NADPH oxidase-derived ROS and the regulation of pulmonary vessel tone.

Pulmonary vessel constriction results from an imbalance between vasodilator and vasoconstrictor factors released by the endothelium including nitric oxide, endothelin, prostanoids, and reactive oxygen species (ROS). ROS, generated by a variety of enzymatic sources (such as mitochondria and NADPH oxidases, a.k.a. Nox), appear to play a pivotal role in vascular homeostasis, whereas elevated levels effect vascular disease. The pulmonary circulation is very sensitive to changes in the partial pressure of oxygen and differs from the systemic circulation in its response to this change. In fact, the pulmonary vessels contract in response to low oxygen tension, whereas systemic vessels dilate. Growing evidence suggests that ROS production and ROS-related pathways may be key factors that underlie this differential response to oxygen tension. A major emphasis of our laboratory is the role of Nox isozymes in cardiovascular disease. In this review, we will focus our attention on the role of Nox-derived ROS in the control of pulmonary vascular tone.

Developmental changes in endothelium-dependent relaxation of the chicken ductus arteriosus.

We tested the hypothesis that endothelium-dependent relaxation in the chicken ductus arteriosus (DA) is developmentally regulated. Isolated DA rings from 15-, 19- and 21-day-old (externally pipped) chicken embryos relaxed to acetylcholine (ACh). This relaxation was unaffected by indomethacin but impaired by endothelium removal, by the NO synthase inhibitor L-NAME, and by the soluble guanylate cyclase inhibitor ODQ, suggesting the involvement of NO. This NO production was confirmed with the fluorescent probe DAF-2DA. The combination of apamin and charybdotoxin with L-NAME produced a further inhibition of ACh-induced relaxation, suggesting the participation of a putative EDHF. In the 21-day DA, the relaxations induced by ACh and sodium nitroprusside (SNP) were markedly reduced and scanning electron microscopy demonstrated an irregular endothelial lining with protrusion and detachment of endothelial cells. The relaxations induced by BAY 41-2272 and 8-Br cGMP were not affected by age. When compared with 5%, lower (0%) and higher (21, 95%) O(2) concentrations impaired ACh-induced relaxation. In summary, we found that ACh induces endothelium-dependent relaxation of the chicken DA and that NO and EDHF are involved in this response. During chicken DA closure, endothelial cells undergo morphologic and functional alterations that result in the lack of endothelium-dependent relaxation.