TRPV4-dependent dilation of peripheral resistance arteries influences arterial pressure

Abstract

Earley S, Pauyo T, Drapp R, Tavares MJ, Liedtke W, Brayden JE. TRPV4-dependent dilation of peripheral resistance arteries influences arterial pressure. Am J Physiol Heart Circ Physiol 297: H1096 -H1102, 2009. First published July 17, 2009 doi:10.1152/ajpheart.00241.2009.-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 ϳ75% 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 ϳ50%. A similar inhibition of these responses was observed following the block of endothelial (small and intermediate conductance) or smooth muscle (large conductance) K ϩ channels, suggesting a link between 11,12-EET activity, TRPV4, and K ϩ 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 THE VASCULAR ENDOTHELIUM produces a variety of potent vasoactive factors that are critically important for blood flow and blood pressure regulation. Epoxyeicosatrienoic acids (EETs) are produced by cytochrome P-450 epoxygenase enzymes from arachidonic acid and act as an endothelium-derived hyperpolarizing factor (EDHF) in some vascular beds (3, 24). Vasodilation and smooth muscle cell hyperpolarization in response to EETs are associated with the increased activity of large-conductance Ca 2ϩ -activated K ϩ (BK Ca ) channels. The vanilloid transient receptor potential channel TRPV4 can be activated by EETs, suggesting that the channel can also serve as a cell-surface receptor for these compounds. We recently demonstrated that in cerebr...

Local control of TRPV4 channels by AKAP150-targeted PKC in arterial smooth muscle

“…However, whereas Ca V 1.2 channels are the preponderant source of Ca 2+ for contraction, TRPV4 channels have been linked to relaxation (Harder et al, 1987;Fleischmann et al, 1994;Rubart et al, 1996;Jaggar et al, 1998;Earley et al, 2005Earley et al, , 2009Navedo et al, 2005;Amberg et al, 2007). The functional role of TRPV4 and Ca V 1.2 sparklets could be caused by differences in Ca 2+ influx through these channels in arterial myocytes.…”

“…Like Ca V 1.2 channels, TRPV4 channels are highly permeable to Ca 2+ (Liedtke et al, 2000;Strotmann et al, 2000). However, while Ca V 1.2 channels are critical for contraction, TRPV4 channels have been linked to relaxation (Earley et al, 2005(Earley et al, , 2009. According to this model, the endotheliumderived factor 11,12-epoxyeicosatrienoic acid (11,12-EET) activates TRPV4 channels, and the resulting influx of Ca 2+ activates nearby ryanodine receptors (RyRs), which release Ca 2+ from the sarcoplasmic reticulum in the form of a Ca 2+ spark.…”

11,12-Epoxyeicosatrienoic acid induces vasodilator response in the rat perfused mesenteric vasculature

“…On the contrary, 11, 12‐EET did not have any action in the mesenteric arteries from TRPV4 (KO) knockout mice 40. Additional reinforcement for the involvement of TRPV4 channels in the responses to 11, 12‐EET, Earley et al 39. found that RuR completely overturned smooth muscle hyperpolarization induced by 11, 12‐EET in arteries from WT mice.…”

“…It has been reported that in vascular smooth muscle and endothelial cells, TRPV4 channels are involved in mediating the inflow of calcium ions, and therefore, TRPV4 are considered as essential moderators of the tone in the vascular beds 38 . Furthermore, it was shown that 11, 12‐EET activated TRPV4 leading to hyperpolarization of the smooth muscle cells’ membrane, causing vasodilation of mesenteric arteries obtained from WT mice 39. On the contrary, 11, 12‐EET did not have any action in the mesenteric arteries from TRPV4 (KO) knockout mice 40.…”

Imbalance and dysfunction of transient receptor potential channels contribute to the pathogenesis of hypertension

“…In freshly isolated rodent mesenteric arteries, activation of TPRV1 by its agonist capsaicin elicited an acute release of NO from ECs and vasodilatation, which was inhibited by the TRPV1 antagonists and was absent from arteries of TRPV1-deficient mice [26]. TRPV4 channels in the vascular ECs and SMCs are critically involved in the vasodilatation of mesenteric arteries in response to endothelial-derived factors [28]. One study found that the genetically encoded loss-of-function of trpv4 resulted in a loss of shear stress-induced vasodilatation, a response pattern largely dependent on endothelial TRPV4 expression [55].…”