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This Article Full Text Full Text (PDF) All Versions of this Article: 297/3/H1096    most recent 00241.2009v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Earley, S. Articles by Brayden, J. E. PubMed PubMed Citation Articles by Earley, S. Articles by Brayden, J. E.

TRPV4-dependent dilation of peripheral resistance arteries influences arterial pressure

¹Department of Pharmacology, University of Vermont College of Medicine, Burlington, Vermont; ²Vascular Physiology Research Group, Department of Biomedical Sciences, Colorado State University, Fort Collins, Colorado; and ³Center for Translational Neuroscience, Duke University Medical Center, Durham, North Carolina

Submitted 10 March 2009 ; accepted in final form 16 July 2009

Transient receptor potential vanilloid 4 (TRPV4) channels have been implicated as mediators of calcium influx in both endothelial and vascular smooth muscle cells and are potentially important modulators of vascular tone. However, very little is known about the functional roles of TRPV4 in the resistance vasculature or how these channels influence hemodynamic properties. In the present study, we examined arterial vasomotor activity in vitro and recorded blood pressure dynamics in vivo using TRPV4 knockout (KO) mice. Acetylcholine-induced hyperpolarization and vasodilation were reduced by 75% in mesenteric resistance arteries from TRPV4 KO versus wild-type (WT) mice. Furthermore, 11,12-epoxyeicosatrienoic acid (EET), a putative endothelium-derived hyperpolarizing factor, activated a TRPV4-like cation current and hyperpolarized the membrane of vascular smooth muscle cells, resulting in the dilation of mesenteric arteries from WT mice. In contrast, 11,12-EET had no effect on membrane potential, diameter, or ionic currents in the mesenteric arteries from TRPV4 KO mice. A disruption of the endothelium reduced 11,12-EET-induced hyperpolarization and vasodilatation by 50%. A similar inhibition of these responses was observed following the block of endothelial (small and intermediate conductance) or smooth muscle (large conductance) K⁺ channels, suggesting a link between 11,12-EET activity, TRPV4, and K⁺ channels in endothelial and smooth muscle cells. Finally, we found that hypertension induced by the inhibition of nitric oxide synthase was greater in TRPV4 KO compared with WT mice. These results support the conclusion that both endothelial and smooth muscle TRPV4 channels are critically involved in the vasodilation of mesenteric arteries in response to endothelial-derived factors and suggest that in vivo this mechanism opposes the effects of hypertensive stimuli.

calcium-activated potassium channels; endothelium; vascular smooth muscle; blood pressure; epoxyeicosatrienoic acid; transient receptor potential vanilloid 4