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

Aya Takaki, Keiko Morikawa, Masato Tsutsui, Yoshinori Murayama, Ender Tekes, Hiroto Yamagishi, Junko Ohashi, Toyotaka Yada, Nobuyuki Yanagihara, Hiroaki Shimokawa

研究成果: Article査読

110 被引用数 (Scopus)


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 (H2O2) 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 EDHF-mediated responses was examined in eNOS-/-, n/eNOS-/-, and n/i/eNOS-/- mice. 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 H 2O2 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 (BH4) synthesis had no effect on EDHF-mediated relaxation, and the BH4/dihydrobiopterin (BH2) ratio was comparable in mesenteric arteries and the aorta. These results provide the first evidence that EDHF-mediated responses are dependent on the NOSs system in mouse mesenteric arteries.

ジャーナルJournal of Experimental Medicine
出版ステータスPublished - 2008 9月 1

ASJC Scopus subject areas

  • 医学(全般)


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