Molecular Mechanisms for Ductus Arteriosus Closure

Abstract

Ductus arteriosus (DA) is essential for fetal circulation and closes immediately after birth. DA closure occurs through the following two mechanisms: 1) vascular constriction mainly due to an increase in blood oxygen level and a decrease in prostaglandin E 2 (PGE 2) and 2) structural remodeling, resulting in easy closure of DA. In ad-dition to the well-known vasodilator action of PGE 2 , we found that the PGE 2 -EP4 signal plays a critical role in characterizing the DA structure, such as the formation of intimal thickening and the disassembly of the internal elastic lamina and loss of elastic fiber in the medial layer. PGE 2 -EP4-adenylyl cyclase type 6-cyclic AMP signal-ing during gestation induces intimal thickening by activating both protein kinase A and Epac. Furthermore, the PGE 2 -EP4 signal inhibits elastogenesis by degrading lysyl oxidase, a key enzyme of elastin cross-linking, through the c-Src-PLCγ pathway. Thus, the PGE 2 -EP4 signal has multiple roles in vasodilation and vascular remodeling of the DA. Our study highlights the importance of understanding DA vascular remodeling better to encourage the design and development of novel pharmacological treatments for patients with patent DA or DA-dependent congenital heart diseases.