183–1190.(Patrice Delafontaine; Yao)