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 N o -nitro-L-arginine methyl ester (L-NAME) potentiated contraction to prostaglandin F 2a (PGF 2a ) 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 2a -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.

Contribution of xanthine oxidase-derived superoxide to chronic hypoxic pulmonary hypertension in neonatal rats

“…In keeping with our present findings in neonatal rats, excessive production of O 2 •Ϫ has been previously implicated in hypoxia-induced inhibition of both endothelium-dependent (22) and -independent (47) pulmonary arterial relaxation in adult animals. While O 2 •Ϫ is not itself a highly reactive oxidant (57), it reacts very efficiently with NO to produce peroxynitrite anion, a ROS that is a major oxidizing and nitrating agent (2).…”

“…Pulmonary vascular ROS were detected in situ utilizing DHE, a dye that fluoresces upon reaction with ROS [predominantly O2 •Ϫ but also H2O2 and hydroxyl radicals (50)], using a method recently described by others (22,24). Briefly, the lungs of two animals per group and time point were snap frozen in Tissue-Tek OCT, as previously described (28), and stored at Ϫ80°C.…”

Cardiac oxidative stress and remodeling following infarction: role of NADPH oxidase

“…Taking together, these studies suggest that gp91 phox has different functions in cardiac remodeling depending on the nature of cardiac damage. In addition to the heart, it has also been reported that in intrapulmonary arteries, endothelial dysfunction induced by chronic hypoxia depends on gp91 phox (45).…”

Role of Gi/o-Src kinase-PI3K/Akt pathway and caveolin-1 in β2-adrenoceptor coupling to endothelial NO synthase in mouse pulmonary artery

“…In a mouse model of chronic hypoxia-induced pulmonary arterial hypertension, we have shown that the relaxant response induced by the β 2 -AR stimulation, which is also endothelium-and eNOSdependent, is preserved, whereas the relaxant response to acetylcholine is decreased [5,6].…”

“…As in other cardiovascular diseases, endothelial dysfunction in models of pulmonary arterial hypertension is established when pulmonary arteries exhibit a decrease in the relaxant response to acetylcholine, the reference endothelium-dependent vasodilator, acting through the activation of endothelial muscarinic receptors coupled to NO production [4,5]. In a mouse model of chronic hypoxia-induced pulmonary arterial hypertension, we have shown that the relaxant response induced by the β 2 -AR stimulation, which is also endothelium-and eNOSdependent, is preserved, whereas the relaxant response to acetylcholine is decreased [5,6].…”