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D Watanabe, H Takagi, K Suzuma, I Suzuma, H Oh, H Ohashi, T Ojima, E Suganami, Y Sato, Y Honda; Vascular Endothelial Growth Factor and Hypoxia Stimulate Ets-1 Expression in Bovine Retinal Microvascular Endothelial Cells . Invest. Ophthalmol. Vis. Sci. 2002;43(13):2737.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose:Ets-1, a prototype of Ets family of transcriptional factors, has been reported to regulate angiogenesis in endothelial cells. We investigated the regulation of Ets-1 by vascular endothelial growth factor (VEGF) and hypoxia in bovine retinal microvascular endothelial cells in culture and in vivo model of ischemia-induced retinal neovasclarization. Methods:Cultured bovine retinal capillary endothelial cells were exposed to human recombinant VEGF under normoxic (95% air, 5% CO2) conditions to assess the effect of VEGF. Hypoxia studies were performed under lower oxygen concentration (0.5%-1.5% 02) induced by nitrogen replacement in constant 5% CO2 conditions. Ets-1 mRNA and protein expression were assessed by northern and western blot analysis. Seven-day-old C57BL/6J mice were exposed to 75% oxygen for 5 days and then returned to room air at postnatal 12 day to produce ischemia-induced retinal neovascularization. Ets-1 mRNA obtained from retina was assessed by northern blot analysis. Results:VEGF increased Ets-1 mRNA levels in a time-dependent manner, reaching a maximum after 4 hours (2.5±0.5-fold, p<0.05). Ets-1 mRNA was up-regulated in a dose-dependent manner at concentrations as low as 0.25 ng/ml. Maximal increases was observed at concentrations of 25ng/ml (2.5±0.1-fold, p<0.0001). Similarly, hypoxia stimulated gene expression of Ets-1 after 24 hours (2.6±0.5-fold, p<0.0001), which was reversed by anti-VEGF neutralizing antibody. VEGF stimulated Ets-1 protein expression after 6 and 12 hours. In a mouse model of ischemia-induced neovasucularization, Ets-1 mRNA was up-regulated from postnatal 15 day to 23 day. Conclusion:These data suggest that Ets-1 upregulation is involved in the development of retinal neovascularization in ischemic retinal diseases.
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