TRPV4 activates cytosolic phospholipase A 2 via Ca 2+ -dependent PKC/ERK1/2 signalling in controlling hypertensive contraction.

Activation of TRPV4 (transient receptor potential vanilloid 4) has been reported to result in endothelium-dependent contraction in the aortae of hypertensive mice. This contraction involved increased cPLA(2) (cytosolic phospholipase A(2)) activity. The mechanism by which TRPV4 regulates cPLA(2) activity to induce contraction in hypertension, however, is unknown. Through measurements of arterial tension and protein level, we showed that high-salt diet induced hypertension increases activity of PKC (protein kinase C) and ERK1/2 (extracellular signal-regulated kinase 1/2). GSK1016790A, a TRPV4 agonist and ACh (acetylcholine) induced contractions were suppressed by Go6983, a PKC inhibitor and PD98059, an ERK1/2 inhibitor. TRPV4 activation increased activity of PKC and ERK1/2 in endothelial cells from hypertensive mice and this response was suppressed by HC067047, a TRPV4 inhibitor and BAPTA/AM, a Ca2+ chelator. PLA(2) assay and western blotting showed that blocking of PKC or ERK1/2 inhibited TRPV4 or ACh-induced cPLA(2) activity. Enzyme immunoassay showed that GSK1016790A or ACh triggered the release of PGF(2 alpha) (prostaglandin F-2 alpha) was reduced by inhibition of PKC or ERK1/2. These data further suggest Ca2+/PKC/ERK1/2 axis as a novel mechanism for TRPV4 in the activation of cPLA(2) in hypertension.