Regulation of vascular endothelial growth factor expression by insulin-like growth factor I

Diabetes. 1997 Oct;46(10):1619-26. doi: 10.2337/diacare.46.10.1619.


Insulin-like growth factor I (IGF-I) and vascular endothelial growth factor (VEGF) levels are correlated with retinal ischemia-associated intraocular neovascularization in humans. Since VEGF is required for iris and retinal neovascularization in animal models of retinal ischemia, we tested whether IGF-I could act as an indirect angiogenic factor by increasing VEGF gene expression. IGF-I increased retinal pigment epithelial (RPE) cell VEGF mRNA in a concentration-dependent manner with an EC50 of 7 nmol/1 (53.6 ng/ml). RPE and bovine smooth muscle cells exposed to 50 nmol/l (383 ng/m1) IGF-I achieved peak VEGF mRNA expression within 2 h. IGF-I-treated RPE cells increased VEGF protein levels in conditioned media and stimulated capillary endothelial cell proliferation. Blockade of the IGF-I receptor with a neutralizing antibody abrogated the VEGF increases in RPE cells. Further, hypoxia-mediated and IGF-I-mediated increases in VEGF mRNA and protein levels were additive in RPE cells, and the hypoxia-induced VEGF increases were independent of endogenous IGF-I. VEGF promoter activity was enhanced by IGF-I in RPE cells, but VEGF transcript half-life was unaltered. In summary, the supplementation of RPE and smooth muscle cell cultures with IGF-I at 5-100 nmol/l increased VEGF mRNA and secreted protein levels. The VEGF increases in RPE cells occurred primarily through enhanced transcription of the VEGF gene and via the IGF-I receptor. Elevated IGF-I levels may promote neovascularization through increased retinal VEGF gene expression.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antibodies / pharmacology
  • Blotting, Northern
  • Capillaries
  • Cell Division
  • Cell Hypoxia
  • Cell Line, Transformed
  • Culture Media, Conditioned
  • Endothelial Growth Factors / biosynthesis
  • Endothelial Growth Factors / genetics*
  • Endothelium, Vascular / cytology
  • Gene Expression Regulation*
  • Humans
  • Insulin-Like Growth Factor I / pharmacology*
  • Kinetics
  • Lymphokines / biosynthesis
  • Lymphokines / genetics*
  • Mice
  • Pigment Epithelium of Eye / metabolism
  • Promoter Regions, Genetic
  • RNA, Messenger / metabolism
  • Receptor, IGF Type 1 / antagonists & inhibitors
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors


  • Antibodies
  • Culture Media, Conditioned
  • Endothelial Growth Factors
  • Lymphokines
  • RNA, Messenger
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • Insulin-Like Growth Factor I
  • Receptor, IGF Type 1