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In blood vessels, the endothelium is a crucial signal transduction interface in control of vascular tone and blood pressure to ensure energy and oxygen supply according to the organs' needs. In response to vasoactive factors and to shear stress elicited by blood flow, the endothelium secretes vasodilating or vasocontracting autacoids, which adjust the contractile state of the smooth muscle. In endothelial sensing of shear stress, the osmo- and mechanosensitive Ca(2+)-permeable TRPV4 channel has been proposed to be candidate mechanosensor. Using TRPV4(-/-) mice, we now investigated whether the absence of endothelial TRPV4 alters shear-stress-induced arterial vasodilation. In TRPV4(-/-) mice, loss of the TRPV4 protein was confirmed by Western blot, immunohistochemistry and by in situ-patch-clamp techniques in carotid artery endothelial cells (CAEC). Endothelium-dependent vasodilation was determined by pressure myography in carotid arteries (CA) from TRPV4(-/-) mice and wild-type littermates (WT). In WT CAEC, TRPV4 currents could be elicited by TRPV4 activators 4alpha-phorbol-12,13-didecanoate (4alphaPDD), arachidonic acid (AA), and by hypotonic cell swelling (HTS). In striking contrast, in TRPV4(-/-) mice, 4alphaPDD did not produce currents and currents elicited by AA and HTS were significantly reduced. 4alphaPDD caused a robust and endothelium-dependent vasodilation in WT mice, again conspicuously absent in TRPV4(-/-) mice. Shear stress-induced vasodilation could readily be evoked in WT, but was completely eliminated in TRPV4(-/-) mice. In addition, flow/reperfusion-induced vasodilation was significantly reduced in TRPV4(-/-) vs. WT mice. Vasodilation in response to acetylcholine, vasoconstriction in response to phenylephrine, and passive mechanical compliance did not differ between genotypes, greatly underscoring the specificity of the above trpv4-dependent phenotype for physiologically relevant shear stress. Genetically encoded loss-of-function of trpv4 results in a loss of shear stress-induced vasodilation, a response pattern critically dependent on endothelial TRPV4 expression. Thus, Ca(2+)-influx through endothelial TRPV4 channels is a molecular mechanism contributing significantly to endothelial mechanotransduction.

1 Modulation of Ca2+‐activated K+ channels (KCa) has been implicated in the control of proliferation in vascular smooth muscle cells (VSMC) and other cell types. In the present study, we investigated the underlying signal transduction mechanisms leading to mitogen‐induced alterations in the expression pattern of intermediate‐conductance KCa in VSMC. 2 Regulation of expression of IKCa/rKCa3.1 and BKCa/rKCa1.1 in A7r5 cells, a cell line derived from rat aortic VSMC, was investigated by patch‐clamp technique, quantitative RT–PCR, immunoblotting procedures, and siRNA strategy. 3 PDGF stimulation for 2 and 48 h induced an 11‐ and 3.5‐fold increase in rKCa3.1 transcript levels resulting in a four‐ and seven‐fold increase in IKCa currents after 4 and 48 h, respectively. Upregulation of rKCa3.1 transcript levels and channel function required phosphorylation of extracellular signal‐regulated kinases (ERK1/2) and Ca2+ mobilization, but not activation of p38‐MAP kinase, c‐Jun NH(2)‐terminal kinase, protein kinase C, calcium‐calmodulin kinase II and Src kinases. 4 In contrast to rKCa3.1, mRNA expression and functions of BKCa/rKCa1.1 were decreased by half following mitogenic stimulation. Downregulation of rKCa1.1 did not require ERK1/2 phosphorylation or Ca2+ mobilization. 5 In an in vitro‐proliferation assay, knockdown of rKCa3.1 expression by siRNA completely abolished functional IKCa channels and mitogenesis. 6 Mitogen‐induced upregulation of rKCa3.1 expression is mediated via activation of the Raf/MEK‐ and ERK‐signaling cascade in a Ca2+‐dependent manner. Upregulation of rKCa3.1 promotes VSMC proliferation and may thus represent a pharmacological target in cardiovascular disease states characterized by abnormal cell proliferation. British Journal of Pharmacology (2006) 148, 909–917. doi:10.1038/sj.bjp.0706793