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

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 pathwayFGF-2 protein, phosphorylation of FGF receptor type 1 (FGFR1), activation of FRS2α (FGFR substrate 2α), phospholipase Cγ, 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.