Disruption of Physiological Balance Between Nitric Oxide and Endothelium-Dependent Hyperpolarization Impairs Cardiovascular Homeostasis in Mice

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 36; no. 1; pp. 97 - 107
• Main Authors: Godo, Shigeo, Sawada, Ayuko, Saito, Hiroki, Ikeda, Shohei, Enkhjargal, Budbazar, Suzuki, Kota, Tanaka, Shuhei, Shimokawa, Hiroaki
• Format: Journal Article
• Language: English
• Published: United States American Heart Association, Inc 01-01-2016
• Subjects: Animals; Biological Factors - metabolism; Cardiomegaly - enzymology; Cardiomegaly - genetics; Cardiomegaly - pathology; Caveolin 1 - deficiency; Caveolin 1 - genetics; Cell Hypoxia; Coronary Circulation; Dose-Response Relationship, Drug; Endothelium, Vascular - drug effects; Endothelium, Vascular - enzymology; Endothelium, Vascular - physiopathology; Enzyme Inhibitors - pharmacology; Genotype; Homeostasis; Hypotension - enzymology; Hypotension - genetics; Hypotension - physiopathology; Isolated Heart Preparation; Male; Membrane Potentials; Mice, Inbred C57BL; Mice, Knockout; Microcirculation; Myocardium - metabolism; Nitric Oxide - metabolism; Nitric Oxide Synthase Type III - antagonists & inhibitors; Nitric Oxide Synthase Type III - biosynthesis; Nitric Oxide Synthase Type III - genetics; Phenotype; Signal Transduction; Systole; Time Factors; Up-Regulation; Vasodilation - drug effects; Vasodilator Agents - pharmacology; Ventricular Dysfunction, Left - enzymology; Ventricular Dysfunction, Left - genetics; Ventricular Dysfunction, Left - physiopathology; Ventricular Function, Left; caveolin-1; endothelium; endothelium-dependent hyperpolarization factor; nitric oxide
• ISSN: 1079-5642; 1524-4636
• DOI: 10.1161/ATVBAHA.115.306499

OBJECTIVE—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 recently demonstrated that endothelial NO synthase (eNOS) is functionally suppressed in resistance vessels through caveolin-1 (Cav-1)-dependent mechanism, switching its function from NO to EDH/hydrogen peroxide generation in mice. Here, we examined the possible importance of the physiological balance between NO and EDH in cardiovascular homeostasis.
APPROACH AND RESULTS—We used 2 genotypes of mice in which eNOS activity is genetically upregulated; Cav-1-knockout (Cav-1-KO) and endothelium-specific eNOS transgenic (eNOS-Tg) mice. Isometric tension recordings and Langendorff experiments with isolated perfused hearts showed that NO-mediated relaxations were significantly enhanced, whereas EDH-mediated relaxations were markedly reduced in microcirculations. Importantly, impaired EDH-mediated relaxations of small mesenteric arteries from Cav-1-KO mice were completely rescued by crossing the mice with those with endothelium-specific overexpression of Cav-1. Furthermore, both genotypes showed altered cardiovascular phenotypes, including cardiac hypertrophy in Cav-1-KO mice and hypotension in eNOS-Tg mice. Finally, we examined cardiac responses to chronic pressure overload by transverse aortic constriction in vivo. When compared with wild-type mice, both Cav-1-KO and eNOS-Tg mice exhibited reduced survival after transverse aortic constriction associated with accelerated left ventricular systolic dysfunction, 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.