The multiple roles of prostaglandin E2 in the regulation of the ductus arteriosus

Abstract

The ductus arteriosus (DA) is a shunt vessel between the aorta and the pulmonary artery during the fetal period. It is well recognized that prostaglandin E2 (PGE2) dilates the DA through activation of its receptor EP4 and subsequent cyclic AMP (cAMP) production during the fetal period and that oxygen constricts the DA by inhibiting potassium channels immediately after birth. In addition to the regulation of vascular tone, morphological remodeling of the DA throughout the perinatal period, such as prominent intimal thickening and poor elastogenesis, has been demonstrated. We recently identified the molecular mechanisms of the acquisition of unique morphological remodeling in the DA during development. During the fetal period, PGE2-EP4 signaling decreases elastic fiber formation through degradation of the cross-linking enzyme lysyl oxidase (LOX) and increases hyaluronanmediated intimal thickening in the DA. This remodeling is mediated by activation of the EP4 receptor via diverse downstream intracellular signaling pathways. Hyaluronan-mediated intimal thickening was induced by the EP4-Gs protein-cyclic AMP-protein kinase A pathway. The attenuation of elastogenesis is mediated through a non-cyclic AMP signaling pathway, such as c-src-phospholipase C (PLC). These data suggest that placental PGE2- mediated vascular remodeling via different signaling pathways orchestrates the subsequent luminal DA reorganization, leading to complete obliteration of the DA.