title: A mitochondrial redox oxygen sensor in the pulmonary vasculature and ductus arteriosus.
abstract: The mammalian homeostatic oxygen sensing system (HOSS) initiates changes in vascular tone, respiration, and neurosecretion that optimize oxygen uptake and tissue oxygen delivery within seconds of detecting altered environmental or arterial PO2. The HOSS includes carotid body type 1 cells, adrenomedullary cells, neuroepithelial bodies, and smooth muscle cells (SMCs) in pulmonary arteries (PAs), ductus arteriosus (DA), and fetoplacental arteries. Hypoxic pulmonary vasoconstriction (HPV) optimizes ventilation-perfusion matching. In utero, HPV diverts placentally oxygenated blood from the non-ventilated lung through the DA. At birth, increased alveolar and arterial oxygen tension dilates the pulmonary vasculature and constricts the DA, respectively, thereby transitioning the newborn to an air-breathing organism. Though modulated by endothelial-derived relaxing and constricting factors, O2 sensing is intrinsic to PASMCs and DASMCs. Within the SMC's dynamic mitochondrial network, changes in PO2 alter the reduction-oxidation state of redox couples (NAD(+)/NADH, NADP(+)/NADPH) and the production of reactive oxygen species, ROS (e.g., H2O2), by complexes I and III of the electron transport chain (ETC). ROS and redox couples regulate ion channels, transporters, and enzymes, changing intracellular calcium [Ca(2+)]i and calcium sensitivity and eliciting homeostatic responses to hypoxia. In PASMCs, hypoxia inhibits ROS production and reduces redox couples, thereby inhibiting O2-sensitive voltage-gated potassium (Kv) channels, depolarizing the plasma membrane, activating voltage-gated calcium channels (CaL), increasing [Ca(2+)]i, and causing vasoconstriction. In DASMCs, elevated PO2 causes mitochondrial fission, increasing ETC complex I activity and ROS production. The DASMC's downstream response to elevated PO2 (Kv channel inhibition, CaL activation, increased [Ca(2+)]i, and rho kinase activation) is similar to the PASMC's hypoxic response. Impaired O2 sensing contributes to human diseases, including pulmonary arterial hypertension and patent DA.
authors.affiliation: Department of Medicine, Queen's University, Etherington Hall, Room 3041, 94 Stuart St, Kingston, ON, K7L 3N6, Canada.
authors.forename: Kimberly J
authors.initials: KJ
authors.lastname: Dunham-Snary
authors.affiliation: Department of Medicine, Queen's University, Etherington Hall, Room 3041, 94 Stuart St, Kingston, ON, K7L 3N6, Canada.
authors.forename: Zhigang G
authors.initials: ZG
authors.lastname: Hong
authors.affiliation: Department of Medicine, Queen's University, Etherington Hall, Room 3041, 94 Stuart St, Kingston, ON, K7L 3N6, Canada.
authors.forename: Ping Y
authors.initials: PY
authors.lastname: Xiong
authors.affiliation: Department of Medicine, Queen's University, Etherington Hall, Room 3041, 94 Stuart St, Kingston, ON, K7L 3N6, Canada.
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Del Paggio
authors.affiliation: Department of Medicine, Queen's University, Etherington Hall, Room 3041, 94 Stuart St, Kingston, ON, K7L 3N6, Canada.
authors.forename: Julia E
authors.initials: JE
authors.lastname: Herr
authors.affiliation: Department of Medicine, Queen's University, Etherington Hall, Room 3041, 94 Stuart St, Kingston, ON, K7L 3N6, Canada.
authors.forename: Amer M
authors.initials: AM
authors.lastname: Johri
authors.affiliation: Department of Medicine, Queen's University, Etherington Hall, Room 3041, 94 Stuart St, Kingston, ON, K7L 3N6, Canada. stephen.archer@queensu.ca.
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Archer
mesh_terms: D000818:Animals; D015220:Calcium Channels / Q000378:metabolism; D004373:Ductus Arteriosus / Q000378:metabolism*; D006801:Humans; D008168:Lung / Q000098:blood supply / Q000378:metabolism*; D008931:Mitochondria, Muscle / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D010100:Oxygen / Q000097:blood / Q000378:metabolism*; D015221:Potassium Channels / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D015220:Calcium Channels; D015221:Potassium Channels; D017382:Reactive Oxygen Species; D010100:Oxygen
keywords: Ductus arteriosus; Hypoxic pulmonary vasoconstriction; Mitochondria; Oxygen-sensitive potassium channels; Patent ductus arteriosus; Pulmonary arterial hypertension