TRPV4-dependent dilation of peripheral resistance arteries influences arterial pressure

1 Department of Pharmacology, University of Vermont College of Medicine, Burlington, Vermont; 2 Vascular Physiology Research Group, Department of Biomedical Sciences, Colorado State University, Fort Collins, Colorado; and 3 Center 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 Address for reprint requests and other correspondence: J. E. Brayden,