Origin of Neointimal Cells in Autologous Vein Graft
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《动脉硬化血栓血管生物学》
From the Department of Cardiovascular Medicine, University of Tokyo, Graduate School of Medicine, Tokyo, Japan.
Since the first aortocoronary vein graft implantation was performed in 1967,1 vascular bypass surgery using saphenous vein grafts has become an established therapeutic procedure for patients with ischemic coronary or peripheral arterial diseases. Despite increasing use of arterial grafts in coronary bypass surgery,2 autologous vein remains an important and convenient conduit for surgical revascularization.3 However, vein grafts are associated with poor long-term patencies.4 During the first year after bypass surgery, up to 15% of venous grafts occlude. Between 1 and 6 years, the graft attrition rate is 1% to 2% per year, which increases to 4% between 6 and 10 years after surgery.5 By 10 years, only 60% of vein grafts are patent and only 50% of patent vein grafts are free of significant stenosis.5
See page 1180
Graft occlusion arises either from early thrombosis or from the later onset of graft narrowing.3 After implantation, the vein graft is exposed to immediate increases in flow, shear stress, circumferential stress, radial deformation, and pulsatile stress.6 Progressive thickening of vein grafts, mainly caused by neointima formation in the inner layer, is supposed to be the adaptation of these vessels from the low-pressure venous system to the arterial circulation. Smooth muscle cell (SMC) accumulation7,8 and matrix biosynthesis by SMCs4,9 are key events in the pathogenesis of neointima formation in vein grafts. However, the molecular mechanism of SMC hyperplasia is largely unknown. Consequently, no effective therapy has been established to prevent vein graft failure.
Experimental models of venous bypass graft have been described in dogs,6 rabbits,10 and rats.11 Recent advance in gene-manipulating techniques enables us to produce various genetically modified mice to determine the role of specific molecules in a variety of biological phenomena including vascular remodeling.12–14 Moreover, genetically modified mice harboring marker genes have become available to identify the origin of the cells that contribute to organ remodeling.15–17 Thus, mouse models of vein graft would greatly facilitate genetic analyses of the pathogenesis of neointimal formation. Recent reports described murine models of vein grafts that produced progressive vessel narrowing caused by SMC hyperplasia.18–20
The first evidence for the origin of neointimal cells was provided by Hu et al, who isografted vena cava segment from wild-type mouse to the carotid artery of another mouse that expressed a marker gene, LacZ, in all tissues (ROSA26 mouse).19,21 The authors found that 40% of SMCs originated from the recipient and 60% from the donor vessel.19 The same group also reported that a large number of endothelial cells in vein grafts underwent apoptosis or necrosis during the first few days and that circulating recipient cells regenerate the endothelium.21 Because it is crucial to identify the exact source of neointimal cells for the development of genetic or pharmacological strategies to prevent vein graft disease,22 the main findings by Hu et al remain to be confirmed by other laboratories.
In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology, Cooley describes a new mouse model of vein graft transplantation.23 The author interpositioned a smaller-diameter graft, a branch of the jugular vein, to the femoral artery. This model has clinical analogy in terms of graft-to-artery diameter match. The grafts were placed into a similar anatomic location as in clinical femoral–popliteal bypass grafting using end-to-end microvascular anastomoses. Compared with other vein graft models of larger species6,10,11 and mice,18,20 the relative neointimal wall thickness was much greater in Cooley’s model, even showing near-occlusive stenosis of the perianastomotic region. However, there was no neointimal formation throughout the arterial graft. Therefore, this graft model seems to be more analogous to human aortocoronary bypass surgery than others. Taking advantage of this model, Cooley investigated the origin of neointimal cells and endothelial cells in vein graft stenotic lesions.23 In contrast to the initial reports by Hu et al,18,19,21 Cooley found that donor-originating cells made a major contribution to neointimal formation. Moreover, the donor-derived endothelial cells also survived and maintained endothelium on the luminal side of the stenotic lesion (Table).
Differences Between 2 Mouse Models of Vein Graft
These opposite results apparently result from different experimental systems to test the hypothesis (Figure). In Hu et al’s model,18,19,21 isogeneic vena cava vein was grafted between the 2 ends of the carotid artery by sleeving the ends of the vein over the cuffs, over which the carotid arterial ends were turned inside-out. In contrast, Cooley interpositioned a smaller-diameter graft to the femoral artery, using 6 to 10 interrupted stitches of nylon suture per end-to-end anastomosis.23 It is plausible that those differences in surgical procedures significantly influenced the cellular composition of the neointima and endothelium, although both models showed similar neointimal hyperplasia throughout the vein grafts. Consistent with this notion, it was reported that the origin of neointimal cells in transplant-associated arteriosclerosis differed among different allograft models.17,24,25 Moreover, we reported that recruitment of bone marrow-derived cells to vascular lesions depends largely on the type of vascular injury.26–28
Contrasting results from different murine models of vein graft. A, Hu et al18,19,21 isografted the vena cava segment from wild-type mouse to the carotid artery of ROSA26 mouse by sleeving the ends of the vein over the cuffs placed at the ends of the carotid artery. In this model, 40% of SMCs originated from the recipient (shown in blue) and 60% from the donor vessel (shown in red). Recipient cells also contributed to regeneration of the endothelium. B, Cooley23 interpositioned a smaller-diameter venous graft to the femoral artery of ROSA 26 mouse using end-to-end microvascular anastomoses. Neointima and endothelium were exclusively composed of donor-originating cells (shown in red).
Given the complexity of human vascular lesions, no animal model would represent exact pathophysiology of human autologous vein graft disease. There are many inherent differences between animals and humans in physiological and pathological responses to mechanical and humoral stimuli. For instance, experimental vein grafts show a characteristic burst of neointimal cell proliferation early after grafting, which leads to a thickened intimal layer by 1 month. This neointimal growth appears to be stabilized beyond 1 to 2 months in most of the animal models,29,30 thus differing from the clinical progression of vein graft narrowing.5 We suggest caution before extrapolating results obtained from an animal model to the pathogenesis of human vein graft stenosis. For better understanding of vein graft disease, we should compare molecular processes of neointima hyperplasia in different models with regard to clinical analogy.
References
Garrett HE, Dennis EW, DeBakey ME. Aortocoronary bypass with saphenous vein graft. Seven-year follow-up. JAMA. 1973; 223: 792–794.
Tatoulis J, Buxton BF, Fuller JA. Patencies of 2127 arterial to coronary conduits over 15 years. Ann Thorac Surg. 2004; 77: 93–101.
Mehta D, Izzat MB, Bryan AJ, Angelini GD. Towards the prevention of vein graft failure. Int J Cardiol. 1997; 62: S55–S63.
Gentile AT, Mills JL, Westerband A, Gooden MA, Berman SS, Boswell CA, Williams SK. Characterization of cellular density and determination of neointimal extracellular matrix constituents in human lower extremity vein graft stenoses. Cardiovasc Surg. 1999; 7: 464–469.
Motwani JG, Topol EJ. Aortocoronary saphenous vein graft disease: pathogenesis, predisposition, and prevention. Circulation. 1998; 97: 916–931.
Dobrin PB, Littooy FN, Endean ED. Mechanical factors predisposing to intimal hyperplasia and medial thickening in autogenous vein grafts. Surgery. 1989; 105: 393–400.
Ross R. Atherosclerosis-An inflammatory disease. N Engl J Med. 1999; 340: 115–126.
Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature. 1993; 362: 801–809.
Westerband A, Mills JL, Marek JM, Heimark RL, Hunter GC, Williams SK. Immunocytochemical determination of cell type and proliferation rate in human vein graft stenoses. J Vasc Surg. 1997; 25: 64–73.
Leville CD, Osipov VO, Jean-Claude JM, Seabrook GR, Towne JB, Cambria RA. All-trans-retinoic acid decreases cell proliferation and increases apoptosis in an animal model of vein bypass grafting. Surgery. 2000; 128: 178–184.
Dilley RJ, McGeachie JK, Tennant M. The role of cell proliferation and migration in the development of a neo-intimal layer in veins grafted into arteries, in rats. Cell Tissue Res. 1992; 269: 281–287.
Sata M, Tanaka K, Ishizaka N, Hirata Y, Nagai R. Absence of p53 Leads to Accelerated Neointimal Hyperplasia After Vascular Injury. Arterioscler Thromb Vasc Biol. 2003; 23: 1548–1552.
Sata M, Sugiura S, Yoshizumi M, Ouchi Y, Hirata Y, Nagai R. Acute and chronic smooth muscle cell apoptosis after mechanical vascular injury can occur independently of the Fas-death pathway. Arterioscler Thromb Vasc Biol. 2001; 21: 1733–1737.
Sata M, Takahashi A, Tanaka K, Washida M, Ishizaka N, Ako J, Yoshizumi M, Ouchi Y, Taniguchi T, Hirata Y, Yokoyama M, Nagai R, Walsh K. Mouse genetic evidence that tranilast reduces smooth muscle cell hyperplasia via a p21(WAF1)-dependent pathway. Arterioscler Thromb Vasc Biol. 2002; 22: 1305–1309.
Saiura A, Sata M, Washida M, Sugawara Y, Hirata Y, Nagai R, Makuuchi M. Little evidence for cell fusion between recipient and Donor-Derived cells. J Surg Res. 2003; 113: 222–227.
Saiura A, Sata M, Hirata Y, Nagai R, Makuuchi M. Circulating smooth muscle progenitor cells contribute to atherosclerosis. Nat Med. 2001; 7: 382–383.
Sata M, Saiura A, Kunisato A, Tojo A, Okada S, Tokuhisa T, Hirai H, Makuuchi M, Hirata Y, Nagai R. Hematopoietic stem cells differentiate into vascular cells that participate in the pathogenesis of atherosclerosis. Nat Med. 2002; 8: 403–409.
Zou Y, Dietrich H, Hu Y, Metzler B, Wick G, Xu Q. Mouse model of venous bypass graft arteriosclerosis. Am J Pathol. 1998; 153: 1301–1310.
Hu Y, Mayr M, Metzler B, Erdel M, Davison F, Xu Q. Both donor and recipient origins of smooth muscle cells in vein graft atherosclerotic lesions. Circ Res. 2002; 91: e13–e20.
Zhang L, Hagen PO, Kisslo J, Peppel K, Freedman NJ. Neointimal hyperplasia rapidly reaches steady state in a novel murine vein graft model. J Vasc Surg. 2002; 36: 824–832.
Xu Q, Zhang Z, Davison F, Hu Y. Circulating progenitor cells regenerate endothelium of vein graft atherosclerosis, which is diminished in ApoE-deficient mice. Circ Res. 2003; 93: e76–e86.
Mann MJ, Dzau VJ. Therapeutic applications of transcription factor decoy oligonucleotides. J Clin Invest. 2000; 106: 1071–1075.
Cooley BC. A murine model of neointimal formation and stenosis in vein grafts. Arterioscler Thromb Vasc Biol. 2004; 24: 1180–1185.
Shimizu K, Sugiyama S, Aikawa M, Fukumoto Y, Rabkin E, Libby P, Mitchell RN. Host bone-marrow cells are a source of donor intimal smooth- muscle-like cells in murine aortic transplant arteriopathy. Nat Med. 2001; 7: 738–741.
Hu Y, Davison F, Ludewig B, Erdel M, Mayr M, Url M, Dietrich H, Xu Q. Smooth muscle cells in transplant atherosclerotic lesions are originated from recipients, but not bone marrow progenitor cells. Circulation. 2002; 106: 1834–1839.
Li S, Fan YS, Chow LH, Van Den Diepstraten C, van Der Veer E, Sims SM, Pickering JG. Innate diversity of adult human arterial smooth muscle cells: cloning of distinct subtypes from the internal thoracic artery. Circ Res. 2001; 89: 517–525.
Zalewski A, Shi Y, Johnson AG. Diverse origin of intimal cells: smooth muscle cells, myofibroblasts, fibroblasts, and beyond? Circ Res. 2002; 91: 652–655.
Tanaka K, Sata M, Hirata Y, Nagai R. Diverse contribution of bone marrow cells to neointimal hyperplasia after mechanical vascular injuries. Circ Res. 2003; 93: 783–790.
Tennant M, McGeachie JK. Adaptive remodelling of smooth muscle in the neo-intima of vein-to-artery grafts in rats: a detailed morphometric analysis. Anat Embryol (Berl). 1993; 187: 161–166.
Hoch JR, Stark VK, Hullett DA, Turnipseed WD. Vein graft intimal hyperplasia: leukocytes and cytokine gene expression. Surgery. 1994; 116: 463–470.(Masataka Sata; Ryozo Naga)
Since the first aortocoronary vein graft implantation was performed in 1967,1 vascular bypass surgery using saphenous vein grafts has become an established therapeutic procedure for patients with ischemic coronary or peripheral arterial diseases. Despite increasing use of arterial grafts in coronary bypass surgery,2 autologous vein remains an important and convenient conduit for surgical revascularization.3 However, vein grafts are associated with poor long-term patencies.4 During the first year after bypass surgery, up to 15% of venous grafts occlude. Between 1 and 6 years, the graft attrition rate is 1% to 2% per year, which increases to 4% between 6 and 10 years after surgery.5 By 10 years, only 60% of vein grafts are patent and only 50% of patent vein grafts are free of significant stenosis.5
See page 1180
Graft occlusion arises either from early thrombosis or from the later onset of graft narrowing.3 After implantation, the vein graft is exposed to immediate increases in flow, shear stress, circumferential stress, radial deformation, and pulsatile stress.6 Progressive thickening of vein grafts, mainly caused by neointima formation in the inner layer, is supposed to be the adaptation of these vessels from the low-pressure venous system to the arterial circulation. Smooth muscle cell (SMC) accumulation7,8 and matrix biosynthesis by SMCs4,9 are key events in the pathogenesis of neointima formation in vein grafts. However, the molecular mechanism of SMC hyperplasia is largely unknown. Consequently, no effective therapy has been established to prevent vein graft failure.
Experimental models of venous bypass graft have been described in dogs,6 rabbits,10 and rats.11 Recent advance in gene-manipulating techniques enables us to produce various genetically modified mice to determine the role of specific molecules in a variety of biological phenomena including vascular remodeling.12–14 Moreover, genetically modified mice harboring marker genes have become available to identify the origin of the cells that contribute to organ remodeling.15–17 Thus, mouse models of vein graft would greatly facilitate genetic analyses of the pathogenesis of neointimal formation. Recent reports described murine models of vein grafts that produced progressive vessel narrowing caused by SMC hyperplasia.18–20
The first evidence for the origin of neointimal cells was provided by Hu et al, who isografted vena cava segment from wild-type mouse to the carotid artery of another mouse that expressed a marker gene, LacZ, in all tissues (ROSA26 mouse).19,21 The authors found that 40% of SMCs originated from the recipient and 60% from the donor vessel.19 The same group also reported that a large number of endothelial cells in vein grafts underwent apoptosis or necrosis during the first few days and that circulating recipient cells regenerate the endothelium.21 Because it is crucial to identify the exact source of neointimal cells for the development of genetic or pharmacological strategies to prevent vein graft disease,22 the main findings by Hu et al remain to be confirmed by other laboratories.
In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology, Cooley describes a new mouse model of vein graft transplantation.23 The author interpositioned a smaller-diameter graft, a branch of the jugular vein, to the femoral artery. This model has clinical analogy in terms of graft-to-artery diameter match. The grafts were placed into a similar anatomic location as in clinical femoral–popliteal bypass grafting using end-to-end microvascular anastomoses. Compared with other vein graft models of larger species6,10,11 and mice,18,20 the relative neointimal wall thickness was much greater in Cooley’s model, even showing near-occlusive stenosis of the perianastomotic region. However, there was no neointimal formation throughout the arterial graft. Therefore, this graft model seems to be more analogous to human aortocoronary bypass surgery than others. Taking advantage of this model, Cooley investigated the origin of neointimal cells and endothelial cells in vein graft stenotic lesions.23 In contrast to the initial reports by Hu et al,18,19,21 Cooley found that donor-originating cells made a major contribution to neointimal formation. Moreover, the donor-derived endothelial cells also survived and maintained endothelium on the luminal side of the stenotic lesion (Table).
Differences Between 2 Mouse Models of Vein Graft
These opposite results apparently result from different experimental systems to test the hypothesis (Figure). In Hu et al’s model,18,19,21 isogeneic vena cava vein was grafted between the 2 ends of the carotid artery by sleeving the ends of the vein over the cuffs, over which the carotid arterial ends were turned inside-out. In contrast, Cooley interpositioned a smaller-diameter graft to the femoral artery, using 6 to 10 interrupted stitches of nylon suture per end-to-end anastomosis.23 It is plausible that those differences in surgical procedures significantly influenced the cellular composition of the neointima and endothelium, although both models showed similar neointimal hyperplasia throughout the vein grafts. Consistent with this notion, it was reported that the origin of neointimal cells in transplant-associated arteriosclerosis differed among different allograft models.17,24,25 Moreover, we reported that recruitment of bone marrow-derived cells to vascular lesions depends largely on the type of vascular injury.26–28
Contrasting results from different murine models of vein graft. A, Hu et al18,19,21 isografted the vena cava segment from wild-type mouse to the carotid artery of ROSA26 mouse by sleeving the ends of the vein over the cuffs placed at the ends of the carotid artery. In this model, 40% of SMCs originated from the recipient (shown in blue) and 60% from the donor vessel (shown in red). Recipient cells also contributed to regeneration of the endothelium. B, Cooley23 interpositioned a smaller-diameter venous graft to the femoral artery of ROSA 26 mouse using end-to-end microvascular anastomoses. Neointima and endothelium were exclusively composed of donor-originating cells (shown in red).
Given the complexity of human vascular lesions, no animal model would represent exact pathophysiology of human autologous vein graft disease. There are many inherent differences between animals and humans in physiological and pathological responses to mechanical and humoral stimuli. For instance, experimental vein grafts show a characteristic burst of neointimal cell proliferation early after grafting, which leads to a thickened intimal layer by 1 month. This neointimal growth appears to be stabilized beyond 1 to 2 months in most of the animal models,29,30 thus differing from the clinical progression of vein graft narrowing.5 We suggest caution before extrapolating results obtained from an animal model to the pathogenesis of human vein graft stenosis. For better understanding of vein graft disease, we should compare molecular processes of neointima hyperplasia in different models with regard to clinical analogy.
References
Garrett HE, Dennis EW, DeBakey ME. Aortocoronary bypass with saphenous vein graft. Seven-year follow-up. JAMA. 1973; 223: 792–794.
Tatoulis J, Buxton BF, Fuller JA. Patencies of 2127 arterial to coronary conduits over 15 years. Ann Thorac Surg. 2004; 77: 93–101.
Mehta D, Izzat MB, Bryan AJ, Angelini GD. Towards the prevention of vein graft failure. Int J Cardiol. 1997; 62: S55–S63.
Gentile AT, Mills JL, Westerband A, Gooden MA, Berman SS, Boswell CA, Williams SK. Characterization of cellular density and determination of neointimal extracellular matrix constituents in human lower extremity vein graft stenoses. Cardiovasc Surg. 1999; 7: 464–469.
Motwani JG, Topol EJ. Aortocoronary saphenous vein graft disease: pathogenesis, predisposition, and prevention. Circulation. 1998; 97: 916–931.
Dobrin PB, Littooy FN, Endean ED. Mechanical factors predisposing to intimal hyperplasia and medial thickening in autogenous vein grafts. Surgery. 1989; 105: 393–400.
Ross R. Atherosclerosis-An inflammatory disease. N Engl J Med. 1999; 340: 115–126.
Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature. 1993; 362: 801–809.
Westerband A, Mills JL, Marek JM, Heimark RL, Hunter GC, Williams SK. Immunocytochemical determination of cell type and proliferation rate in human vein graft stenoses. J Vasc Surg. 1997; 25: 64–73.
Leville CD, Osipov VO, Jean-Claude JM, Seabrook GR, Towne JB, Cambria RA. All-trans-retinoic acid decreases cell proliferation and increases apoptosis in an animal model of vein bypass grafting. Surgery. 2000; 128: 178–184.
Dilley RJ, McGeachie JK, Tennant M. The role of cell proliferation and migration in the development of a neo-intimal layer in veins grafted into arteries, in rats. Cell Tissue Res. 1992; 269: 281–287.
Sata M, Tanaka K, Ishizaka N, Hirata Y, Nagai R. Absence of p53 Leads to Accelerated Neointimal Hyperplasia After Vascular Injury. Arterioscler Thromb Vasc Biol. 2003; 23: 1548–1552.
Sata M, Sugiura S, Yoshizumi M, Ouchi Y, Hirata Y, Nagai R. Acute and chronic smooth muscle cell apoptosis after mechanical vascular injury can occur independently of the Fas-death pathway. Arterioscler Thromb Vasc Biol. 2001; 21: 1733–1737.
Sata M, Takahashi A, Tanaka K, Washida M, Ishizaka N, Ako J, Yoshizumi M, Ouchi Y, Taniguchi T, Hirata Y, Yokoyama M, Nagai R, Walsh K. Mouse genetic evidence that tranilast reduces smooth muscle cell hyperplasia via a p21(WAF1)-dependent pathway. Arterioscler Thromb Vasc Biol. 2002; 22: 1305–1309.
Saiura A, Sata M, Washida M, Sugawara Y, Hirata Y, Nagai R, Makuuchi M. Little evidence for cell fusion between recipient and Donor-Derived cells. J Surg Res. 2003; 113: 222–227.
Saiura A, Sata M, Hirata Y, Nagai R, Makuuchi M. Circulating smooth muscle progenitor cells contribute to atherosclerosis. Nat Med. 2001; 7: 382–383.
Sata M, Saiura A, Kunisato A, Tojo A, Okada S, Tokuhisa T, Hirai H, Makuuchi M, Hirata Y, Nagai R. Hematopoietic stem cells differentiate into vascular cells that participate in the pathogenesis of atherosclerosis. Nat Med. 2002; 8: 403–409.
Zou Y, Dietrich H, Hu Y, Metzler B, Wick G, Xu Q. Mouse model of venous bypass graft arteriosclerosis. Am J Pathol. 1998; 153: 1301–1310.
Hu Y, Mayr M, Metzler B, Erdel M, Davison F, Xu Q. Both donor and recipient origins of smooth muscle cells in vein graft atherosclerotic lesions. Circ Res. 2002; 91: e13–e20.
Zhang L, Hagen PO, Kisslo J, Peppel K, Freedman NJ. Neointimal hyperplasia rapidly reaches steady state in a novel murine vein graft model. J Vasc Surg. 2002; 36: 824–832.
Xu Q, Zhang Z, Davison F, Hu Y. Circulating progenitor cells regenerate endothelium of vein graft atherosclerosis, which is diminished in ApoE-deficient mice. Circ Res. 2003; 93: e76–e86.
Mann MJ, Dzau VJ. Therapeutic applications of transcription factor decoy oligonucleotides. J Clin Invest. 2000; 106: 1071–1075.
Cooley BC. A murine model of neointimal formation and stenosis in vein grafts. Arterioscler Thromb Vasc Biol. 2004; 24: 1180–1185.
Shimizu K, Sugiyama S, Aikawa M, Fukumoto Y, Rabkin E, Libby P, Mitchell RN. Host bone-marrow cells are a source of donor intimal smooth- muscle-like cells in murine aortic transplant arteriopathy. Nat Med. 2001; 7: 738–741.
Hu Y, Davison F, Ludewig B, Erdel M, Mayr M, Url M, Dietrich H, Xu Q. Smooth muscle cells in transplant atherosclerotic lesions are originated from recipients, but not bone marrow progenitor cells. Circulation. 2002; 106: 1834–1839.
Li S, Fan YS, Chow LH, Van Den Diepstraten C, van Der Veer E, Sims SM, Pickering JG. Innate diversity of adult human arterial smooth muscle cells: cloning of distinct subtypes from the internal thoracic artery. Circ Res. 2001; 89: 517–525.
Zalewski A, Shi Y, Johnson AG. Diverse origin of intimal cells: smooth muscle cells, myofibroblasts, fibroblasts, and beyond? Circ Res. 2002; 91: 652–655.
Tanaka K, Sata M, Hirata Y, Nagai R. Diverse contribution of bone marrow cells to neointimal hyperplasia after mechanical vascular injuries. Circ Res. 2003; 93: 783–790.
Tennant M, McGeachie JK. Adaptive remodelling of smooth muscle in the neo-intima of vein-to-artery grafts in rats: a detailed morphometric analysis. Anat Embryol (Berl). 1993; 187: 161–166.
Hoch JR, Stark VK, Hullett DA, Turnipseed WD. Vein graft intimal hyperplasia: leukocytes and cytokine gene expression. Surgery. 1994; 116: 463–470.(Masataka Sata; Ryozo Naga)