TRPV4 channel mediates flow‐induced dilation in mouse small mesenteric arteries

Abstract

We previously found that TRPV4 channel is an important mediator of flow‐induced, endothelium‐derived hyperpolarizing factor (EDHF)‐mediated dilation in human coronary arterioles. Here we further investigated the role of the mechanosensitive TRPV4 channel in flow‐induced dilation using the TRPV4 knockout (TRPV4−/−) mouse model. Using RT‐PCR and Western blots, TRPV4 mRNA and protein were detected in mesenteric arteries. Small mesenteric arteries from TRPV4−/− mice and their wild‐type (WT) control were constricted with U46619 and subjected to step‐wise increase in luminal flow. Relaxation response to flow was markedly reduced in TRPV4−/− vs. WT mice (maximal relaxations of 32±8% vs. 51±6% respectively; n=7, p<0.05). Ruthenium red, a TRPV4 blocker, inhibited flow‐induced dilation in mesenteric arteries from WT mice (maximal relaxation of 11±8%; n=5, P<0.05) but not in TRPV4−/− mice (maximal relaxation of 26±10%, n=3). Papaverine‐induced relaxations were similar between WT and TRPV4−/− mice. In WT mice, flow‐induced dilation was inhibited by the NO synthase inhibitor L‐NAME (maximal relaxation of 25±7%; n=7, P<0.05). We conclude that TRPV4 channel is involved in flow‐induced, endothelium‐dependent (possibly NO‐mediated) vasodilation of murine small mesenteric arteries. TRPV4 channel may represent a mechanical‐chemical signal transduction mechanism linking shear and vasomotor response.