Astrocytes produce nitric oxide via nitrite reduction in mitochondria to regulate cerebral blood flow during brain hypoxia
Isabel N. Christie,
Shefeeq M. Theparambil,
Alice Braga,
Maxim Doronin,
Patrick S. Hosford,
Alexey Brazhe,
Alexander Mascarenhas,
Shereen Nizari,
Anna Hadjihambi,
Jack A. Wells,
Adrian Hobbs,
Alexey Semyanov,
Andrey Y. Abramov,
Plamena R. Angelova,
Alexander V. Gourine
Affiliations
Isabel N. Christie
Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology & Pharmacology, University College London, London WC1E 6BT, UK
Shefeeq M. Theparambil
Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology & Pharmacology, University College London, London WC1E 6BT, UK; Corresponding author
Alice Braga
Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology & Pharmacology, University College London, London WC1E 6BT, UK
Maxim Doronin
College of Medicine, Jiaxing University, Jiaxing 314001, China
Patrick S. Hosford
Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology & Pharmacology, University College London, London WC1E 6BT, UK
Alexey Brazhe
Department of Molecular Neurobiology, Institute of Bioorganic Chemistry, Moscow 117997, Russian Federation; Faculty of Biology, Lomonosov Moscow State University, Moscow 119234, Russian Federation
Alexander Mascarenhas
Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology & Pharmacology, University College London, London WC1E 6BT, UK
Shereen Nizari
Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology & Pharmacology, University College London, London WC1E 6BT, UK; Centre for Advanced Biomedical Imaging, Division of Medicine, University College London, London WC1E 6BT, UK
Anna Hadjihambi
The Roger Williams Institute of Hepatology, Foundation for Liver Research, and Faculty of Life Sciences and Medicine, King’s College London, London SE5 9NT, UK
Jack A. Wells
Centre for Advanced Biomedical Imaging, Division of Medicine, University College London, London WC1E 6BT, UK
Adrian Hobbs
William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, London EC1M 6BQ, UK
Alexey Semyanov
College of Medicine, Jiaxing University, Jiaxing 314001, China; Department of Molecular Neurobiology, Institute of Bioorganic Chemistry, Moscow 117997, Russian Federation
Andrey Y. Abramov
Department of Clinical and Movement Neurosciences, Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK
Plamena R. Angelova
Department of Clinical and Movement Neurosciences, Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK
Alexander V. Gourine
Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology & Pharmacology, University College London, London WC1E 6BT, UK; Corresponding author
Summary: During hypoxia, increases in cerebral blood flow maintain brain oxygen delivery. Here, we describe a mechanism of brain oxygen sensing that mediates the dilation of intraparenchymal cerebral blood vessels in response to reductions in oxygen supply. In vitro and in vivo experiments conducted in rodent models show that during hypoxia, cortical astrocytes produce the potent vasodilator nitric oxide (NO) via nitrite reduction in mitochondria. Inhibition of mitochondrial respiration mimics, but also occludes, the effect of hypoxia on NO production in astrocytes. Astrocytes display high expression of the molybdenum-cofactor-containing mitochondrial enzyme sulfite oxidase, which can catalyze nitrite reduction in hypoxia. Replacement of molybdenum with tungsten or knockdown of sulfite oxidase expression in astrocytes blocks hypoxia-induced NO production by these glial cells and reduces the cerebrovascular response to hypoxia. These data identify astrocyte mitochondria as brain oxygen sensors that regulate cerebral blood flow during hypoxia via release of nitric oxide.
