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lüll Transient receptor potential vanilloid type 4-deficient mice exhibit impaired endothelium-dependent relaxation induced by acetylcholine in vitro and in vivo Zhang DX; Mendoza SA; Bubolz AH; Mizuno A; Ge ZD; Li R; Warltier DC; Suzuki M; Gutterman DDHypertension 2009[Mar]; 53 (3): 532-8Agonist-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 4alpha-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.|Acetylcholine/*pharmacology[MESH]|Animals[MESH]|Blood Pressure/drug effects[MESH]|Calcium Signaling/drug effects[MESH]|Carotid Arteries/drug effects/metabolism[MESH]|Disease Models, Animal[MESH]|Endothelium, Vascular/drug effects/*metabolism[MESH]|Enzyme Inhibitors/pharmacology[MESH]|Hypertension/metabolism[MESH]|Male[MESH]|Mesenteric Arteries/drug effects/metabolism[MESH]|Mice[MESH]|Mice, Knockout[MESH]|NG-Nitroarginine Methyl Ester/pharmacology[MESH]|Nitric Oxide/metabolism[MESH]|RNA, Messenger/metabolism[MESH]|TRPV Cation Channels/genetics/*metabolism[MESH]|Vasodilation/*drug effects[MESH]|Vasodilator Agents/*pharmacology[MESH] |