Circulation Research. 2002
Published online before print June 6, 2002, doi: 10.1161/01.RES.0000024689.07590.C2
Published online before print June 6, 2002, doi: 10.1161/01.RES.0000024689.07590.C2
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Submitted on October 30, 2000
Revised on May 23, 2002
Accepted on May 23, 2002
Diversity in Mitochondrial Function Explains Differences in Vascular Oxygen Sensing
Evangelos D. Michelakis *;
From the Department of Medicine (Cardiology) and the Vascular Biology Group (E.D.M., A.N., X.W., G.H., A.L., R.G., S.L.A.), University of Alberta, Edmonton, Alberta, Canada; and Charles University, Physiology (V.H.), Prague, Czech Republic.
* To whom correspondence should be addressed. E-mail: emichela{at}cha.ab.ca.
Renal arteries (RAs) dilate in response to hypoxia, whereas the pulmonary arteries (PAs) constrict. In the PA, O2 tension is detected by an unidentified redox sensor, which controls K+ channel function and thus smooth muscle cell (SMC) membrane potential and cytosolic calcium. Mitochondria are important regulators of cellular redox status and are candidate vascular O2 sensors. Mitochondria-derived activated oxygen species (AOS), like H2O2, can diffuse to the cytoplasm and cause vasodilatation by activating sarcolemmal K+ channels. We hypothesize that mitochondrial diversity between vascular beds explains the opposing responses to hypoxia in PAs versus RAs. The effects of hypoxia and proximal electron transport chain (pETC) inhibitors (rotenone and antimycin A) were compared in rat isolated arteries, vascular SMCs, and perfused organs. Hypoxia and pETC inhibitors decrease production of AOS and outward K+ current and constrict PAs while increasing AOS production and outward K+ current and dilating RAs. At baseline, lung mitochondria have lower respiratory rates and higher rates of AOS and H2O2 production. Similarly, production of AOS and H2O2 is greater in PA versus RA rings. SMC mitochondrial membrane potential is more depolarized in PAs versus RAs. These differences relate in part to the lower expression of proximal ETC components and greater expression of mitochondrial manganese superoxide dismutase in PAs versus RAs. Differential regulation of a tonically produced, mitochondria-derived, vasodilating factor, possibly H2O2, can explain the opposing effects of hypoxia on the PAs versus RAs. We conclude that the PA and RA have different mitochondria.
Key words: rotenone • K+ channels • redox • pulmonary circulation • oxygen sensor
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