Calcitonin gene-related peptide/protein kinase A: A novel pathway to regulate patency of ductus arteriosus

The closure of ductus arteriosus (DA) is mediated by vasoconstriction and subsequent vascular remodeling. Calcitonin gene-related peptide (CGRP) has been shown to have vasodilatory and anti-remodeling effects, but its role in DA is unknown. This study aimed to elucidate the effects and mechanisms of CGRP in the regulation of DA. In vivo, we investigated the impact of CGRP on DA patency and vascular remodeling in neonatal rats, while for ex vivo, the vasodilatory effect was examined in DA rings. In vitro, the effects of CGRP on anti-remodeling and its underlying mechanisms were examined in DA smooth muscle cells (DASMCs), with the roles of the protein kinase A (PKA) and CGRP receptors in CGRP signaling also being examined. Our results reveal, for the first time, that CGRP mitigates intimal thickening and maintains DA patency in neonatal rats. In DA rings, CGRP reduced oxygen-induced vasoconstriction. In DASMCs, CGRP attenuated proliferation, migration, reactive oxygen species (ROS) production, calcium release, and the activation of MAPKs and Akt induced by platelet-derived growth factor (PDGF)-BB. These in vitro effects were attenuated by both the PKA inhibitor and the CGRP receptor antagonist. In summary, CGRP promotes vasodilation with anti-remodeling effects via the PKA pathway, thereby preventing DA closure, indicating that CGRP could be a novel pharmacologic target for modulating DA patency in clinical management.