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Cardiovascular Research Advance Access [Accepted Manuscript] published online on August 5, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn207
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

Role of cytochrome P450-dependent TRPV4 activation in flow-induced vasodilatation

Annemarieke E. Loota, Rüdiger Poppa, Beate Fisslthalera, Joris Vriensb, Bernd Niliusb and Ingrid Fleminga,*

a Vascular Signalling Group, Institut für Kardiovaskuläre Physiologie, Goethe-Universität, Frankfurt, Germany
b Department of Physiology, Katholieke Universiteit Leuven, Leuven, Belgium

* Author for correspondence: Ingrid Fleming PhD Vascular Signalling Group Institut für Kardiovaskuläre Physiologie Goethe-Universität Theodor-Stern-Kai 7 D-60590 Frankfurt am Main Germany Tel: (+)49 69 6301 6972 Fax: (+)49 69 6301 7668 E-mail: fleming{at}em.uni-frankfurt.de

Aims: Fluid shear stress elicits endothelium-dependent vasodilatation via nitric oxide and prostacyclin-dependent, as well as -independent mechanisms. The latter include the opening of Ca2+-operated potassium (KCa) 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 hyperpolarization factor (EDHF).

Methods and Results: In the presence of L-NAME 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 with 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.

Conclusions: We conclude that the TRPV4 channel is involved in flow-induced, endothelium-dependent vasodilatation of murine carotid arteries. Moreover, activation of the TRPV4 channel by flow requires an active CYP epoxygenase and the translocation of the channel to the cell membrane.

Time for primary review: 38 days


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