title: Transcription factor Ets-1 mediates ischemia- and vascular endothelial growth factor-dependent retinal neovascularization.
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.
authors.affiliation: Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Watanabe
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Takagi
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Suzuma
authors.forename: Izumi
authors.initials: I
authors.lastname: Suzuma
authors.forename: Hideyasu
authors.initials: H
authors.lastname: Oh
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Ohashi
authors.forename: Seiji
authors.initials: S
authors.lastname: Kemmochi
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Uemura
authors.forename: Tomonari
authors.initials: T
authors.lastname: Ojima
authors.forename: Eri
authors.initials: E
authors.lastname: Suganami
authors.forename: Noriko
authors.initials: N
authors.lastname: Miyamoto
authors.forename: Yasufumi
authors.initials: Y
authors.lastname: Sato
authors.forename: Yoshihito
authors.initials: Y
authors.lastname: Honda
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D042702:Angiopoietin-2 / Q000096:biosynthesis; D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D002070:Butadienes / Q000494:pharmacology; D002227:Carbazoles / Q000494:pharmacology; D002417:Cattle; D002455:Cell Division; D004247:DNA / Q000737:chemistry; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D005799:Genes, Dominant; D006801:Humans; D000860:Hypoxia; D007211:Indoles / Q000494:pharmacology; D008301:Maleimides / Q000494:pharmacology; D051379:Mice; D008954:Models, Biological; D009389:Neovascularization, Pathologic; D039942:Neuropilin-1 / Q000096:biosynthesis; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation; D050784:Proto-Oncogene Protein c-ets-1; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D050783:Proto-Oncogene Proteins c-ets; D012333:RNA, Messenger / Q000378:metabolism; D015427:Reperfusion Injury; D012160:Retina / Q000473:pathology*; D019311:Staurosporine / Q000494:pharmacology; D013997:Time Factors; D014157:Transcription Factors / Q000502:physiology*; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D042702:Angiopoietin-2; D002070:Butadienes; D002227:Carbazoles; C494041:ETS1 protein, human; D004791:Enzyme Inhibitors; C494042:Ets1 protein, mouse; D005419:Flavonoids; D007211:Indoles; D008301:Maleimides; D009570:Nitriles; D050784:Proto-Oncogene Protein c-ets-1; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D012333:RNA, Messenger; D014157:Transcription Factors; C113580:U 0126; D042461:Vascular Endothelial Growth Factor A; C081021:Go 6976; D039942:Neuropilin-1; D004247:DNA; D019311:Staurosporine; C070515:bisindolylmaleimide I; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one