REGULATION OF VASCULAR ENDOTHELIAL GROWTH-FACTOR EXPRESSION BY INSULIN-LIKE-GROWTH-FACTOR-I

Insulin-like growth factor I (IGF-I) and vascular endothelial growth f actor (VEGF) levels are correlated with retinal ischemia-associated in traocular neovascularization in humans, Since VEGF is required for iri s and retinal neovascularization in animal models of retinal ischemia, we tested whether IGF-I could act as an indirect angiogenic factor by increasing VEGF gene expression, IGF-I increased retinal pigment epit helial (RPE) cell VEGF mRNA in a concentration-dependent manner with a n EC50 of 7 nmol/l (53.6 ng/ml), RPE and bovine smooth muscle cells ex posed to 50 nmol/l (383 ng/ml) IGF-I achieved peak VEGF mRNA expressio n within 2 h. IGF-I-treated RPE cells increased VEGF protein levels in conditioned media and stimulated capillary endothelial cell prolifera tion, Blockade of the IGF-I receptor with a neutralizing antibody abro gated the VEGF increases in RPE cells, Further, hypoxia-mediated and I GF-I-mediated increases in VEGF mRNA and protein levels were additive in RPE cells, and the hypoxia-induced VEGF increases were independent of endogenous IGF-I. VEGF promoter activity was enhanced by IGF-I in R PE cells, but VEGF transcript half-life was unaltered, In summary, the supplementation of RPE and smooth muscle cell cultures with IGF-I at 5-100 nmol/l increased VEGF mRNA and secreted protein levels, The VEGF increases in RPE cells occurred primarily through enhanced transcript ion of the VEGF gene and via the IGF-I receptor, Elevated IGF-I levels may promote neovascularization through increased retinal VEGF gene ex pression.