Role of reactive oxygen species and gp91phox in endothelial dysfunction of pulmonary arteries induced by chronic hypoxia

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 No-nitro-L-arginine methyl ester (L-NAME) potentiated contraction to prostaglandin F-2 alpha (PGF(2 alpha)) 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 PGF(2 alpha)-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.