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 E2 (PGE2) and 2) structural remodeling, resulting in easy closure of DA. In addition to the well-known vasodilator action of PGE2, we found that the PGE2-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. PGE2-EP4-adenylyl cyclase type 6-cyclic AMP signaling during gestation induces intimal thickening by activating both protein kinase A and Epac. Furthermore, the PGE2-EP4 signal inhibits elastogenesis by degrading lysyl oxidase, a key enzyme of elastin cross-linking, through the c-Src-PLCγ pathway. Thus, the PGE2-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.
