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M. L. Clark, Q. Song, J. M. Barnett, J. S. Penn; COX-2 Promotes VEGF-Induced Angiogenesis in Retinal Endothelial Cells. Invest. Ophthalmol. Vis. Sci. 2007;48(13):1722.
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COX-2, through the induction of prostanoid synthesis, has demonstrated angiogenic activity in cancer models and other contexts. The purpose of the present study was to determine the role of COX-2 in modulating VEGF-induced angiogenic behavior in retinal microvascular endothelial cells (RMEC) and to determine the specific prostanoids responsible.
Protein and mRNA were collected from VEGF-treated human RMEC, and COX-2 levels were analyzed by RT-PCR and western blot. Cell lysates and growth medium from VEGF-treated HRMEC were subjected to gas chromatography-mass spectrometry to identify which prostanoids are upregulated by VEGF. HRMEC were transfected with siRNA directed against COX-2 to test for COX-2-dependent VEGF-induced tube formation.
VEGF treatment of HRMEC increased COX-2 mRNA by 23-fold after 0.5 hours and COX-2 protein by 19-fold after 3 hours, while COX-1 mRNA and protein levels remained constant. Prostanoids PGD2, PGE2, PGF2α, and PGI2 from HRMEC lysates and medium were increased between 1.8- and 4.5-fold at 6 hours of VEGF treatment. The VEGF-induced tube formation was abolished in COX-2 knockdown HRMEC.
VEGF upregulates COX-2 in HRMEC, leading to increased production of PGD2, PGE2, PGF2α, and PGI2. COX-2, through the action of one or more of these prostanoids, promotes VEGF-induced tube formation, suggesting that prostanoids and their receptors may constitute therapeutic targets in neovascular eye disease.
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