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(Hypertension. 2009;53:532.)
© 2009 American Heart Association, Inc.

Original Articles

Transient Receptor Potential Vanilloid Type 4–Deficient Mice Exhibit Impaired Endothelium-Dependent Relaxation Induced by Acetylcholine In Vitro and In Vivo

David X. Zhang; Suelhem A. Mendoza; Aaron H. Bubolz; Atsuko Mizuno; Zhi-Dong Ge; Rongshan Li; David C. Warltier; Makoto Suzuki; David D. Gutterman

From the Department of Medicine (D.X.Z., S.A.M., A.H.B., D.D.G.), Cardiovascular Center (D.X.Z., S.A.M., A.H.B., D.C.W., D.D.G.), and Departments of Anesthesiology (Z.-D.G., D.C.W.), and Pathology (R.L.), Medical College of Wisconsin, Milwaukee; Veterans Administration Medical Center (D.D.G.), Milwaukee, Wis; and the Department of Pharmacology (A.M., M.S.), Jichi Medical University, Tochigi, Japan.

Correspondence to David X. Zhang, Department of Medicine, Cardiovascular Center, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226. E-mail xfzhang{at}mcw.edu

Agonist-induced Ca²⁺ entry is important for the synthesis and release of vasoactive factors in endothelial cells. The transient receptor potential vanilloid type 4 (TRPV4) channel, a Ca²⁺-permeant cation channel, is expressed in endothelial cells and involved in the regulation of vascular tone. Here we investigated the role of TRPV4 channels in acetylcholine-induced vasodilation in vitro and in vivo using the TRPV4 knockout mouse model. The expression of TRPV4 mRNA and protein was detected in both conduit and resistance arteries from wild-type mice. In small mesenteric arteries from wild-type mice, the TRPV4 activator 4-phorbol-12,13-didecanoate increased endothelial [Ca²⁺]_i in situ, which was reversed by the TRPV4 blocker ruthenium red. In wild-type animals, acetylcholine dilated small mesenteric arteries that involved both NO and endothelium-derived hyperpolarizing factors. In TRPV4-deficient mice, the NO component of the relaxation was attenuated and the endothelium-derived hyperpolarizing factor component was largely eliminated. Compared with their wild-type littermates, TRPV4-deficient mice demonstrated a blunted endothelial Ca²⁺ response to acetylcholine in mesenteric arteries and reduced NO release in carotid arteries. Acetylcholine (5 mg/kg, IV) decreased blood pressure by 37.0±6.2 mm Hg in wild-type animals but only 16.6±2.7 mm Hg in knockout mice. We conclude that acetylcholine-induced endothelium-dependent vasodilation is reduced both in vitro and in vivo in TRPV4 knockout mice. These findings may provide novel insight into mechanisms of Ca²⁺ entry evoked by chemical agonists in endothelial cells.

Key Words: transient receptor potential • endothelium • endothelium-derived factors • NO • calcium

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