Abstract
Transient receptor potential vallinoid 4 (TRPV‐4), is a Ca2+‐permeant cation channel implicated in endothelial‐dependent vasorelaxation to mechanical stimuli but limited information exists for agonist‐induced responses. We hypothesized that TRPV‐4 is required for agonist‐induced vasodilation by regulating Ca2+ entry. Isometric tension was measured in isolated mesenteric arteries (MA) from wild type (WT) and TRPV‐4 knockout mice using a wire myograph. Dilation to acetylcholine (Ach, 10−9–10−5 M) was diminished in TRPV‐4−/− vs. WT MA (% max relaxation, 44±12 and 86±5, respectively n=4, P<0.05). L‐NAME, blocked Ach relaxation in TRPV‐4−/− and WT MA (11±4 and 35±11, respectively n=4, P<0.05). Responses to papaverine were similar in WT and TRPV‐4−/− MA. Intracellular calcium ([Ca2+]i) was assessed after intraluminal fura‐2 (fluorescence) in MA. Ach (10−5 M) increased endothelial [Ca2+]i in WT and TRPV‐4−/− MA (Δ[Ca2+]i, 49±4.6nM and 26±2.1nM, respectively n=4). The addition of 4α‐PDD, a TRPV4 opener, increased [Ca2+]i in WT but not in TRPV‐4−/− (Δ[Ca2+]i, 164±30nM and 15±1.3nM, respectively n=4). In endothelium of WT MA the increase in [Ca2+] was abolished by the TRPV‐4 blocker ruthenium red (Δ[Ca2+]i, RR, 19±1.2nM n=4). These data suggest an important role for the TRPV‐4 channels in vasodilation to Ach, and regulation of endothelial intracellular Ca2+in mice MA.
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