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(American Journal of Pathology. 2004;164:1827-1835.)
© 2004 American Society for Investigative Pathology

Transcription Factor Ets-1 Mediates Ischemia- and Vascular Endothelial Growth Factor-Dependent Retinal Neovascularization

Daisuke Watanabe^*, Hitoshi Takagi^*, Kiyoshi Suzuma^*, Izumi Suzuma^*, Hideyasu Oh^*, Hirokazu Ohashi^*, Seiji Kemmochi^*, Akiyoshi Uemura^*, Tomonari Ojima^*, Eri Suganami^*, Noriko Miyamoto^*, Yasufumi Sato and Yoshihito Honda^*

From the Department of Ophthalmology and Visual Sciences,^* Kyoto University Graduate School of Medicine, Kyoto; and the Department of Vascular Biology, Institute of Development, Aging, and Cancer, Tohoku University, Sendai, Japan

Transcription factor Ets-1 has been reported to regulate angiogenesis in vascular endothelial cells. Here, we investigated a mechanism that may regulate the expression of Ets-1 in vascular endothelial growth factor (VEGF)- and hypoxia-induced retinal neovascularization and that may have potential to inhibit ocular neovascular diseases. VEGF and hypoxia increased Ets-1 expression in cultured bovine retinal endothelial cells. The VEGF-induced mRNA increase of Ets-1 was suppressed by a tyrosine kinase inhibitor (genistein), by inhibitors of MEK (mitogen-activated protein and extracellular signal-regulated kinase kinase) (PD98059 and UO126), and by inhibitors of protein kinase C (GF109203X, staurosporine, and Gö6976). Dominant-negative Ets-1 inhibited VEGF-induced cell proliferation, tube formation, and the expression of neuropilin-1 and angiopoietin-2. In a mouse model of proliferative retinopathy, Ets-1 mRNA was up-regulated. Intravitreal injection of dominant-negative Ets-1 suppressed retinal angiogenesis in a mouse model of proliferative retinopathy. In conclusion, VEGF induces Ets-1 expression in bovine retinal endothelial cells and its expression is protein kinase C/ERK pathway-dependent. Ets-1 up-regulation is involved in the development of retinal neovascularization, and inhibition of Ets-1 may be beneficial in the treatment of ischemic ocular diseases.

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