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Transient receptor potential vanilloid type 4-deficient mice exhibit impaired endothelium-dependent relaxation induced by acetylcholine in vitro and in vivo. Hypertension 2009 Mar;53(3):532-8

Date

02/04/2009

Pubmed ID

19188524

Pubmed Central ID

PMC2694062

DOI

10.1161/HYPERTENSIONAHA.108.127100

Scopus ID

2-s2.0-61749092039   129 Citations

Abstract

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 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.

Author List

Zhang DX, Mendoza SA, Bubolz AH, Mizuno A, Ge ZD, Li R, Warltier DC, Suzuki M, Gutterman DD

Authors

David D. Gutterman MD Sr Associate Director, Professor in the Medicine department at Medical College of Wisconsin
David X. Zhang MD, PhD Associate Professor in the Medicine department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Acetylcholine
Animals
Blood Pressure
Calcium Signaling
Carotid Arteries
Disease Models, Animal
Endothelium, Vascular
Enzyme Inhibitors
Hypertension
Male
Mesenteric Arteries
Mice
Mice, Knockout
NG-Nitroarginine Methyl Ester
Nitric Oxide
RNA, Messenger
TRPV Cation Channels
Vasodilation
Vasodilator Agents
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