S. L. Archer, X.-C. Wu, B. Thébaud, R. Moudgil, K. Hashimoto, E.D. Michelakis
O2 sensing in the human ductus arteriosus: redox-sensitive K+ channels are regulated by mitochondria-derived hydrogen peroxide
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 endothelialderived
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 voltagegated K+ channels
(Kv) in DASMC. The resulting membrane depolarization
activates Ltype 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 DAs O2-sensor pathway, both characterized by
decreased O2-constriction and Kv expression: (i) preterm
rabbit DA, (ii) ionicallyremodeled, 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.
Biological Chemistry, Walter de Gruyter
Print ISSN: 1431-6730
Volume: 385, 04/2004
Pages: 205 - 216
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