title: Prostaglandin E-mediated molecular mechanisms driving remodeling of the ductus arteriosus.
abstract: The ductus arteriosus (DA), a fetal arterial connection between the pulmonary arteries and aorta, normally closes after birth. Persistent DA patency usually has life-threatening consequences. In certain DA-dependent congenital heart diseases, however, patient survival depends on maintaining DA patency. Complete closure of the DA involves both functional closure, induced by muscle contraction, and anatomical closure, achieved through morphological and molecular remodeling. Anatomical closure of the DA is associated with the formation of intimal thickening, which is characterized by deposition of extracellular matrix in the subendothelial region, sparse elastic fiber formation, and migration of medial smooth muscle cells into the subendothelial space. In addition, fetal molecular remodeling that is suitable for postnatal muscle contraction has been observed in the DA. After the second trimester, high concentration of prostaglandin E2 (PGE2) causes the DA to dilate through the remainder of the fetal period. Emerging evidence from studies using pharmacological approaches and genetically modified mice suggests that, in addition to its vasodilatory effect, this chronic exposure to PGE2 promotes DA-specific anatomical and molecular remodeling through EP4, one of four receptor subtypes for PGE2. Signals that are downstream of PGE2-EP4, such as cyclic AMP (cAMP)-protein kinase A (PKA), exchange protein activated by cAMP (Epac), phospholipase C, and Wnt/β-catenin, may be involved in the regulation of intimal thickening, elastogenesis, and contraction-related genes. Understanding the physiological role of PGE2 in DA remodeling could enable more effective regulation of PDA, both in isolation and in the context of congenital cardiac anomalies.
authors.affiliation: Cardiovascular Research Institute, Yokohama City University, Yokohama, Kanagawa, Japan.
authors.forename: Utako
authors.identifier: http://orcid.org/0000-0003-1803-0155
authors.initials: U
authors.lastname: Yokoyama
mesh_terms: D015232:Dinoprostone / Q000378:metabolism*; D004373:Ductus Arteriosus / Q000378:metabolism / Q000503:physiopathology*; D004374:Ductus Arteriosus, Patent / Q000000981:diagnostic imaging / Q000378:metabolism / Q000503:physiopathology; D004730:Endothelium, Vascular / Q000503:physiopathology*; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D011247:Pregnancy; D066253:Vascular Remodeling / Q000502:physiology*
chemical_list: D015232:Dinoprostone
keywords: arterial intima; ductus arteriosus; prostaglandin E; prostanoid receptor EP4; vascular remodeling