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 reti nopathy, 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 nece ssary for induction of maximal neovascularization by vascular endothelial g rowth factor (VEGF). IGF-1 receptor regulation of VEGF action is mediated a t least in part through control of VEGF activation of p44/42 mitogen- activ ated protein kinase, establishing a hierarchical relationship between IGF-1 and VECF receptors. These findings establish an essential role for IGF-1 i n angiogenesis and demonstrate a new target for control of retinopathy. The y also explain why diabetic retinopathy initially increases with the onset of insulin treatment. IGF-1 levels, low in untreated diabetes, rise with in sulin therapy, permitting VEGF-induced retinopathy.