Cytochrome P450 (CYP) epoxygenase-derived epoxyeicosa- trienoic acids (EETs) activate the transient receptor potential (TRP)V4 channel in vascular endothelial cells leading to an influx of Ca2+ that can then induce endothelial hyper-polarization via Ca2+ -activated potassium channels. In vitro studies have also shown activation of TRPV4 in response to mechanical stimuli, such as shear stress. We therefore hypothesized that the TRPV4 channel is involved in the flow-induced vasodilation attributed to the endothelium-derived hyperpolarization factor (EDHF). Mouse carotid arteries constricted with phenylephrine and subjected to step-wise increases in luminal flow displayed a considerable EDHF-dependent, flow-induced vasodilation that could be inhibited by the TRPV4 blocker ruthenium red (RuR). Moreover, TRPV4-deficient mice showed a blunted EDHF-mediated response to increases in luminal flow in comparison to their wild- type littermates. In comparison to arteries infected with a control adenovirus, carotid arteries infected with Ad-CYP2C9 showed an enhanced response to flow that could be blocked with RuR.

We conclude that the TRPV4 channel is involved in flow- induced, endothelium-dependent vasodilatation of murine carotid arteries and that activation of the TRPV4 channel by flow requires production of EETs by CYP.