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, Yoshihito Honda

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Abstract

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.

Original languageEnglish
Pages (from-to)1827-1835
Number of pages9
JournalAmerican Journal of Pathology
Volume164
Issue number5
DOIs
Publication statusPublished - 2004 May

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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    Watanabe, D., Takagi, H., Suzuma, K., Suzuma, I., Oh, H., Ohashi, H., Kemmochi, S., Uemura, A., Ojima, T., Suganami, E., Miyamoto, N., Sato, Y., & Honda, Y. (2004). Transcription Factor Ets-1 Mediates Ischemia- and Vascular Endothelial Growth Factor-Dependent Retinal Neovascularization. American Journal of Pathology, 164(5), 1827-1835. https://doi.org/10.1016/S0002-9440(10)63741-8