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.

In pulmonary arteries from control mice, the NO‐synthase inhibitor N^ω‐nitro‐L‐arginine methyl ester (L‐NAME) potentiated contraction to prostaglandin F_2α (PGF_2α) 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.

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_2α‐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.

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.

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.