Cardiovascular Research Advance Access first published online on August 5, 2008
This version [Corrected Proof] published online on August 27, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn207
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Role of cytochrome P450-dependent transient receptor potential V4 activation in flow-induced vasodilatation
1 Vascular Signalling Group, Institut für Kardiovaskuläre Physiologie, Goethe-Universität, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany
2 Department of Molecular Cell Biology, Division of Physiology, Laboratory of Ion Channel Research, Katholieke Universiteit Leuven, Leuven, Belgium
* Corresponding author. Tel: +49 69 6301 6972; fax: +49 69 6301 7668.E-mail address: fleming{at}em.uni-frankfurt.de
Aims: Fluid shear stress elicits endothelium-dependent vasodilatation via nitric oxide and prostacyclin-dependent and -independent mechanisms. The latter includes the opening of Ca2+-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 Ca2+ 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
-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.
KEYWORDS Cytochrome P450 epoxygenase; Transient receptor potential channel V4; Fluid shear stress; Mechanotransduction; Endothelium
Time for primary review: 38 days
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