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J. Biol. Chem., Vol. 283, Issue 4, 2139-2146, January 25, 2008

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Prostaglandin E₂ Regulates Angiogenesis via Activation of Fibroblast Growth Factor Receptor-1^*

From the Department of Molecular Biology, University of Siena, Via Aldo Moro, 2, 53100 Siena, Italy

Prostaglandin E₂ (PGE₂) behaves as a mitogen in epithelial tumor cells as well as in many other cell types. We investigated the actions of PGE₂ on microvascular endothelial cells (capillary venular endothelial cells) with the purpose of delineating the signaling pathway leading to the acquisition of the angiogenic phenotype and to new vessel formation. PGE₂ (100 nM) produced activation of the fibroblast growth factor receptor 1 (FGFR-1), as measured by its phosphorylation, but not of vascular endothelial growth factor receptor 2. PGE₂ stimulated the EP3 subtype receptor, as deduced by abrogation of EP3 G_i subunit activity through pertussis toxin. Consistent with this result, in human umbilical venular endothelial cells missing the EP3 receptor, PGE₂ did not phosphorylate FGFR-1. Upon binding to its receptor, PGE₂ initiated an autocrine/paracrine signaling cascade involving the intracellular activation of c-Src, activation of matrix metalloproteinase (predominantly MMP2), which in turn caused the mobilization of membrane-anchored fibroblast growth factor-2 (FGF-2). In fact, in cells unable to release FGF-2 the transfection with both FGFR-1 and EP3 did not result in FGFR-1 phosphorylation in response to PGE₂. Relevance for the FGF2-FGFR-1 system was highlighted by confocal analysis, showing receptor internalization after cell exposure to the prostanoid. ERK1/2 appeared to be the distal signal involved, its phosphorylation being sensitive to either cSrc inhibitor or FGFR-1 blocker. Finally, PGE₂ stimulated cell migration and capillary formation in aortic rings, which were severely reduced by inhibitors of signaling molecules or by receptor antagonist. In conclusion, this study provides evidence for the involvement of FGFR-1 through FGF2 in eliciting PGE₂ angiogenic responses. This signaling pattern is similar to the autocrine-paracrine mechanism which operates in endothelial cells to support neovascular growth.

Received for publication, April 12, 2007 , and in revised form, November 26, 2007.

^* This work was supported in part by European Union project EICOSANOX FP6 funding (LSHM-CT-2004-0050333). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1S and 2S.

¹ To whom correspondence should be addressed: Dept. of Molecular Biology, Pharmacology Angiogenesis Laboratory, University of Siena, Via Aldo Moro, 2, 53100, Siena, Italy. Tel.: 39-0577-234439; Fax: 39-0577-234343; E-mail: donnini4{at}unisi.it.

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