Crucial role of nitric oxide synthases system in endothelium-dependent hyperpolarization in mice

Abstract

The endothelium plays an important role in maintaining vascular homeostasis by synthesizing and releasing several relaxing factors, such as prostacyclin, nitric oxide (NO), and endothelium-derived hyperpolarizing factor (EDHF). We have previously demonstrated in animals and humans that endothelium-derived hydrogen peroxide (H 2 O 2 ) is an EDHF that is produced in part by endothelial NO synthase ( eNOS). In this study, we show that genetic disruption of all three NOS isoforms (neuronal [nNOS], inducible [iNOS], and endothelial [eNOS]) abolishes EDHF responses in mice.The contribution of the NOS system to EDHFmediated responses was examined in eNOS ؊ / ؊ , n/eNOS ؊ / ؊ , and n/i/eNOS ؊ / ؊ mice. EDHFmediated relaxation and hyperpolarization in response to acetylcholine of mesenteric arteries were progressively reduced as the number of disrupted NOS genes increased, whereas vascular smooth muscle function was preserved. Loss of eNOS expression alone was compensated for by other NOS genes, and endothelial cell production of H 2 O 2 and EDHF-mediated responses were completely absent in n/i/eNOS ؊ / ؊ mice, even after antihypertensive treatment with hydralazine. NOS uncoupling was not involved, as modulation of tetrahydrobiopterin (BH 4 ) synthesis had no effect on EDHF-mediated relaxation, and the BH 4 /dihydrobiopterin (BH 2 ) ratio was comparable in mesenteric arteries and the aorta. These results provide the fi rst evidence that EDHF-mediated responses are dependent on the NOSs system in mouse mesenteric arteries.

Sex‐Specific Mechanisms of Resistance Vessel Endothelial Dysfunction Induced by Cardiometabolic Risk Factors

“…In addition, many such studies, regardless of sex, measured endothelial responses in the mouse aorta,27, 30 a conduit vessel that is larger and thus easier to study. Resistance vessels differ from conduit vessels, in which NO is the major endothelium‐dependent relaxation factor, and no role has yet been identified for endothelial SK and IK channels 11, 41, 42. Because aortic vasodilation does not contribute substantially to regulation of blood flow or pressure, it can be speculated that conduit vessels have fewer redundant pathways to maintain this function, but further studies are needed to test that hypothesis.…”

The relationships between visit-to-visit blood pressure variability and renal and endothelial function in chronic kidney disease

“…Endothelium-derived NO stimulates guanylyl cyclase (GC) activity, leading to further reduction in vascular tone. 22 It is therefore considered that FMD is mediated by serial interactions between endothelial and smooth muscle cells. In contrast, NMD measures the ability of vascular relaxation following administration of nitroglycerin, which directly reduces smooth muscle tonus via intrinsic GC activation independent of endothelial NO pathways.…”

Reactive oxygen species and vascular biology: implications in human hypertension

“…123 ROS have been implicated in the regulation of vascular tone by modulating vasodilation directly (H 2 O 2 may have vasodilator actions) or indirectly by decreasing nitric oxide bioavailability through quenching by O 2 À to form ONOO À . [124][125][126][127][128] ROS, through the regulation of hypoxia-inducible factor-1, are also important in O 2 sensing, 125 which is essential for maintaining normal O 2 homeostasis. In pathological conditions ROS are involved in inflammation, endothelial dysfunction, cell proliferation, migration and activation, extracellular matrix deposition, fibrosis, angiogenesis and vascular remodeling [129][130][131] ( Figure 3).…”