[II-JCKAP5-1-1] Exendin-4, A Glucagon-Like Peptide-1 Receptor Agonist, Regulates Ductus Arteriosus by Vasodilation and Anti-Remodeling Through the PKA Pathway
Keywords:GLP-1, ductus ateriosus , anti-remodeling
Objective:
The mechanisms of ductus arteriosus (DA) closure involve vasoconstriction and vascular remodeling. We have previously found that glucagon-like peptide-1 receptor agonist (GLP-1RA) conveys antihypertensive and anti-remodeling effects in pulmonary circulation. This study was to investigate if exendin-4 (Ex-4), a GLP-1RA, can prevent DA closure in neonatal rats.
Methods:
In vivo, we first examined the GLP-1R expression on DA. In addition, neonatal rats were intraperitoneally injected Ex-4 or normal saline immediately after birth. We observed luminal patency and intimal thickening of DA 2h later. Ex vivo, in isolated DA rings, we determined effects of Ex-4 on vasodilation after oxygen-induced constriction. In vitro, in cultured DA smooth muscle cells (DASMCs), we investigated mechanisms underlying DA regulation including proliferation, migration, reactive oxygen species (ROS), MAPK, and Akt signal transduction.
Results:
In vivo, we demonstrated GLP-1 receptor expression in DA declined after birth. In addition, Ex-4 prevented DA closure and intimal thickening at 2h. Ex vivo, Ex-4 attenuated oxygen-induced DA constriction which was blunted by the PKA-inhibitor. In vitro, our results showed that Ex-4 inhibited PDGF-induced proliferation and migration of DASMCs with downregulation of mitochondrial ROS production, MAPK, and Akt signaling.
Conclusion:
Ex-4 maintains postnatal DA patency by vasodilatation and anti-remodeling through the PKA pathway. The GLP-1R/PKA pathway can be a promising target of DA patency in clinical management.
The mechanisms of ductus arteriosus (DA) closure involve vasoconstriction and vascular remodeling. We have previously found that glucagon-like peptide-1 receptor agonist (GLP-1RA) conveys antihypertensive and anti-remodeling effects in pulmonary circulation. This study was to investigate if exendin-4 (Ex-4), a GLP-1RA, can prevent DA closure in neonatal rats.
Methods:
In vivo, we first examined the GLP-1R expression on DA. In addition, neonatal rats were intraperitoneally injected Ex-4 or normal saline immediately after birth. We observed luminal patency and intimal thickening of DA 2h later. Ex vivo, in isolated DA rings, we determined effects of Ex-4 on vasodilation after oxygen-induced constriction. In vitro, in cultured DA smooth muscle cells (DASMCs), we investigated mechanisms underlying DA regulation including proliferation, migration, reactive oxygen species (ROS), MAPK, and Akt signal transduction.
Results:
In vivo, we demonstrated GLP-1 receptor expression in DA declined after birth. In addition, Ex-4 prevented DA closure and intimal thickening at 2h. Ex vivo, Ex-4 attenuated oxygen-induced DA constriction which was blunted by the PKA-inhibitor. In vitro, our results showed that Ex-4 inhibited PDGF-induced proliferation and migration of DASMCs with downregulation of mitochondrial ROS production, MAPK, and Akt signaling.
Conclusion:
Ex-4 maintains postnatal DA patency by vasodilatation and anti-remodeling through the PKA pathway. The GLP-1R/PKA pathway can be a promising target of DA patency in clinical management.