title: Role of reactive oxygen species and gp91phox in endothelial dysfunction of pulmonary arteries induced by chronic hypoxia.
abstract: 1. This study investigates the role of nitric oxide (NO) and reactive oxygen species (ROS) on endothelial function of pulmonary arteries in a mice model of hypoxia-induced pulmonary hypertension. 2. In pulmonary arteries from control mice, the NO-synthase inhibitor Nomega-nitro-L-arginine methyl ester (L-NAME) potentiated contraction to prostaglandin F2alpha (PGF2alpha) and completely abolished relaxation to acetylcholine. In extrapulmonary but not intrapulmonary arteries, acetylcholine-induced relaxation was slightly inhibited by polyethyleneglycol-superoxide dismutase (PEG-SOD) or catalase. 3. In pulmonary arteries from hypoxic mice, ROS levels (evaluated using dihydroethidium staining) were higher than in controls. In these arteries, relaxation to acetylcholine (but not to sodium nitroprusside) was markedly diminished. L-NAME abolished relaxation to acetylcholine, but failed to potentiate PGF2-induced contraction. PEG-SOD or catalase blunted residual relaxation to acetylcholine in extrapulmonary arteries, but did not modify it in intrapulmonary arteries. Hydrogen peroxide elicited comparable (L-NAME-insensitive) relaxations in extra- and intrapulmonary arteries from hypoxic mice. 4. Exposure of gp91phox(-/-) mice to chronic hypoxia also decreased the relaxant effect of acetylcholine in extrapulmonary arteries. However, in intrapulmonary arteries from hypoxic gp91phox(-/-) mice, the effect of acetylcholine was similar to that obtained in mice not exposed to hypoxia. 5. Chronic hypoxia increases ROS levels and impairs endothelial NO-dependent relaxation in mice pulmonary arteries. Mechanisms underlying hypoxia-induced endothelial dysfunction differ along pulmonary arterial bed. In extrapulmonary arteries from hypoxic mice, endothelium-dependent relaxation appears to be mediated by ROS, in a gp91phox-independent manner. In intrapulmonary arteries, endothelial dysfunction depends on gp91phox, the latter being rather the trigger than the mediator of impaired endothelial NO-dependent relaxation
authors.affiliation: Université Victor Segalen Bordeaux 2, INSERM E356, 146 rue Léo Saignat, F-33076 Bordeaux, cedex, France.
authors.forename: Fleur
authors.initials: F
authors.lastname: Fresquet
authors.forename: Fabrice
authors.initials: F
authors.lastname: Pourageaud
authors.forename: Véronique
authors.initials: V
authors.lastname: Leblais
authors.forename: Ralf P
authors.initials: RP
authors.lastname: Brandes
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Savineau
authors.forename: Roger
authors.initials: R
authors.lastname: Marthan
authors.forename: Bernard
authors.initials: B
authors.lastname: Muller
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000502:physiology*; D006861:Hydrogen Peroxide / Q000494:pharmacology; D006976:Hypertension, Pulmonary / Q000209:etiology* / Q000235:genetics; D000860:Hypoxia / Q000150:complications*; D008168:Lung / Q000098:blood supply; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics / Q000502:physiology*; D009569:Nitric Oxide / Q000502:physiology; D011651:Pulmonary Artery / Q000737:chemistry / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000032:analysis / Q000494:pharmacology*; D014661:Vasoconstriction / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D008562:Membrane Glycoproteins; D017382:Reactive Oxygen Species; D014665:Vasodilator Agents; D009569:Nitric Oxide; D006861:Hydrogen Peroxide; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D000109:Acetylcholine