Role of Dynamin-Related Protein 1 (Drp1)-Mediated Mitochondrial Fission in Oxygen Sensing and Constriction of the Ductus Arteriosus

RATIONALE:Closure of the ductus arteriosus (DA) is essential for the transition from fetal to neonatal patterns of circulation. Initial PO2-dependent vasoconstriction causes functional DA closure within minutes. Within days a fibrogenic, proliferative mechanism causes anatomic closure. Though modulated by endothelial-derived vasodilators and constrictors, O2 sensing is intrinsic to ductal smooth muscle cells and oxygen-induced DA constriction persists in the absence of endothelium, endothelin, and cyclooxygenase mediators. O2 increases mitochondrial-derived H2O2, which constricts ductal smooth muscle cells by raising intracellular calcium and activating rho kinase. However, the mechanism by which oxygen changes mitochondrial function is unknown. OBJECTIVE:The purpose of this study was to determine whether mitochondrial fission is crucial for O2-induced DA constriction and closure. METHODS AND RESULTS:Using DA harvested from 30 term infants during correction of congenital heart disease, as well as DA from term rabbits, we demonstrate that mitochondrial fission is crucial for O2-induced constriction and closure. O2 rapidly (