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The paradoxical patent ductus arteriosus
Kathryn N. Ivey and Deepak Srivastava
Gladstone Institute of Cardiovascular Disease, Department of Pediatrics, and Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, California, USA.
Address correspondence to: Deepak Srivastava, Gladstone Institute of Cardiovascular Disease, 1650 Owens Street, San Francisco, California 94158, USA. Phone: (415) 734-2716; Fax: (415) 355-0141; E-mail: dsrivastava@gladstone.ucsf.edu.
Find articles by Ivey, K. in: JCI | PubMed | Google Scholar
Gladstone Institute of Cardiovascular Disease, Department of Pediatrics, and Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, California, USA.
Address correspondence to: Deepak Srivastava, Gladstone Institute of Cardiovascular Disease, 1650 Owens Street, San Francisco, California 94158, USA. Phone: (415) 734-2716; Fax: (415) 355-0141; E-mail: dsrivastava@gladstone.ucsf.edu.
Find articles by Srivastava, D. in: JCI | PubMed | Google Scholar
Published November 1, 2006 - More info
J Clin Invest. 2006;116(11):2863–2865. https://doi.org/10.1172/JCI30349.
© 2006 The American Society for Clinical Investigation
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Abstract
PGE, a potent vasodilator, plays a primary role in maintaining the patency of the ductus arteriosus (DA). Genetic disruption of the PGE-specific receptor EP4, however, paradoxically results in fatal patent DA (PDA) in mice. Here we demonstrate that EP4-mediated signals promote DA closure by hyaluronic acid–mediated (HA-mediated) intimal cushion formation (ICF). Chronic EP4 stimulation by ONO-AE1-329, a selective EP4 agonist, significantly enhanced migration and HA production in rat DA smooth muscle cells. When HA production was inhibited, EP4-mediated migration was negated. Activation of EP4, adenylyl cyclase, and PKA all increased HA production and the level of HA synthase 2 (HAS2) transcripts. In immature rat DA explants, ICF was promoted by EP4/PKA stimuli. Furthermore, adenovirus-mediated Has2 gene transfer was sufficient to induce ICF in EP4-disrupted DA explants in which the intimal cushion had not formed. Accordingly, signals through EP4 have 2 essential roles in DA development, namely, vascular dilation and ICF. The latter would lead to luminal narrowing, helping adhesive occlusion and permanent closure of the vascular lumen. Our results imply that HA induction serves as an alternative therapeutic strategy for the treatment of PDA to the current one, i.e., inhibition of PGE signaling by cyclooxygenase inhibitors, which might delay PGE-mediated ICF in immature infants.
Authors
Utako Yokoyama, Susumu Minamisawa, Hong Quan, Shibnath Ghatak, Toru Akaike, Eri Segi-Nishida, Shiho Iwasaki, Mari Iwamoto, Suniti Misra, Kouichi Tamura, Hideaki Hori, Shumpei Yokota, Bryan P. Toole, Yukihiko Sugimoto, Yoshihiro Ishikawa
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).
Figure 1DA during fetal-neonatal circulatory transition. Left: During fetal development, the DA shunts blood away from the lungs and directly into the systemic circulation via the aorta. Right: At birth, as PGE levels fall, SMCs in the DA constrict, bringing the intimal cushions of the DA into contact and occluding the DA lumen, so that blood flows to the neonatal lungs. This remodeling process supports the change from a fetal circulation, where blood is oxygenated in the placenta, to a neonatal circulation, where gas exchange occurs in the lungs. Blue represents oxygen-poor blood; red represents oxygen-rich blood. RA, right atrium; LA, left atrium.
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.
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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.
Figure 2PGE both positively and negatively affects patency of the DA. Binding of PGE2 to its receptor, EP4, in the DA results in accumulation of cAMP and activation of PKA. This, in turn, has two somewhat opposing effects on the DA. PKA activation directly promotes vasodilation by inhibiting myosin light chain kinase (MLCK) to maintain DA patency during fetal development. PKA also increases activity of HAS2, leading to HA production that promotes migration of DA SMCs. This process is necessary for formation of intimal cushions that are ultimately required for functional closure of the DA at birth.
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.
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