Transcription factor Ets-1 mediates ischemia- and vascular endothelial growth factor-dependent retinal neovascularization

Am J Pathol. 2004 May;164(5):1827-35. doi: 10.1016/S0002-9440(10)63741-8.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / genetics
  • Angiopoietin-2 / biosynthesis
  • Animals
  • Blotting, Northern
  • Blotting, Western
  • Butadienes / pharmacology
  • Carbazoles / pharmacology
  • Cattle
  • Cell Division
  • DNA / chemistry
  • Disease Models, Animal
  • Enzyme Inhibitors / pharmacology
  • Flavonoids / pharmacology
  • Genes, Dominant
  • Humans
  • Hypoxia
  • Indoles / pharmacology
  • Maleimides / pharmacology
  • Mice
  • Models, Biological
  • Neovascularization, Pathologic*
  • Neuropilin-1 / biosynthesis
  • Nitriles / pharmacology
  • Phosphorylation
  • Proto-Oncogene Protein c-ets-1
  • Proto-Oncogene Proteins / physiology*
  • Proto-Oncogene Proteins c-ets
  • RNA, Messenger / metabolism
  • Reperfusion Injury*
  • Retina / pathology*
  • Staurosporine / pharmacology
  • Time Factors
  • Transcription Factors / physiology*
  • Up-Regulation
  • Vascular Endothelial Growth Factor A / metabolism*


  • Angiopoietin-2
  • Butadienes
  • Carbazoles
  • ETS1 protein, human
  • Enzyme Inhibitors
  • Ets1 protein, mouse
  • Flavonoids
  • Indoles
  • Maleimides
  • Nitriles
  • Proto-Oncogene Protein c-ets-1
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-ets
  • RNA, Messenger
  • Transcription Factors
  • U 0126
  • Vascular Endothelial Growth Factor A
  • Go 6976
  • Neuropilin-1
  • DNA
  • Staurosporine
  • bisindolylmaleimide I
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one