Prostaglandin E(2) primes the angiogenic switch via a synergic interaction with the fibroblast growth factor-2 pathway

RATIONALE: Prostaglandin (PG)E(2) exerts temporally distinct actions on blood vessels, immediate vasodilatation, and long-term activation of angiogenesis. OBJECTIVE: To study the mechanism of PGE(2) 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 PGE(2) induced upregulation of components of the FGF-2 pathway: FGF-2 protein, phosphorylation of FGF receptor type 1 (FGFR1), activation of FRS2alpha (FGFR substrate 2alpha), phospholipase Cgamma, endothelial nitric oxide synthase, extracellular signal-regulated kinase 1/2, and the transcription factor STAT-3. Synergism between PGE(2) 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 PGE(2) was directly related to FGF-2 availability which determined the extent of FGFR1 activation. In fact, PGE(2) induction of angiogenesis in vitro was impaired in FGF-2(-/-) endothelial cells and FGFR1 blockade abrogated PGE(2) 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 PGE(2) and FGF-2 synergistic interaction. The synergism between the PGE(2) 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.