TRPV4 activates cytosolic phospholipase A₂ via Ca²⁺‐dependent PKC/ERK1/2 signalling in controlling hypertensive contraction

Abstract

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 (cytosolic phospholipase A ) activity. The mechanism by which TRPV4 regulates cPLA 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 Ca chelator. PLA assay and western blotting showed that blocking of PKC or ERK1/2 inhibited TRPV4 or ACh-induced cPLA activity. Enzyme immunoassay showed that GSK1016790A or ACh triggered the release of PGF (prostaglandin F ) was reduced by inhibition of PKC or ERK1/2. These data further suggest Ca /PKC/ERK1/2 axis as a novel mechanism for TRPV4 in the activation of cPLA in hypertension.

The Role of TRPV4 Cation Channels in Smooth Muscle Contractile Activity in Rats

“…Prostaglandin F2α (PGF2α) is the endothelium-derived contracting factor (EDCFs) induced by TRPV4 activation [32]. It was also shown that GSK1016790A or acetylcholine triggered the release of PGF2α (prostaglandin F2α) that was reduced by inhibition of PKC or ERK1/2 [33].…”

TRPV4: A trigger of pathological RhoA activation in neurological disease

“…Activation of TRPV4 by various stimuli leads to opening of the channel pore and influx of extracellular cations, particularly calcium, which initiate diverse downstream intracellular signaling cascades. [ 21 ] For example, TRPV4-mediated calcium influx been shown to affect signaling via ATP/pannexin, [ 22 , 23 ] nitric oxide, [ 24 , 25 ] phospholipase A2, [ 26 ] ERK1/2, [ 27 ] CaMKII, [ 28 , 29 ] and IP3, [ 30 , 31 ] among many others. [ 26 ] Notably, many of these signaling cascades converge on pathways that regulate cytoskeletal remodeling machinery.…”

“…[ 21 ] For example, TRPV4-mediated calcium influx been shown to affect signaling via ATP/pannexin, [ 22 , 23 ] nitric oxide, [ 24 , 25 ] phospholipase A2, [ 26 ] ERK1/2, [ 27 ] CaMKII, [ 28 , 29 ] and IP3, [ 30 , 31 ] among many others. [ 26 ] Notably, many of these signaling cascades converge on pathways that regulate cytoskeletal remodeling machinery. For example, in trabecular meshwork cells of the eye, stretch-induced TRPV4 activation leads to phosphorylation of focal adhesion kinases and cytoskeletal stress fiber formation.…”

Osmotic Adaptation by Na+-Dependent Transporters and ACE2: Correlation with Hemostatic Crisis in COVID-19

“…Epithelial or endothelial cells express AQP1 and AQP5 (reviewed in [35]). PKC [36] can activate AQP1, whereas a transient receptor potential vanilloid 4 (TRPV4)-triggered [37] mechanism has been proposed for AQP5-mediated water flux reducing lung edema, potentially via PKC activation [38]. Ang II/AT1R mobilizes ENaC for Na + influx and its transit through the cell with the help of Na + /K + ATPase (detailed in Figure 4).…”