Regulation of vascular endothelial growth factor-dependent retinal neovascularization by insulin-like growth factor-1 receptor

Abstract

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.

Figure 1: The histological effect of IGF-1R inhibition on ischemia-induced retinal neovascularization.
Figure 2: Antagonism of IGF-1R in vivo inhibits ischemia-induced retinal neovascularization in mice.
Figure 3: Western and northern blot analysis of VEGF and VEGF receptors in retinas from IGF-1R-inhibited mice with induced retinal neovascularization.
Figure 4: IGF-1R antagonism in bovine retinal endothelial cells suppresses subsequent VEGF-activation of the MAP kinase pathway.

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Acknowledgements

We thank R. Sullivan for assistance. This work was supported in part by grants from the V. Kann Rasmussen Foundation and the National Eye Institute (EY08670) to L.E.H.S.

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Correspondence to Lois E. H. Smith.

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Smith, L., Shen, W., Perruzzi, C. et al. Regulation of vascular endothelial growth factor-dependent retinal neovascularization by insulin-like growth factor-1 receptor. Nat Med 5, 1390–1395 (1999). https://doi.org/10.1038/70963

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