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D. Watanabe, H. Takagi, K. Suzuma, I. Suzuma, H. Oh, H. Ohashi, S. Kenmochi, A. Uemura, Y. Sato, Y. Honda; Transcription Factor Ets-1 Mediates Ischemia and VEGF-Dependent Retinal Neovascularization . Invest. Ophthalmol. Vis. Sci. 2003;44(13):2268.
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Purpose: Transcription factor Ets-1 has been reported to regulate angiogenesis in vascular endothelial cells. Ets-1 is up-regulated by vascular endothelial growth factor (VEGF) and hypoxia in bovine retinal microvascular endothelial cells (BREC) in culture. In this study, we investigated the effects of Ets-1 on angiogenic activity stimulated by VEGF in BREC. Methods: Cultured bovine retinal capillary endotherial cells were exposed to human recombinant VEGF. To investigate the effects of Ets-1 on angiogenic activity of BREC, we used adenovirus vector encoding dominant negative Ets-1. Effects of Ets-1 on the angiogenesis in vitro was studied by cell growth assay and by tube formation assay. Cell growth assay was performed by measuring DNA concentrations of BREC. Tube formation assay was done by using three dimentional collage gel. The effects of Ets-1 on the expression of neuropilin-1 and angiopoietin-2 that are suggested to regulate angiogenesis, were studied by Northern blot analysis and Western blot analysis after transfection adenovirus encoding dominant negative Ets-1. Results: VEGF-induced DNA synthesis of adenovirus encoding dominant negative Ets-1 transfectants was significantly reduced in comparison with that of control (58% ± 11%, p < 0.001). VEGF induced tube formation at 14.3 ± 0.3mm / field, while treatment with dominant negative Ets-1 transfectants inhibited the VEGF-induced tube formation by 8.3 ± 0.4mm / field compared to VEGF stimulation alone (p < 0.001). Both neuroipilin-1 and angiopoietin-2 expression were decreased by dominant negative ets-1. Conclusions:These data suggest that Ets-1 may play a rule in angiogenesis of bovine retinal endothelial cells, and that Ets-1 may regulate the expression of neuropilin-1 and angiopoietin-2. Inhibition of Ets-1 may be benefical for the prevention of ischemic ocular diseases such as diabetic retinopathy.
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