{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T06:24:00Z","timestamp":1789885440973,"version":"4.0.1"},"reference-count":54,"publisher":"National Academy of Sciences","issue":"14","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[1999,7,6]]},"abstract":"<jats:p>\n                    The rapid response to hypoxia in the pulmonary artery (PA), carotid body, and ductus arteriosus is partially mediated by O\n                    <jats:sub>2<\/jats:sub>\n                    -responsive K\n                    <jats:sup>+<\/jats:sup>\n                    channels. K\n                    <jats:sup>+<\/jats:sup>\n                    channels in PA smooth muscle cells (SMCs) are inhibited by hypoxia, causing membrane depolarization, increased cytosolic calcium, and hypoxic pulmonary vasoconstriction. We hypothesize that the K\n                    <jats:sup>+<\/jats:sup>\n                    channels are not themselves \u201cO\n                    <jats:sub>2<\/jats:sub>\n                    sensors\u201d but rather respond to the reduced redox state created by hypoxic inhibition of candidate O\n                    <jats:sub>2<\/jats:sub>\n                    sensors (NADPH oxidase or the mitochondrial electron transport chain). Both pathways shuttle electrons from donors, down a redox gradient, to O\n                    <jats:sub>2<\/jats:sub>\n                    . Hypoxia inhibits these pathways, decreasing radical production and causing cytosolic accumulation of unused, reduced, freely diffusible electron donors. PASMC K\n                    <jats:sup>+<\/jats:sup>\n                    channels are redox responsive, opening when oxidized and closing when reduced. Inhibitors of NADPH oxidase (diphenyleneiodonium) and mitochondrial complex 1 (rotenone) both inhibit PASMC whole-cell K\n                    <jats:sup>+<\/jats:sup>\n                    current but lack the specificity to identify the O\n                    <jats:sub>2<\/jats:sub>\n                    -sensor pathway. We used mice lacking the gp91 subunit of NADPH oxidase [chronic granulomatous disease (CGD) mice] to assess the hypothesis that NADPH oxidase is a PA O\n                    <jats:sub>2<\/jats:sub>\n                    -sensor. In wild-type lungs, gp91 phox and p22 phox subunits are present (relative expression: macrophages &gt; airways and veins &gt; PASMCs). Deletion of gp91 phox did not alter p22 phox expression but severely inhibited activated O\n                    <jats:sub>2<\/jats:sub>\n                    species production. Nonetheless, hypoxia caused identical inhibition of whole-cell K\n                    <jats:sup>+<\/jats:sup>\n                    current (in PASMCs) and hypoxic pulmonary vasoconstriction (in isolated lungs) from CGD vs. wild-type mice. Rotenone vasoconstriction was preserved in CGD mice, consistent with a role for the mitochondrial electron transport chain in O\n                    <jats:sub>2<\/jats:sub>\n                    sensing. NADPH oxidase, though a major source of lung radical production, is not the pulmonary vascular O\n                    <jats:sub>2<\/jats:sub>\n                    sensor in mice.\n                  <\/jats:p>","DOI":"10.1073\/pnas.96.14.7944","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T10:38:21Z","timestamp":1027679901000},"page":"7944-7949","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":234,"title":["O\n                    <sub>2<\/sub>\n                    sensing is preserved in mice lacking the gp91 phox subunit of NADPH oxidase"],"prefix":"10.1073","volume":"96","author":[{"given":"Stephen L.","family":"Archer","sequence":"first","affiliation":[{"name":"Department of Medicine, Division of Cardiology, and Department of Pathology, University of Alberta, Edmonton, Canada T69 2B7; Department of Medicine, Veterans Administration Medical Center, Minneapolis, MN 55417; Department of Physiology, University of Minnesota, Minneapolis, MN 55455; and Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen L.","family":"Reeve","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Cardiology, and Department of Pathology, University of Alberta, Edmonton, Canada T69 2B7; Department of Medicine, Veterans Administration Medical Center, Minneapolis, MN 55417; Department of Physiology, University of Minnesota, Minneapolis, MN 55455; and Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evangelos","family":"Michelakis","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Cardiology, and Department of Pathology, University of Alberta, Edmonton, Canada T69 2B7; Department of Medicine, Veterans Administration Medical Center, Minneapolis, MN 55417; Department of Physiology, University of Minnesota, Minneapolis, MN 55455; and Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lakshmi","family":"Puttagunta","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Cardiology, and Department of Pathology, University of Alberta, Edmonton, Canada T69 2B7; Department of Medicine, Veterans Administration Medical Center, Minneapolis, MN 55417; Department of Physiology, University of Minnesota, Minneapolis, MN 55455; and Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ross","family":"Waite","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Cardiology, and Department of Pathology, University of Alberta, Edmonton, Canada T69 2B7; Department of Medicine, Veterans Administration Medical Center, Minneapolis, MN 55417; Department of Physiology, University of Minnesota, Minneapolis, MN 55455; and Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel P.","family":"Nelson","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Cardiology, and Department of Pathology, University of Alberta, Edmonton, Canada T69 2B7; Department of Medicine, Veterans Administration Medical Center, Minneapolis, MN 55417; Department of Physiology, University of Minnesota, Minneapolis, MN 55455; and Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary C.","family":"Dinauer","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Cardiology, and Department of Pathology, University of Alberta, Edmonton, Canada T69 2B7; Department of Medicine, Veterans Administration Medical Center, Minneapolis, MN 55417; Department of Physiology, University of Minnesota, Minneapolis, MN 55455; and Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E. 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