title: O2 sensing in the human ductus arteriosus: redox-sensitive K+ channels are regulated by mitochondria-derived hydrogen peroxide.
abstract: The ductus arteriosus (DA) is a fetal artery that allows blood ejected from the right ventricle to bypass the pulmonary circulation in utero. At birth, functional closure of the DA is initiated by an O2-induced, vasoconstrictor mechanism which, though modulated by endothelial-derived endothelin and prostaglandins, is intrinsic to the smooth muscle cell (DASMC) [Michelakis et al., Circ. Res. 91 (2002); pp. 478-486]. As pO2 increases, a mitochondrial O2-sensor (electron transport chain complexes I or III) is activated, which generates a diffusible redox mediator (H2O2). H2O2 inhibits voltage-gated K+ channels (Kv) in DASMC. The resulting membrane depolarization activates L-type Ca2+ channels, thereby promoting vasoconstriction. Conversely, inhibiting mitochondrial ETC complexes I or III mimics hypoxia, depolarizing mitochondria, and decreasing H2O2 levels. The resulting increase in K+ current hyperpolarizes the DASMC and relaxes the DA. We have developed two models for study of the DA's O2-sensor pathway, both characterized by decreased O2-constriction and Kv expression: (i) preterm rabbit DA, (ii) ionically-remodeled, human term DA. The O2-sensitive channels Kv1.5 and Kv2.1 are important to DA O2-constriction and overexpression of either channel enhances DA constriction in these models. Understanding this O2-sensing pathway offers therapeutic targets to modulate the tone and patency of human DA in vivo, thereby addressing a common form of congenital heart disease in preterm infants.
authors.affiliation: Vascular Biology Group, University of Alberta, WMC 2C2.36, 8440 112th Street, Edmonton, Alberta T6G 2B7, Canada. sarcher@cha.ab.ca
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Archer
authors.forename: Xi-Chen
authors.initials: XC
authors.lastname: Wu
authors.forename: Bernard
authors.initials: B
authors.lastname: Thébaud
authors.forename: Rohit
authors.initials: R
authors.lastname: Moudgil
authors.forename: Kyoko
authors.initials: K
authors.lastname: Hashimoto
authors.forename: Evangelos D
authors.initials: ED
authors.lastname: Michelakis
mesh_terms: D000818:Animals; D004373:Ductus Arteriosus / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D008931:Mitochondria, Muscle / Q000378:metabolism*; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism*; D024642:Potassium Channels, Voltage-Gated / Q000378:metabolism*
chemical_list: D024642:Potassium Channels, Voltage-Gated; D006861:Hydrogen Peroxide; D010100:Oxygen