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(Circulation Research. 2009;105:657.)
© 2009 American Heart Association, Inc.

Cellular Biology

Prostaglandin E₂ Primes the Angiogenic Switch via a Synergic Interaction With the Fibroblast Growth Factor-2 Pathway

Federica Finetti^*, Sandra Donnini^*, Antonio Giachetti, Lucia Morbidelli, Marina Ziche

From the Department of Molecular Biology, University of Siena; and Istituto Toscano Tumori, Italy.

Correspondence to Marina Ziche, Department of Molecular Biology, University of Siena, Via Aldo Moro, 2, 53100, Siena, Italy. E-mail ziche{at}unisi.it

Rationale: Prostaglandin (PG)E₂ exerts temporally distinct actions on blood vessels, immediate vasodilatation, and long-term activation of angiogenesis.

Objective: To study the mechanism of PGE₂ induction of angiogenesis, we characterized its effect on fibroblast growth factor (FGF)-2 signaling in cultured endothelial cells and in ex vivo and in vivo assays of blood vessel formation.

Methods and Results: Using Western blotting assay, we demonstrated that PGE₂ induced upregulation of components of the FGF-2 pathway: FGF-2 protein, phosphorylation of FGF receptor type 1 (FGFR1), activation of FRS2 (FGFR substrate 2), phospholipase C, endothelial nitric oxide synthase, extracellular signal-regulated kinase 1/2, and the transcription factor STAT-3. Synergism between PGE₂ and FGF-2 promoted endothelial cell proliferation and robust angiogenesis in vivo, in rabbit cornea and Matrigel assays. The magnitude of the angiogenic response to PGE₂ was directly related to FGF-2 availability which determined the extent of FGFR1 activation. In fact, PGE₂ induction of angiogenesis in vitro was impaired in FGF-2^–/– endothelial cells and FGFR1 blockade abrogated PGE₂ action on the endothelium, preventing the activation of FGF-2 signaling.

Conclusion: We propose a model for the angiogenic switch based on the autocrine/paracrine FGF-2/FGFR1 activation by PGE₂ and FGF-2 synergistic interaction. The synergism between the PGE₂ and FGF-2 signaling pathways here described may explain the mechanism of action of drug combinations, the most notable being cyclooxygenase inhibitors with growth factors or growth factor receptor inhibitors.

Key Words: prostaglandin E₂ • angiogenesis • fibroblast growth factor-2 • fibroblast growth factor receptor type1 • inflammation