Modulation of the Ca2+ permeable cation channel TRPV4 by cytochrome P450 epoxygenases in vascular endothelium

J. Vriens, G. Owsianik, B. Fisslthaler, M. Suzuki, A. Janssens, T. Voets, C. Morisseau, B. D. Hammock, I. Fleming, R. Busse, B. Nilius

Research output: Contribution to journalArticle

267 Citations (Scopus)

Abstract

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 4α-phorbol 12,13-didecanoate (4α-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 hypotonie 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 4α-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.

Original languageEnglish (US)
Pages (from-to)908-915
Number of pages8
JournalCirculation Research
Volume97
Issue number9
DOIs
StatePublished - Oct 28 2005

Fingerprint

Vascular Endothelium
Arachidonic Acid
Cytochrome P-450 Enzyme System
Cations
Endothelial Cells
Sulfaphenazole
Transient Receptor Potential Channels
Epoxide Hydrolases
Phorbol Esters
Nifedipine
Prostaglandin-Endoperoxide Synthases
Indomethacin
Hydrolysis
Up-Regulation
Hot Temperature
Lipids
Temperature
Acids

Keywords

  • Endothelium
  • Epoxide hydrolases
  • Epoxygenases
  • TRP channels

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Vriens, J., Owsianik, G., Fisslthaler, B., Suzuki, M., Janssens, A., Voets, T., ... Nilius, B. (2005). Modulation of the Ca2+ permeable cation channel TRPV4 by cytochrome P450 epoxygenases in vascular endothelium. Circulation Research, 97(9), 908-915. https://doi.org/10.1161/01.RES.0000187474.47805.30

Modulation of the Ca2+ permeable cation channel TRPV4 by cytochrome P450 epoxygenases in vascular endothelium. / Vriens, J.; Owsianik, G.; Fisslthaler, B.; Suzuki, M.; Janssens, A.; Voets, T.; Morisseau, C.; Hammock, B. D.; Fleming, I.; Busse, R.; Nilius, B.

In: Circulation Research, Vol. 97, No. 9, 28.10.2005, p. 908-915.

Research output: Contribution to journalArticle

Vriens, J, Owsianik, G, Fisslthaler, B, Suzuki, M, Janssens, A, Voets, T, Morisseau, C, Hammock, BD, Fleming, I, Busse, R & Nilius, B 2005, 'Modulation of the Ca2+ permeable cation channel TRPV4 by cytochrome P450 epoxygenases in vascular endothelium', Circulation Research, vol. 97, no. 9, pp. 908-915. https://doi.org/10.1161/01.RES.0000187474.47805.30
Vriens, J. ; Owsianik, G. ; Fisslthaler, B. ; Suzuki, M. ; Janssens, A. ; Voets, T. ; Morisseau, C. ; Hammock, B. D. ; Fleming, I. ; Busse, R. ; Nilius, B. / Modulation of the Ca2+ permeable cation channel TRPV4 by cytochrome P450 epoxygenases in vascular endothelium. In: Circulation Research. 2005 ; Vol. 97, No. 9. pp. 908-915.
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abstract = "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 4α-phorbol 12,13-didecanoate (4α-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 hypotonie 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 4α-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.",
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AU - Owsianik, G.

AU - Fisslthaler, B.

AU - Suzuki, M.

AU - Janssens, A.

AU - Voets, T.

AU - Morisseau, C.

AU - Hammock, B. D.

AU - Fleming, I.

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