Endothelium plays an important role in maintaining vascular homeostasis by synthesizing and releasing several relaxing factors, such as prostacyclin, NO, and endothelium-derived hyperpolarizing factor Decitabine cell line (EDHF). Shimokawa et al. demonstrated in animals and humans that endothelium-derived

hydrogen peroxide (H2O2) is an EDHF, and that H2O2 is produced in part by eNOS (50) and (51). Shimokawa et al. subsequently examined the contribution of NOSs to EDHF-mediated responses in the single eNOS null, double n/eNOSs null, and triple n/i/eNOSs null mice (52). EDHF-mediated 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 H2O2 and EDHF-mediated responses were completely absent in the triple NOSs null mice, even after antihypertensive treatment with hydralazine. NOS uncoupling, which is caused by a deficiency of tetrahydrobiopterin, a cofactor of NOS, was not involved, as modulation of tetrahydrobiopterin synthesis had no effect on EDHF-mediated relaxation, and the tetrahydrobiopterin/dihydrobiopterin ratio was comparable in the

mesenteric arteries and the aorta. These results demonstrate that EDHF-mediated responses are totally dependent on the NOSs system in mouse

mesenteric Pfizer Licensed Compound Library arteries. Collectively, this study provides a novel concept on the diverse roles of the endothelial NOSs system mainly contributing to the EDHF/H2O2 responses in small-sized arteries while serving as a NO-generating system in large arteries. The eNOS null and triple NOSs null mice manifested metabolic syndrome-like phenotypes, including hypertension, hypertriglycemia, visceral obesity, impaired glucose tolerance, 3-mercaptopyruvate sulfurtransferase and insulin resistance (33). The extents of hypertension, hypertriglycemia, and visceral obesity were comparable in the two genotypes, whereas the extents of impaired glucose tolerance and insulin resistance were greater in the triple NOSs null than in the eNOS null genotypes, and hyper-low-density-lipoprotein (LDL)-emia was observed only in the triple NOSs null genotype. It is thus possible that NOSs play an important role in the pathogenesis of metabolic syndrome. Adiponectin is an anti-metabolic and anti-atherogenic adipocytokine, improving hypertriglyceridemia, glucose metabolism, and insulin resistance, and inhibiting the progression of arteriosclerosis (53), (54) and (55). The deficiency of adiponectin is thought to contribute to the progression of metabolic syndrome and its vascular complications (54).