Circulation Research. 2002;90:1307-1315
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
© 2002 American Heart Association, Inc.
Integrative Physiology |
Diversity in Mitochondrial Function Explains Differences in Vascular Oxygen Sensing
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.
Correspondence to Evangelos D. Michelakis, MD, Cardiology, University of Alberta, 2C2.36 Walter Mackenzie Health Sciences Centre, Edmonton, AB, Canada T6G 2B7. 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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|
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|
|
|
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|
|
|
|
|
|
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|
|
|
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|
|
|
|
|
|
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|
|
|
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|
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|
|
|
|
|
|
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|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
 |
|
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|
|
|
|
 |
|
 S. Y. Cheranov and J. H. Jaggar Mitochondrial modulation of Ca2+ sparks and transient KCa currents in smooth muscle cells of rat cerebral arteries J. Physiol., May 1, 2004; 556(3): 755 - 771. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Lopez-Barneo, R. del Toro, K. L. Levitsky, M. D. Chiara, and P. Ortega-Saenz Regulation of oxygen sensing by ion channels J Appl Physiol, March 1, 2004; 96(3): 1187 - 1195. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. C. Hool Differential regulation of the slow and rapid components of guinea-pig cardiac delayed rectifier K+ channels by hypoxia J. Physiol., February 1, 2004; 554(3): 743 - 754. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. R. Duchen Roles of Mitochondria in Health and Disease Diabetes, February 1, 2004; 53(90001): S96 - 102. [Abstract] [Full Text]
|
|
|
|
|
|
Y. Liu, H. Zhao, H. Li, B. Kalyanaraman, A. C. Nicolosi, and D. D. Gutterman Mitochondrial Sources of H2O2 Generation Play a Key Role in Flow-Mediated Dilation in Human Coronary Resistance Arteries Circ. Res., September 19, 2003; 93(6): 573 - 580. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Q. Liu, J. S. K. Sham, L. A. Shimoda, P. Kuppusamy, and J. T. Sylvester Hypoxic constriction and reactive oxygen species in porcine distal pulmonary arteries Am J Physiol Lung Cell Mol Physiol, August 1, 2003; 285(2): L322 - L333. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. P T Ward Mitochondria and oxygen sensing: fuelling the controversy J. Physiol., May 1, 2003; 548(3): 664 - 664. [Full Text] [PDF]
|
|
|
|
|
|
R. Paddenberg, B. Ishaq, A. Goldenberg, P. Faulhammer, F. Rose, N. Weissmann, R. C. Braun-Dullaeus, and W. Kummer Essential role of complex II of the respiratory chain in hypoxia-induced ROS generation in the pulmonary vasculature Am J Physiol Lung Cell Mol Physiol, May 1, 2003; 284(5): L710 - L719. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
|
|
J. S.K. Sham Hypoxic Pulmonary Vasoconstriction: Ups and Downs of Reactive Oxygen Species Circ. Res., October 18, 2002; 91(8): 649 - 651. [Full Text] [PDF]
|
|
|
|
|
|
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|
|