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lüll Role of cytochrome P450-dependent transient receptor potential V4 activation in flow-induced vasodilatation Loot AE; Popp R; Fisslthaler B; Vriens J; Nilius B; Fleming ICardiovasc Res 2008[Dec]; 80 (3): 445-52AIMS: Fluid shear stress elicits endothelium-dependent vasodilatation via nitric oxide and prostacyclin-dependent and -independent mechanisms. The latter includes the opening of Ca(2+)-operated potassium channels by cytochrome P450 (CYP) epoxygenase-derived epoxyeicosatrienoic acids (EETs) leading to endothelial hyperpolarization. We previously reported that EETs activate the transient receptor potential (TRP) V4 channel in vascular endothelial cells and that Ca(2+) influx in these cells in response to mechanical stimuli is dependent on the activation of CYP epoxygenases. We therefore hypothesized that the TRPV4 channel is involved in the flow-induced vasodilatation attributed to the endothelium-derived hyperpolarizing factor (EDHF). METHODS AND RESULTS: In the presence of N(omega)-nitro-l-arginine methyl ester and diclofenac, precontracted mouse carotid arteries displayed a considerable vasodilatation in response to step-wise increases in luminal flow. The EDHF-mediated, flow-induced vasodilatation could be inhibited by the epoxygenase inhibitor MS-PPOH, was abolished after down-regulation of CYP epoxygenases in tissue culture, and could be restored by viral expression of CYP2C9 in the endothelium. The TRPV4-channel inhibitor ruthenium red (RuR) inhibited the EDHF-mediated flow response, but the combination of MS-PPOH and RuR had no further effect. RuR also inhibited the response in CYP2C9-overexpressing vessels. Moreover, TRPV4-deficient mice demonstrated a blunted EDHF-mediated response to increases in luminal flow in comparison to their wild-type littermates, and the addition of MS-PPOH was without effect in these mice (up to 38 +/- 3% in TRPV4(-/-) vs. 57 +/- 6% in TRPV4(+/+), P < 0.01). In cultured human endothelial cells, exposure to fluid shear stress induced the translocation of the TRPV4 channel from a perinuclear localization to the cell membrane. CONCLUSION: We conclude that the TRPV4 channel is involved in flow-induced, endothelium-dependent vasodilatation of murine carotid arteries. Moreover, the activation of the TRPV4 channel by flow requires an active CYP epoxygenase and the translocation of the channel to the cell membrane.|8,11,14-Eicosatrienoic Acid/analogs & derivatives/metabolism[MESH]|Animals[MESH]|Biological Factors/metabolism[MESH]|Carotid Arteries/*physiology[MESH]|Cell Membrane/metabolism[MESH]|Cell Nucleus/metabolism[MESH]|Cells, Cultured[MESH]|Cytochrome P-450 Enzyme System/*physiology[MESH]|Endothelium, Vascular/cytology/metabolism[MESH]|Epoprostenol/metabolism[MESH]|Humans[MESH]|Male[MESH]|Mice[MESH]|Mice, Inbred C57BL[MESH]|Mice, Knockout[MESH]|Nitric Oxide/metabolism[MESH]|Regional Blood Flow/*physiology[MESH]|TRPV Cation Channels/genetics/*physiology[MESH]|Vasodilation/*physiology[MESH] |