The paradoxical patent ductus arteriosus
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《临床调查学报》
Gladstone Institute of Cardiovascular Disease, Department of Pediatrics, and Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, California, USA.
Abstract
The ductus arteriosus (DA) is a vessel whose patency is required for fetal survival but is incompatible with postnatal life. Because of developmental insufficiency, the DA in preterm infants often fails to close in a condition known as patent DA (PDA). Although COX inhibitors can be used to close the PDA by lowering circulating prostaglandin levels, their effectiveness is correlated with birth weight, and severely premature infants often require surgical repair. Paradoxically, targeted deletion of COX pathway components in mice results in PDA. In this issue of the JCI, Yokoyama et al. describe dual roles for prostaglandins in DA development and closure, offering new insights into the mechanism of negative effects of COX inhibitors that may influence the treatment of severely premature infants with PDA and lead to improvement of their outcomes (see the related article beginning on page 3026).
The ductus arteriosus (DA) is a fetal vessel that bridges the pulmonary and systemic circulation during gestation, when oxygenation of fetal blood occurs in the placenta (Figure 1). In utero, circulating prostaglandins, formed by the action of COX enzymes, exert their vasodilatory effect on the DA to maintain its patency (1). Activation of the G protein–coupled receptor EP4 by PGE2, the primary prostaglandin regulating ductal tone, leads to DA smooth muscle relaxation (1). During late gestation, in preparation for birth, SMCs within the DA migrate toward the endothelial lining, forming mounds known as intimal cushions (2). A sharp decline in prostaglandin levels at birth results in constriction of the DA, bringing the intimal cushions into contact and occluding the DA lumen (1).
Failure of DA closure, called patent DA (PDA), is the third most common congenital heart defect, and its incidence is increased in preterm infants (3). Fortunately, pharmacological inhibition of the COXs is an effective means of closing the DA postnatally (4, 5). However, COX inhibitors are less effective for DA closure in severely premature infants (4, 5), a fact that has long been attributed to the immaturity of their DA smooth muscle and its inability to contract, even as prostaglandins are withdrawn. Conversely, in the case of some congenital heart defects, systemic blood flow relies on maintenance of DA patency, in which case prostaglandins are administered to keep the DA open until surgical repair of the heart or vessels can be performed.
The paradox of PDA
Given the known role of prostaglandins in maintaining DA patency, a logical corollary would be that mice with targeted deletions of genes that negatively affect prostaglandin synthesis or signaling would result in premature closure of the DA. Surprisingly, mice lacking the DA-enriched prostaglandin receptor EP4, or mice with combined deficiency of the COX enzymes, COX-1 and COX-2, were found to have PDA (6, 7). How is it that depleting a signaling pathway in mice has the same effect as activating that pathway in humans
Yokoyama et al. shed light on this question in their study published in this issue of the JCI (8). They establish that PGE2, acting via its receptor, EP4, has an additional prenatal role in the maturation of the fetal DA, preparing it for closure at birth by promoting intimal cushion formation (Figure 2). Using agonists and antagonists of the EP4 receptor, the authors show that EP4 controls DA smooth muscle migration to form intimal cushions while stimulating synthesis and secretion of hyaluronic acid (HA; also known as hyaluronan), an extracellular matrix component through which the SMCs traverse. With elegant use of siRNA-mediated knockdown of HA synthase 2 (HAS2), as well as HA depletion from EP4-activated cultures, the authors confirm that PGE-induced SMC migration occurs through EP4 stimulation of HA production.
These findings offer a likely explanation for why mice lacking prostaglandin signaling in the DA do not experience premature closure of the fetal vessel. EP4-null mice fail to form intimal cushions, so the vasodilatory effects of prostaglandins are likely not required for maintenance of DA patency before birth. Instead, patency persists postnatally in the absence of prostaglandin signaling because, without intimal cushion formation, occlusion of the DA lumen cannot occur.
While we believe that the study by Yokoyama et al. (8) is the first to uncover a role for prostaglandins in intimal cushion formation, the idea that DA remodeling is more important than vasoconstriction for DA closure is not new. The DA of mice lacking smooth muscle myosin, which is required for contraction of DA smooth muscle, also closes appropriately after birth (9), demonstrating that functional closure can occur without vessel wall contraction. Interestingly, comparison of the effects of genetic COX deficiency and administration of COX inhibitors at varying points of mouse gestation also revealed that prostaglandins have a novel role in the development of the DA, beyond their direct vasodilatory effect (10).
In addition to explaining the paradox of PDA in mice deficient in prostaglandin signaling, the elucidation by Yokoyama et al. (8) of a developmental role for prostaglandins during DA maturation may also add to our understanding of important clinical findings that have yet gone unexplained. In spite of their vasoconstrictive effect on the DA at birth, use of COX inhibitors by pregnant mothers increases the incidence of PDA in newborns (11, 12). If prostaglandin signaling is, indeed, required for intimal cushion formation in humans as in rodents, then infants who develop under conditions of insufficient PGE, as in the case of maternal use of COX inhibitors, may be born with an underdeveloped DA that remains patent in spite of PGE withdrawal. The current results also imply that, while DA smooth muscle development is not as advanced in premature infants as in their full-term counterparts, DA smooth muscle immaturity may not be the primary cause for the lack of DA constriction in response to COX inhibitors, as previously thought. Instead, a lack of intimal cushions, whose further development is blocked by the delivery of COX inhibitors, may preclude DA closure in preterm infants.
Implications for pharmacological intervention for PDA
While COX inhibitors offer an effective means to close the DA in near-term infants, for severely premature babies, COX inhibitors may exacerbate the problem by preventing the formation of intimal cushions required for closure. Yokoyama et al. (8) suggest that HAS activation, combined with prostaglandin blockade, might be an effective means to treat PDA in severely premature infants. Certainly their results suggest that, upon appropriate delivery of directed HAS stimulation, this may be a successful tactic in rodents, and future studies will determine whether a combined therapy is sufficient to promote DA maturation and closure in a timely manner.
It is important to note that, while the underlying molecular pathways controlling DA development and closure are strikingly similar in rodents and larger mammals, there are significant differences in their developmental physiology and the timing of critical closure events. For instance, while functional closure of the DA happens quite rapidly in rodents, occurring within the first few hours after birth (13), normal closure in newborn humans takes place over several days (14). More relevant to the early effects of prostaglandins, intimal cushion formation occurs much earlier and is far more pronounced in larger mammals than in small rodents (15). It has been hypothesized that, due to their increased luminal diameter, larger mammals require highly developed intimal cushions for contraction of the surrounding smooth muscle to effectively close the lumen (15). So while mice, rats, and even rabbits offer amenable models for genetic and initial pharmacological studies of DA development and closure, other large animals, such as lambs, pigs, or dogs, must be used to more directly model the physiology and pathophysiology of the human DA. Given the impact and potential clinical application of the study by Yokoyama et al., further studies of this kind will no doubt be undertaken in larger model organisms, hopefully offering answers that can be directly applicable to neonatal medicine and improve the outcomes of the multitude of low-birth-weight babies that struggle with this disease.
Footnotes
Nonstandard abbreviations used: DA, ductus arteriosus; HA, hyaluronic acid; HAS2, HA synthase 2; PDA, patent DA.
Conflict of interest: The authors have declared that no conflict of interest exists.
Citation for this article: J. Clin. Invest. 116:2863–2866 (2006). doi:10.1172/JCI30349.
See the related article beginning on page 3026.
References
Smith G.C. 1998. The pharmacology of the ductus arteriosus. Pharmacol. Rev. 50:35–58.
Gittenberger-de Groot, A.C. 1977. Morphology of the normal human ductus arteriosus. InThe ductus arteriosus, report of the 75th Ross Conference on Pediatric Research. M.A. Heymann and A.M. Rudolph, editors. Ross Laboratories. Columbus, Ohio, USA. 3–9..
Hoffman J.I. and Kaplan S. 2002. The incidence of congenital heart disease. J. Am. Coll. Cardiol. 39:1890–1900.
Heymann M.A., Rudolph A.M., Silverman N.H. 1976. Closure of the ductus arteriosus in premature infants by inhibition of prostaglandin synthesis. N. Engl. J. Med. 295:530–533.
Friedman W.F., Hirschklau M.J., Printz M.P., Pitlick P.T., Kirkpatrick S.E. 1976. Pharmacologic closure of patent ductus arteriosus in the premature infant. N. Engl. J. Med. 295:526–529.
Nguyen M., et al. 1997. The prostaglandin receptor EP4 triggers remodelling of the cardiovascular system at birth. Nature. 390:78–81.
Loftin C.D., et al. 2001. Failure of ductus arteriosus closure and remodeling in neonatal mice deficient in cyclooxygenase-1 and cyclooxygenase-2. Proc. Natl. Acad. Sci. U. S. A. 98:1059–1064.
Yokoyama U., et al. 2006. Chronic activation of the prostaglandin receptor EP4 promotes hyaluronan-mediated neointimal formation in the ductus arteriosus. J. Clin. Invest. 116:3026–3034 doi: 10.1172/JCI28639.
Morano I., et al. 2000. Smooth-muscle contraction without smooth-muscle myosin. Nat. Cell Biol. 2:371–375.
Reese J., Anderson J.D., Brown N., Roman C., Clyman R.I. 2006. Inhibition of cyclooxygenase isoforms in late- but not mid-gestation decreases contractility of the ductus arteriosus and prevents postnatal closure in mice. Am. J. Physiol. Regul. Integr. Comp. Physiol. doi: 10.1152/ajpregu.00259.2006.
Norton M.E., Merrill J., Cooper B.A., Kuller J.A., Clyman R.I. 1993. Neonatal complications after the administration of indomethacin for preterm labor. N. Engl. J. Med. 329:1602–1607.
Hammerman C., et al. 1998. Indomethacin tocolysis increases postnatal patent ductus arteriosus severity. Pediatrics. 102:E56.
Tada T. and Kishimoto H. 1990. Ultrastructural and histological studies on closure of the mouse ductus arteriosus. Acta Anat. (Basel). 139:326–334.
Gentile R., et al. 1981. Pulsed Doppler echocardiographic determination of time of ductal closure in normal newborn infants. J. Pediatr. 98:443–448.
Bergwerff M., DeRuiter M.C., Gittenberger-de Groot A.C. 1999. Comparative anatomy and ontogeny of the ductus arteriosus, a vascular outsider. Anat. Embryol. (Berl.). 200:559–571.(Kathryn N. Ivey and Deepa)
Abstract
The ductus arteriosus (DA) is a vessel whose patency is required for fetal survival but is incompatible with postnatal life. Because of developmental insufficiency, the DA in preterm infants often fails to close in a condition known as patent DA (PDA). Although COX inhibitors can be used to close the PDA by lowering circulating prostaglandin levels, their effectiveness is correlated with birth weight, and severely premature infants often require surgical repair. Paradoxically, targeted deletion of COX pathway components in mice results in PDA. In this issue of the JCI, Yokoyama et al. describe dual roles for prostaglandins in DA development and closure, offering new insights into the mechanism of negative effects of COX inhibitors that may influence the treatment of severely premature infants with PDA and lead to improvement of their outcomes (see the related article beginning on page 3026).
The ductus arteriosus (DA) is a fetal vessel that bridges the pulmonary and systemic circulation during gestation, when oxygenation of fetal blood occurs in the placenta (Figure 1). In utero, circulating prostaglandins, formed by the action of COX enzymes, exert their vasodilatory effect on the DA to maintain its patency (1). Activation of the G protein–coupled receptor EP4 by PGE2, the primary prostaglandin regulating ductal tone, leads to DA smooth muscle relaxation (1). During late gestation, in preparation for birth, SMCs within the DA migrate toward the endothelial lining, forming mounds known as intimal cushions (2). A sharp decline in prostaglandin levels at birth results in constriction of the DA, bringing the intimal cushions into contact and occluding the DA lumen (1).
Failure of DA closure, called patent DA (PDA), is the third most common congenital heart defect, and its incidence is increased in preterm infants (3). Fortunately, pharmacological inhibition of the COXs is an effective means of closing the DA postnatally (4, 5). However, COX inhibitors are less effective for DA closure in severely premature infants (4, 5), a fact that has long been attributed to the immaturity of their DA smooth muscle and its inability to contract, even as prostaglandins are withdrawn. Conversely, in the case of some congenital heart defects, systemic blood flow relies on maintenance of DA patency, in which case prostaglandins are administered to keep the DA open until surgical repair of the heart or vessels can be performed.
The paradox of PDA
Given the known role of prostaglandins in maintaining DA patency, a logical corollary would be that mice with targeted deletions of genes that negatively affect prostaglandin synthesis or signaling would result in premature closure of the DA. Surprisingly, mice lacking the DA-enriched prostaglandin receptor EP4, or mice with combined deficiency of the COX enzymes, COX-1 and COX-2, were found to have PDA (6, 7). How is it that depleting a signaling pathway in mice has the same effect as activating that pathway in humans
Yokoyama et al. shed light on this question in their study published in this issue of the JCI (8). They establish that PGE2, acting via its receptor, EP4, has an additional prenatal role in the maturation of the fetal DA, preparing it for closure at birth by promoting intimal cushion formation (Figure 2). Using agonists and antagonists of the EP4 receptor, the authors show that EP4 controls DA smooth muscle migration to form intimal cushions while stimulating synthesis and secretion of hyaluronic acid (HA; also known as hyaluronan), an extracellular matrix component through which the SMCs traverse. With elegant use of siRNA-mediated knockdown of HA synthase 2 (HAS2), as well as HA depletion from EP4-activated cultures, the authors confirm that PGE-induced SMC migration occurs through EP4 stimulation of HA production.
These findings offer a likely explanation for why mice lacking prostaglandin signaling in the DA do not experience premature closure of the fetal vessel. EP4-null mice fail to form intimal cushions, so the vasodilatory effects of prostaglandins are likely not required for maintenance of DA patency before birth. Instead, patency persists postnatally in the absence of prostaglandin signaling because, without intimal cushion formation, occlusion of the DA lumen cannot occur.
While we believe that the study by Yokoyama et al. (8) is the first to uncover a role for prostaglandins in intimal cushion formation, the idea that DA remodeling is more important than vasoconstriction for DA closure is not new. The DA of mice lacking smooth muscle myosin, which is required for contraction of DA smooth muscle, also closes appropriately after birth (9), demonstrating that functional closure can occur without vessel wall contraction. Interestingly, comparison of the effects of genetic COX deficiency and administration of COX inhibitors at varying points of mouse gestation also revealed that prostaglandins have a novel role in the development of the DA, beyond their direct vasodilatory effect (10).
In addition to explaining the paradox of PDA in mice deficient in prostaglandin signaling, the elucidation by Yokoyama et al. (8) of a developmental role for prostaglandins during DA maturation may also add to our understanding of important clinical findings that have yet gone unexplained. In spite of their vasoconstrictive effect on the DA at birth, use of COX inhibitors by pregnant mothers increases the incidence of PDA in newborns (11, 12). If prostaglandin signaling is, indeed, required for intimal cushion formation in humans as in rodents, then infants who develop under conditions of insufficient PGE, as in the case of maternal use of COX inhibitors, may be born with an underdeveloped DA that remains patent in spite of PGE withdrawal. The current results also imply that, while DA smooth muscle development is not as advanced in premature infants as in their full-term counterparts, DA smooth muscle immaturity may not be the primary cause for the lack of DA constriction in response to COX inhibitors, as previously thought. Instead, a lack of intimal cushions, whose further development is blocked by the delivery of COX inhibitors, may preclude DA closure in preterm infants.
Implications for pharmacological intervention for PDA
While COX inhibitors offer an effective means to close the DA in near-term infants, for severely premature babies, COX inhibitors may exacerbate the problem by preventing the formation of intimal cushions required for closure. Yokoyama et al. (8) suggest that HAS activation, combined with prostaglandin blockade, might be an effective means to treat PDA in severely premature infants. Certainly their results suggest that, upon appropriate delivery of directed HAS stimulation, this may be a successful tactic in rodents, and future studies will determine whether a combined therapy is sufficient to promote DA maturation and closure in a timely manner.
It is important to note that, while the underlying molecular pathways controlling DA development and closure are strikingly similar in rodents and larger mammals, there are significant differences in their developmental physiology and the timing of critical closure events. For instance, while functional closure of the DA happens quite rapidly in rodents, occurring within the first few hours after birth (13), normal closure in newborn humans takes place over several days (14). More relevant to the early effects of prostaglandins, intimal cushion formation occurs much earlier and is far more pronounced in larger mammals than in small rodents (15). It has been hypothesized that, due to their increased luminal diameter, larger mammals require highly developed intimal cushions for contraction of the surrounding smooth muscle to effectively close the lumen (15). So while mice, rats, and even rabbits offer amenable models for genetic and initial pharmacological studies of DA development and closure, other large animals, such as lambs, pigs, or dogs, must be used to more directly model the physiology and pathophysiology of the human DA. Given the impact and potential clinical application of the study by Yokoyama et al., further studies of this kind will no doubt be undertaken in larger model organisms, hopefully offering answers that can be directly applicable to neonatal medicine and improve the outcomes of the multitude of low-birth-weight babies that struggle with this disease.
Footnotes
Nonstandard abbreviations used: DA, ductus arteriosus; HA, hyaluronic acid; HAS2, HA synthase 2; PDA, patent DA.
Conflict of interest: The authors have declared that no conflict of interest exists.
Citation for this article: J. Clin. Invest. 116:2863–2866 (2006). doi:10.1172/JCI30349.
See the related article beginning on page 3026.
References
Smith G.C. 1998. The pharmacology of the ductus arteriosus. Pharmacol. Rev. 50:35–58.
Gittenberger-de Groot, A.C. 1977. Morphology of the normal human ductus arteriosus. InThe ductus arteriosus, report of the 75th Ross Conference on Pediatric Research. M.A. Heymann and A.M. Rudolph, editors. Ross Laboratories. Columbus, Ohio, USA. 3–9..
Hoffman J.I. and Kaplan S. 2002. The incidence of congenital heart disease. J. Am. Coll. Cardiol. 39:1890–1900.
Heymann M.A., Rudolph A.M., Silverman N.H. 1976. Closure of the ductus arteriosus in premature infants by inhibition of prostaglandin synthesis. N. Engl. J. Med. 295:530–533.
Friedman W.F., Hirschklau M.J., Printz M.P., Pitlick P.T., Kirkpatrick S.E. 1976. Pharmacologic closure of patent ductus arteriosus in the premature infant. N. Engl. J. Med. 295:526–529.
Nguyen M., et al. 1997. The prostaglandin receptor EP4 triggers remodelling of the cardiovascular system at birth. Nature. 390:78–81.
Loftin C.D., et al. 2001. Failure of ductus arteriosus closure and remodeling in neonatal mice deficient in cyclooxygenase-1 and cyclooxygenase-2. Proc. Natl. Acad. Sci. U. S. A. 98:1059–1064.
Yokoyama U., et al. 2006. Chronic activation of the prostaglandin receptor EP4 promotes hyaluronan-mediated neointimal formation in the ductus arteriosus. J. Clin. Invest. 116:3026–3034 doi: 10.1172/JCI28639.
Morano I., et al. 2000. Smooth-muscle contraction without smooth-muscle myosin. Nat. Cell Biol. 2:371–375.
Reese J., Anderson J.D., Brown N., Roman C., Clyman R.I. 2006. Inhibition of cyclooxygenase isoforms in late- but not mid-gestation decreases contractility of the ductus arteriosus and prevents postnatal closure in mice. Am. J. Physiol. Regul. Integr. Comp. Physiol. doi: 10.1152/ajpregu.00259.2006.
Norton M.E., Merrill J., Cooper B.A., Kuller J.A., Clyman R.I. 1993. Neonatal complications after the administration of indomethacin for preterm labor. N. Engl. J. Med. 329:1602–1607.
Hammerman C., et al. 1998. Indomethacin tocolysis increases postnatal patent ductus arteriosus severity. Pediatrics. 102:E56.
Tada T. and Kishimoto H. 1990. Ultrastructural and histological studies on closure of the mouse ductus arteriosus. Acta Anat. (Basel). 139:326–334.
Gentile R., et al. 1981. Pulsed Doppler echocardiographic determination of time of ductal closure in normal newborn infants. J. Pediatr. 98:443–448.
Bergwerff M., DeRuiter M.C., Gittenberger-de Groot A.C. 1999. Comparative anatomy and ontogeny of the ductus arteriosus, a vascular outsider. Anat. Embryol. (Berl.). 200:559–571.(Kathryn N. Ivey and Deepa)