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J. Biol. Chem., Vol. 282, Issue 23, 16959-16968, June 8, 2007
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Prostaglandin E2-EP4 Receptor Promotes Endothelial Cell Migration via ERK Activation and Angiogenesis in Vivo*
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From the
Departments of Medicine (Division of Nephrology), Cancer Biology, and ¶Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee 37232 and the ||Department of Medicine, Veterans Affairs Hospital, Nashville, Tennessee 37232
Prostaglandin E2 (PGE2), a major product of cyclooxygenase, exerts its functions by binding to four G protein-coupled receptors (EP1–4) and has been implicated in modulating angiogenesis. The present study examined the role of the EP4 receptor in regulating endothelial cell proliferation, migration, and tubulogenesis. Primary pulmonary microvascular endothelial cells were isolated from EP4flox/flox mice and were rendered null for the EP4 receptor with adenoCre virus. Whereas treatment with PGE2 or the EP4 selective agonists PGE1-OH and ONO-AE1–329 induced migration, tubulogenesis, ERK activation and cAMP production in control adenovirus-transduced endothelial EP4flox/flox cells, no effects were seen in adenoCre-transduced EP4flox/flox cells. The EP4 agonist-induced endothelial cell migration was inhibited by ERK, but not PKA inhibitors, defining a functional link between PGE2-induced endothelial cell migration and EP4-mediated ERK signaling. Finally, PGE2, as well as PGE1-OH and ONO-AE1–329, also promoted angiogenesis in an in vivo sponge assay providing evidence that the EP4 receptor mediates de novo vascularization in vivo.
Received for publication, February 8, 2007 , and in revised form, March 30, 2007.
* This work was supported by National Institutes of Health Grants RO1-DK074359 (to A. P.) and RO1-DK74116 (to M. D. B.), by an American Heart Beginning grant-in-aid (to R. R.), by National Institutes of Health Grant RO1-DK 69921 (to R. Z.), and by a Merit award from the Department of Veterans Affairs (to R. Z.). 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.
1 To whom correspondence should be addressed: Dept. of Medicine, Division of Nephrology, Medical Center North, B3109, Vanderbilt University, Nashville, TN 37232. Tel.: 615-322-4637; Fax: 615-322-4690; E-mail: ambra.pozzi{at}vanderbilt.edu.
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