Transcription factor Ets-1 mediates ischemia- and vascular endothelial growth factor-dependent retinal neovascularization.
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.
Watanabe
Daisuke
D
Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Takagi
Hitoshi
H
Suzuma
Kiyoshi
K
Suzuma
Izumi
I
Oh
Hideyasu
H
Ohashi
Hirokazu
H
Kemmochi
Seiji
S
Uemura
Akiyoshi
A
Ojima
Tomonari
T
Suganami
Eri
E
Miyamoto
Noriko
N
Sato
Yasufumi
Y
Honda
Yoshihito
Y
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*
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