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MR Castro, D Lutz, JL Edelman; Cyclooxygenase-2 (COX-2) Mediates Inflammatory Angiogenesis via Modulation of VEGF Expression but Not Downstream VEGF-Receptor Signaling . Invest. Ophthalmol. Vis. Sci. 2002;43(13):2740.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: Previous studies suggest that vascular endothelial growth factor (VEGF) receptor activation leads to increased cyclooxygenase (COX) activity and subsequent eicosanoid production, extravasation, and angiogenesis. The goals of the current studies were to 1) determine a potential role for COX in two in vivo models of VEGF-mediated ocular angiogenesis, and to 2) determine the position of COX within the VEGF-VEGF receptor signaling cascade. Methods: Non-selective COX inhibitors (indomethacin and/or flunixin) were administered either orally or i.p., and the COX-1 selective SC-560 and COX-2 selective NS-398 were administered either s.c. or i.p. VEGF-induced dermal extravasation was measured in Hartley guinea pigs. Choroidal neovascularization (CNV) was elicited by argon laser photocoagulation in Brown Norway rats and the extent of CNV was measured 10 days after lasering. Corneal neovascularization in Sprague Dawley rats was elicited by alkaline cautery and the extent of angiogenesis was measured 4 days after cautery. Levels of VEGF in the cornea were assayed by ELISA 24 and 48 hrs after cautery. Results: Indomethacin (7.5 or 20 mg/kg) or flunixin (12.5 mg/kg) failed to inhibit VEGF-induced dermal extravasation. Similarly, daily dosing of indomethacin (1 or 3 mg/kg), NS-398 (20 mg/kg), or SC-560 (20 mg/kg) failed to inhibit laser-induced CNV. In contrast, daily dosing with 3.5 mg/kg or 7 mg/kg indomethacin inhibited cautery-induced corneal angiogenesis by 56% and 68%, respectively. Similar inhibition was observed with the COX-2 selective inhibitor NS-398 (10 or 20 mg/kg) but not with the COX-1 selective inhibitor SC-560 (10 or 20 mg/kg). VEGF protein was dramatically upregulated 24 or 48 hrs after cautery, and this upregulation was inhibited by indomethacin or NS-398, but not by SC-560. Conclusion: COX appears to not play a role in downstream VEGF receptor signaling in vivo. Its role in inflammatory angiogenesis may be upstream of VEGF receptor via modulation of VEGF expression.
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