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


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.


CONCLUSIONS
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.
Finetti
Federica
F
Department of Molecular Biology, University of Siena, and Istituto Toscano Tumori, Italy.
Donnini
Sandra
S
Giachetti
Antonio
A
Morbidelli
Lucia
L
Ziche
Marina
M
D000818:Animals; D002417:Cattle; D049109:Cell Proliferation; D002478:Cells, Cultured; D016510:Corneal Neovascularization / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism*; D042783:Endothelial Cells / Q000201:enzymology / Q000378:metabolism*; D016222:Fibroblast Growth Factor 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D018919:Neovascularization, Physiologic; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D051966:Phospholipase C gamma / Q000378:metabolism; D010766:Phosphorylation; D034622:RNA Interference; D011817:Rabbits; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D040521:Subcutaneous Tissue / Q000098:blood supply; D013997:Time Factors; D014162:Transfection
C488187:FRS2alpha protein, mouse; D008565:Membrane Proteins; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D016222:Fibroblast Growth Factor 2; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; C496349:Fgfr1 protein, mouse; D051496:Receptor, Fibroblast Growth Factor, Type 1; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D051966:Phospholipase C gamma; D015232:Dinoprostone