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

• Published in: The Journal of clinical investigation 2003-06, Vol.111 (12), p.1835-1842
• Main Authors: Kondo, Tatsuya, Vicent, David, Suzuma, Kiyoshi, Yanagisawa, Masashi, King, George L, Holzenberger, Martin, Kahn, C Ronald
• Format: Article
• Language: English
• Subjects: Angiogenesis; Animals; Biomedical research; Cell growth; Diabetes; Diabetic retinopathy; Diabetic Retinopathy - etiology; Diabetic Retinopathy - pathology; Diabetic Retinopathy - physiopathology; Diabetic Retinopathy - prevention & control; Disease Models, Animal; Endothelial Growth Factors - physiology; Endothelin-1 - physiology; Endothelium; Endothelium, Vascular - pathology; Endothelium, Vascular - physiopathology; Humans; Hypoxia; Hypoxia - pathology; Hypoxia - physiopathology; Insulin; Insulin - physiology; Insulin-like growth factors; 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
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/jci200317455

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.