Knockout of insulin and IGF-1 receptors on vascular endothelial cells protects against retinal neovascularization.
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.
Kondo
Tatsuya
T
Research Division, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215, USA.
Vicent
David
D
Suzuma
Kiyoshi
K
Yanagisawa
Masashi
M
King
George L
GL
Holzenberger
Martin
M
Kahn
C Ronald
CR
D000818:Animals; D003930:Diabetic Retinopathy / Q000209:etiology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D016228:Endothelial Growth Factors / Q000502:physiology; D019332:Endothelin-1 / Q000502:physiology; D004730:Endothelium, Vascular / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D000860:Hypoxia / Q000473:pathology / Q000503:physiopathology; D007328:Insulin / Q000502:physiology; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology; D008222:Lymphokines / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic; D019001:Nitric Oxide Synthase / Q000502:physiology; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D017526:Receptor, IGF Type 1 / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D011972:Receptor, Insulin / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D012171:Retinal Vessels / Q000473:pathology*; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D019332:Endothelin-1; D007328:Insulin; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin