Regulation of vascular endothelial growth factor-dependent retinal neovascularization by insulin-like growth factor-1 receptor.
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.
Smith
L E
LE
Department of Ophthalmology, Harvard Medical School and Children's Hospital, 300 Longwood Avenue, Boston, Massachusetts 02115, USA. smith_lo@a1.tch.harvard.edu
Shen
W
W
Perruzzi
C
C
Soker
S
S
Kinose
F
F
Xu
X
X
Robinson
G
G
Driver
S
S
Bischoff
J
J
Zhang
B
B
Schaeffer
J M
JM
Senger
D R
DR
D000818:Animals; D016228:Endothelial Growth Factors / Q000502:physiology*; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000031:analogs & derivatives / Q000494:pharmacology; D007511:Ischemia / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control; D008222:Lymphokines / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000209:etiology / Q000503:physiopathology* / Q000517:prevention & control; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D020794:Receptor Protein-Tyrosine Kinases / Q000502:physiology; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D017978:Receptors, Growth Factor / Q000502:physiology; D040262:Receptors, Vascular Endothelial Growth Factor; D012171:Retinal Vessels / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D006131:Growth Inhibitors; D007328:Insulin; D008222:Lymphokines; D017978:Receptors, Growth Factor; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C096150:insulin-like growth factor-1 D peptide; D007334:Insulin-Like Growth Factor I; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; D017526:Receptor, IGF Type 1; D040262:Receptors, Vascular Endothelial Growth Factor