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Cited by 309Mitochondrial Function and PathologyNitric Oxide and Endothelin EffectsPulmonary Hypertension Research and Treatments

Diversity in Mitochondrial Function Explains Differences in Vascular Oxygen Sensing

Michelakis, Evangelos D., Hampl, Vaclav, Nsair, Ali, Wu, XiCheng, Harry, Gwyneth, Haromy, Al, Gurtu, Rachita, Archer, Stephen L.·2002·Circulation Research
DOI 10.1161/01.res.0000024689.07590.c2
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Abstract

Renal arteries (RAs) dilate in response to hypoxia, whereas the pulmonary arteries (PAs) constrict. In the PA, O 2 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 O 2 sensors. Mitochondria-derived activated oxygen species (AOS), like H 2 O 2 , 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 H 2 O 2 production. Similarly, production of AOS and H 2 O 2 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 H 2 O 2 , can explain the opposing effects of hypoxia on the PAs versus RAs. We conclude that the PA and RA have different mitochondria.

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Authors
Michelakis, E. D., Hampl, V., Nsair, A., Wu, X., Harry, G., Haromy, A., Gurtu, R., & Archer, S. L.
Affiliations
  • University of Alberta (CA)
  • 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.
ORCID
Venue
Circulation Research
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2002-06-28
Volume
90
Issue
12
Pages
1307-1315
ISSN
  • 0009-7330 (ISSN-L)
  • 1524-4571
DOI
10.1161/01.res.0000024689.07590.c2
OpenAlex
W2146572449
Cited by
309
References
49
Citations by year
2026: 3 · 2025: 2 · 2024: 7 · 2023: 7 · 2022: 5 · 2021: 8 · 2020: 8 · 2019: 3 · 2018: 6 · 2017: 10 · 2016: 12 · 2015: 13 · 2014: 12 · 2013: 13 · 2012: 12
FWCI
7.40
Type
journal article
Language
en
Open access
closed
Locations
  • Circulation Research (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Pulmonary Hypertension Research and Treatments
Keywords
mitochondrial diversity, hypoxia, pulmonary artery, renal artery, reactive oxygen species, hydrogen peroxide, electron transport chain inhibitors, rotenone, antimycin A, smooth muscle cells, potassium channels, mitochondrial membrane potential, manganese superoxide dismutase, redox signaling, pulmonary vasoconstriction, renal vasodilation
MeSH terms
Animals, Cells, Cultured, Electron Transport, Humans, Hydrogen Peroxide, Kidney, Lung, Mitochondria, Muscle, Smooth, Vascular, Oxidation-Reduction, Pulmonary Artery, Pulmonary Circulation, Renal Artery, Renal Circulation, Rotenone, Uncoupling Agents, Vasoconstriction, Vasodilation, Potassium Channels, Cell Hypoxia, Reactive Oxygen Species, Culture Techniques, Rats

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