Regulation of vascular endothelial growth factor-dependent retinal neovascularization by insulin-like growth factor-1 receptor

Nat Med. 1999 Dec;5(12):1390-5. doi: 10.1038/70963.

Abstract

Although insulin-like growth factor 1 (IGF-1) has been associated with retinopathy, proof of a direct relationship has been lacking. Here we show that an IGF-1 receptor antagonist suppresses retinal neovascularization in vivo, and infer that interactions between IGF-1 and the IGF-1 receptor are necessary for induction of maximal neovascularization by vascular endothelial growth factor (VEGF). IGF-1 receptor regulation of VEGF action is mediated at least in part through control of VEGF activation of p44/42 mitogen-activated protein kinase, establishing a hierarchical relationship between IGF-1 and VEGF receptors. These findings establish an essential role for IGF-1 in angiogenesis and demonstrate a new target for control of retinopathy. They also explain why diabetic retinopathy initially increases with the onset of insulin treatment. IGF-1 levels, low in untreated diabetes, rise with insulin therapy, permitting VEGF-induced retinopathy.

Publication types

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

MeSH terms

  • Animals
  • Endothelial Growth Factors / physiology*
  • Growth Inhibitors / pharmacology
  • Humans
  • Insulin / pharmacology
  • Insulin-Like Growth Factor I / analogs & derivatives
  • Insulin-Like Growth Factor I / pharmacology
  • Ischemia / etiology
  • Ischemia / physiopathology
  • Ischemia / prevention & control
  • Lymphokines / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Neovascularization, Pathologic / etiology
  • Neovascularization, Pathologic / physiopathology*
  • Neovascularization, Pathologic / prevention & control
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Receptor Protein-Tyrosine Kinases / physiology
  • Receptor, IGF Type 1 / antagonists & inhibitors
  • Receptor, IGF Type 1 / physiology*
  • Receptors, Growth Factor / physiology
  • Receptors, Vascular Endothelial Growth Factor
  • Retinal Vessels / drug effects
  • Retinal Vessels / physiology*
  • Signal Transduction
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors

Substances

  • Endothelial Growth Factors
  • Growth Inhibitors
  • Insulin
  • Lymphokines
  • Receptors, Growth Factor
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • insulin-like growth factor-1 D peptide
  • Insulin-Like Growth Factor I
  • Protein-Tyrosine Kinases
  • Receptor Protein-Tyrosine Kinases
  • Receptor, IGF Type 1
  • Receptors, Vascular Endothelial Growth Factor