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