Hypoxia-Inducible Factor-1-Dependent and-Independent Regulation of Insulin-Like Growth Factor-1-Stimulated Vascular Endothelial Growth Factor Secretion□S

Hypoxia-induced stress plays a central role in retinal vascular disease and cancer. Increased hypoxia-inducible factor-1 (Hif-1) expression leads to HIF-1 formation and the production of vascular endothelial growth factor (VEGF). Cytokines, includ-ing insulin-like growth factor-1 (IGF-1), also stimulate VEGF secretion. In this study, we examined the relationship between IGF-1 signaling, HIF-1 protein turnover and VEGF secretion in the ARPE-19 retinal pigment epithelial cell line. Northern anal-ysis revealed that IGF-1 stimulated Hif-1message expression, whereas the hypoxia-mimetic CoCl2 did not. CoCl2 treatment increased Hif-1 protein accumulation to a greater extent than IGF-1 treatment. However, IGF-1 stimulated a more significant increase in VEGF secretion. IGF-1-stimulated VEGF promoter activity was phosphatidylinositol 3-kinase (PI3K)/Akt/mTO