Knockout of insulin and IGF-1 receptors on vascular endothelial cells protects against retinal neovascularization

J Clin Invest. 2003 Jun;111(12):1835-42. doi: 10.1172/JCI17455.

Abstract

Both insulin and IGF-1 have been implicated in control of retinal endothelial cell growth, neovascularization, and diabetic retinopathy. To precisely define the role of insulin and IGF-1 signaling in endothelium in these processes, we have used the oxygen-induced retinopathy model to study mice with a vascular endothelial cell-specific knockout of the insulin receptor (VENIRKO) or IGF-1 receptor (VENIFARKO). Following relative hypoxia, VENIRKO mice show a 57% decrease in retinal neovascularization as compared with controls. This is associated with a blunted rise in VEGF, eNOS, and endothelin-1. By contrast, VENIFARKO mice show only a 34% reduction in neovascularization and a very modest reduction in mediator generation. These data indicate that both insulin and IGF-1 signaling in endothelium play a role in retinal neovascularization through the expression of vascular mediators, with the effect of insulin being most important in this process.

Publication types

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

MeSH terms

  • Animals
  • Diabetic Retinopathy / etiology
  • Diabetic Retinopathy / pathology
  • Diabetic Retinopathy / physiopathology
  • Diabetic Retinopathy / prevention & control*
  • Disease Models, Animal
  • Endothelial Growth Factors / physiology
  • Endothelin-1 / physiology
  • Endothelium, Vascular / pathology
  • Endothelium, Vascular / physiopathology
  • Humans
  • Hypoxia / pathology
  • Hypoxia / physiopathology
  • Insulin / physiology
  • Intercellular Signaling Peptides and Proteins / physiology
  • Lymphokines / physiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred DBA
  • Mice, Knockout
  • Neovascularization, Pathologic*
  • Nitric Oxide Synthase / physiology
  • Nitric Oxide Synthase Type II
  • Nitric Oxide Synthase Type III
  • Receptor, IGF Type 1 / deficiency*
  • Receptor, IGF Type 1 / genetics
  • Receptor, IGF Type 1 / physiology
  • Receptor, Insulin / deficiency*
  • Receptor, Insulin / genetics
  • Receptor, Insulin / physiology
  • Retinal Vessels / pathology*
  • Signal Transduction
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors

Substances

  • Endothelial Growth Factors
  • Endothelin-1
  • Insulin
  • Intercellular Signaling Peptides and Proteins
  • Lymphokines
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • NOS3 protein, human
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type II
  • Nitric Oxide Synthase Type III
  • Nos3 protein, mouse
  • Receptor, IGF Type 1
  • Receptor, Insulin