O2 sensing in the human ductus arteriosus: redox-sensitive K+ channels are regulated by mitochondria-derived hydrogen peroxide

Biol Chem. Mar-Apr 2004;385(3-4):205-16. doi: 10.1515/BC.2004.014.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Ductus Arteriosus / metabolism*
  • Endothelium, Vascular / metabolism
  • Humans
  • Hydrogen Peroxide / metabolism*
  • Mitochondria, Muscle / metabolism*
  • Oxidation-Reduction
  • Oxygen / metabolism*
  • Potassium Channels, Voltage-Gated / metabolism*

Substances

  • Potassium Channels, Voltage-Gated
  • Hydrogen Peroxide
  • Oxygen