Abstract 12737: Physiological Balance Between Nitric Oxide and Endothelium-Derived Hyperpolarizing Factor Plays a Crucial Role in Cardiovascular Homeostasis
Background: The endothelium modulates vascular tone by synthesizing and releasing endothelium-derived relaxing factors (EDRFs), including prostacyclin, nitric oxide (NO) and endothelium-derived hyperpolarizing factors (EDHFs). The contribution of each EDRF to endothelium-dependent vasodilatation varies depending on the vessel size; conduit arteries are primarily regulated by NO and resistance arteries by EDHFs, regardless of species and blood vessels tested. We have recently demonstrated that caveolin-1 (Cav-1), which functionally inhibits the activity of endothelial NO synthase (eNOS), is substantially involved in the functional inhibition of eNOS in resistance vessels in mice. However, the significance of the physiological balance between NO and EDHF in cardiovascular homeostasis remains to be elucidated.
Methods and Results: We used 3 genotypes of mice including wild-type (WT), Cav-1-knockout (Cav-1-KO) and endothelium-specific eNOS transgenic (eNOS-Tg) mice; in the latter 2 genotypes eNOS activity is genetically up-regulated. Isometric tension experiments showed that in small mesenteric arteries from both Cav-1-KO and eNOS-Tg, NO-mediated relaxations were significantly enhanced, whereas EDHF-mediated responses were markedly reduced (n=7 each). Langendorff experiments also showed that EDHF-mediated coronary flow responses were significantly reduced in both Cav-1-KO and eNOS-Tg (n=6 each). Furthermore, both genotypes showed altered cardiovascular phenotypes, including hypotension in eNOS-Tg and cardiac hypertrophy in Cav-1-KO. Finally, we examined the cardiac responses to chronic pressure overload by transverse aortic constriction (TAC). Both Cav-1-KO and eNOS-Tg showed reduced survival rate after TAC, associated with more progressive left ventricular systolic dysfunction and more reduced coronary flow reserves as compared with WT (n=15 each).
Conclusions: These results indicate that the physiological balance between NO and EDHFs plays a crucial role in cardiovascular homeostasis in mice in vivo.
Author Disclosures: S. Godo: None. H. Saito: None. A. Sawada: None. S. Sato: None. S. Tanaka: None. H. Shimokawa: None.
- © 2014 by American Heart Association, Inc.