title: Disruption of Physiological Balance Between Nitric Oxide and Endothelium-Dependent Hyperpolarization Impairs Cardiovascular Homeostasis in Mice.
abstract: 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.
  
  
  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.
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Shigeo
authors.initials: S
authors.lastname: Godo
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Ayuko
authors.initials: A
authors.lastname: Sawada
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Saito
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Shohei
authors.initials: S
authors.lastname: Ikeda
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Budbazar
authors.initials: B
authors.lastname: Enkhjargal
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Kota
authors.initials: K
authors.lastname: Suzuki
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Shuhei
authors.initials: S
authors.lastname: Tanaka
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan. shimo@cardio.med.tohoku.ac.jp.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Shimokawa
mesh_terms: D000818:Animals; D001685:Biological Factors / Q000378:metabolism*; D006332:Cardiomegaly / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D051242:Caveolin 1 / Q000172:deficiency / Q000235:genetics; D015687:Cell Hypoxia; D003326:Coronary Circulation; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005838:Genotype; D006706:Homeostasis; D007022:Hypotension / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D000067268:Isolated Heart Preparation; D008297:Male; D008564:Membrane Potentials; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008833:Microcirculation; D009206:Myocardium / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D010641:Phenotype; D015398:Signal Transduction; D013599:Systole; D013997:Time Factors; D015854:Up-Regulation; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology; D018487:Ventricular Dysfunction, Left / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D016277:Ventricular Function, Left
chemical_list: D001685:Biological Factors; C495541:Cav1 protein, mouse; D051242:Caveolin 1; D004791:Enzyme Inhibitors; D014665:Vasodilator Agents; C067410:endothelium-dependent hyperpolarization factor; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse
keywords: caveolin-1; endothelium; endothelium-dependent hyperpolarization factor; nitric oxide