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

• Published in: Hypertension (Dallas, Tex. 1979) Tex. 1979), 2009-03, Vol.53 (3), p.532-538
• Main Authors: Zhang, David X, Mendoza, Suelhem A, Bubolz, Aaron H, Mizuno, Atsuko, Ge, Zhi-Dong, Li, Rongshan, Warltier, David C, Suzuki, Makoto, Gutterman, David D
• Format: Article
• Language: English
• Subjects: Acetylcholine - pharmacology; Animals; Arterial hypertension. Arterial hypotension; Biological and medical sciences; Blood and lymphatic vessels; Blood Pressure - drug effects; Calcium Signaling - drug effects; Cardiology. Vascular system; Carotid Arteries - drug effects; Carotid Arteries - metabolism; Clinical manifestations. Epidemiology. Investigative techniques. Etiology; Disease Models, Animal; Endothelium, Vascular - drug effects; Endothelium, Vascular - metabolism; Enzyme Inhibitors - pharmacology; Hypertension - metabolism; Male; Medical sciences; Mesenteric Arteries - drug effects; Mesenteric Arteries - metabolism; Mice; Mice, Knockout; NG-Nitroarginine Methyl Ester - pharmacology; Nitric Oxide - metabolism; RNA, Messenger - metabolism; TRPV Cation Channels - genetics; TRPV Cation Channels - metabolism; Vasodilation - drug effects; Vasodilator Agents - pharmacology
• ISSN: 0194-911X; 1524-4563
• DOI: 10.1161/HYPERTENSIONAHA.108.127100

Agonist-induced Ca entry is important for the synthesis and release of vasoactive factors in endothelial cells. The transient receptor potential vanilloid type 4 (TRPV4) channel, a Ca-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 4α-phorbol-12,13-didecanoate increased endothelial [Ca]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 Ca 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 Ca entry evoked by chemical agonists in endothelial cells.