Circulation Research. 2005
Published online before print September 22, 2005, doi: 10.1161/01.RES.0000187474.47805.30
Published online before print September 22, 2005, doi: 10.1161/01.RES.0000187474.47805.30
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Submitted on June 8, 2005
Revised on September 7, 2005
Accepted on September 12, 2005
Modulation of the Ca2+ Permeable Cation Channel TRPV4 by Cytochrome P450 Epoxygenases in Vascular Endothelium
J. Vriens ;
From the Department of Physiology (J.V., G.O., A.J., T.V., B.N.), Campus Gasthuisberg, KU Leuven, Belgium; Institut für Kardiovaskuläre Physiologie (B.F., I.F., R.B.), Johann Wolfgang Goethe-Universität Theodor-Stern Kai 7, Frankfurt am Main, Germany; Department of Entomology and UC Davis Cancer Center (C.M., B.D.H.), University of California, Davis; and Jichi Medical School (M.S.) Yakushiji, Kawachi, Tochigi, Japan.
* To whom correspondence should be addressed. E-mail: bernd.nilius{at}med.kuleuven.ac.be.
TRPV4 is a broadly expressed Ca2+-permeable cation channel in the vanilloid subfamily of transient receptor potential channels. TRPV4 gates in response to a large variety of stimuli, including cell swelling, warm temperatures, the synthetic phorbol ester 4
-phorbol 12,13-didecanoate (4-PDD), and the endogenous lipid arachidonic acid (AA). Activation by cell swelling and AA requires cytochrome P450 (CYP) epoxygenase activity to convert AA to epoxyeicosatrienoic acids (EETs) such as 5,6-EET, 8,9-EET, which both act as direct TRPV4 agonists. To evaluate the role of TRPV4 and its modulation by the CYP pathway in vascular endothelial cells, we performed Ca2+ imaging and patch-clamp measurements on mouse aortic endothelial cells (MAECs) isolated from wild-type and TRPV4-/- mice. All TRPV4-activating stimuli induced robust Ca2+ responses in wild-type MAECs but not in MAECs isolated from TRPV4-/- mice. Upregulation of CYP2C expression by preincubation with nifedipine enhanced the responses to AA and cell swelling in wild-type MAECs, whereas responses to other stimuli remained unaffected. Conversely, inhibition of CYP2C9 activity with sulfaphenazole abolished the responses to AA and hypotonic solution (HTS). Moreover, suppression of EET hydrolysis using 1-adamantyl-3-cyclo-hexylurea or indomethacin, inhibitors of soluble epoxide hydrolases (sEHs), and cyclooxygenases, respectively, enhanced the TRPV4-dependent responses to AA, HTS, and EETs but not those to 4-PDD or heat. Together, our data establish that CYP-derived EETs modulate the activity of TRPV4 channels in endothelial cells and shows the unraveling of novel modulatory pathways via CYP2C modulation and sEH inhibition.
Key words: TRP channels • endothelium • epoxygenases • epoxide hydrolases
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