Abstract 14092: Physiological Balance Between Nitric Oxide and Endothelium-dependent Hyperpolarization Plays Important Roles in Microvascular Homeostasis in Mice
Introduction: Endothelium-derived nitric oxide (NO) and endothelium-dependent hyperpolarization (EDH) play important roles in modulating vascular tone in a distinct vessel-size-dependent manner; NO plays a dominant role in conduit arteries and EDH in resistance vessels. We have previously demonstrated that caveolin-1 (Cav-1), a negative regulator of endothelial NO synthase (eNOS), switches eNOS function from NO production to EDH/H2O2 generation in resistance vessels in mice. In the present study, we examined the possible importance of the physiological balance between NO and EDH in microvascular homeostasis.
Methods and Results: We employed Cav-1-knockout (Cav-1-KO) and endothelium-specific eNOS transgenic (eNOS-Tg) mice, both of which have genetically up-regulated eNOS activity in the whole vasculature. Isometric tension recordings and Langendorff experiments with isolated perfused hearts showed that in both Cav-1-KO and eNOS-Tg mice, NO-mediated relaxations were significantly enhanced as expected, whereas EDH-mediated relaxations were markedly reduced in microcirculations. Pretreatment of the aorta and mesenteric arteries from these mice with a soluble guanylate cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), increased the sensitivity to exogenous hydrogen peroxide-induced relaxations only in the vascular beds where NO-mediated responses were dominant. Importantly, impaired EDH-mediated relaxations of small mesenteric arteries from Cav-1-KO mice were completely rescued by the re-expression of Cav-1 in the endothelium, indicating the primary role of endothelial Cav-1. Finally, in order to examine the impacts of the imbalance in NO and EDH in vivo, we performed transverse aortic constriction (TAC). As compared with wild-type mice, both Cav-1-KO and eNOS-Tg mice exhibited reduced survival after TAC associated with, reduced coronary flow reserve and enhanced myocardial hypoxia.
Conclusions: These results indicate that excessive endothelium-derived NO with reduced EDH impairs cardiovascular homeostasis in mice in vivo, suggesting that maintaining EDH-mediated relaxations in microcirculation could be a novel therapeutic target for cardiovascular diseases.
Author Disclosures: S. Godo: None. S. Tanaka: None. A. Ito: None. Y. Ikumi: None. H. Shimokawa: Speakers Bureau; Modest; Daiichi-Sankyo, Bayer Yakuhin.
- © 2016 by American Heart Association, Inc.