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J. Biol. Chem., Vol. 280, Issue 29, 27138-27146, July 22, 2005

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Characterization of 5,6- and 8,9-Epoxyeicosatrienoic Acids (5,6- and 8,9-EET) as Potent in Vivo Angiogenic Lipids^*

Ambra Pozzi¶||, Ines Macias-Perez, Tristin Abair, Shouzuo Wei, Yan Su, Roy Zent¶**, John R. Falck, and Jorge H. Capdevila

From the Division of Nephrology, Department of Medicine and Departments of Cancer Biology and Biochemistry, Vanderbilt University Medical Center, Nashville, Tennessee 37232, the ^¶Veterans Affairs Hospital, Nashville, Tennessee 37212, and the Departments of Biochemistry and Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75390

The cytochrome P450 arachidonic acid epoxygenase metabolites, the epoxyeicosatrienoic acids (EETs) are powerful, nonregioselective, stimulators of cell proliferation. In this study we compared the ability of the four EETs (5,6-, 8,9-, 11,12-, and 14,15-EETs) to regulate endothelial cell proliferation in vitro and angiogenesis in vivo and determined the molecular mechanism by which EETs control these events. Inhibition of the epoxygenase blocked serum-induced endothelial cell proliferation, and exogenously added EETs rescued cell proliferation from epoxygenase inhibition. Studies with selective ERK, p38 MAPK, or PI3K inhibitors revealed that whereas activation of p38 MAPK is required for the proliferative responses to 8,9- and 11,12-EET, activation of PI3K is necessary for the cell proliferation induced by 5,6- and 14,15-EET. Among the four EETs, only 5,6- and 8,9-EET are capable of promoting endothelial cell migration and the formation of capillary-like structures, events that are dependent on EET-mediated activation of ERK and PI3K. Using subcutaneous sponge models, we showed that 5,6- and 8,9-EET are pro-angiogenic in mice and that their neo-vascularization effects are enhanced by the co-administration of an inhibitor of EET enzymatic hydration, presumably because of reduced EET metabolism and inactivation. These studies identify 5,6- and 8,9-EET as powerful and selective angiogenic lipids, provide a functional link between the EET proliferative chemotactic properties and their angiogenic activity, and suggest a physiological role for them in angiogenesis and de novo vascularization.

Received for publication, February 15, 2005 , and in revised form, April 29, 2005.

^* These studies were supported in part by United States Public Health Service/National Institutes of Health Grants CA94849-01 (to A. P.), GM 37922 (to J. H. C.), DK069921 (to R. Z), GM31278 (to J. R. F.), Robert A. Welch Foundation, and by Vanderbilt University Mass Spectrometry Center, supported in part by Cancer Center Grant CA-68485. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^** Supported by an Advanced Career Development and Merit award from the Veterans Administration, an American Heart Association grant in aid award, and a Clinician Scientist award from NKF.

^|| To whom correspondence should be addressed: Dept. of Medicine, Div. of Nephrology and Hypertension, Vanderbilt University, Medical Center N., B3109, Nashville, TN 37215. Tel.: 615-322-4537; Fax: 615-322-4690; E-mail: ambra.pozzi{at}vanderbilt.edu.

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