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RECEPTORS AND SIGNAL TRANSDUCTION

Autocrine effects of IGF-I-induced VEGF and IGFBP-3 secretion in retinal pigment epithelial cell line ARPE-19

Department of Cell and Molecular Pharmacology and Experimental Therapeutics and Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina 29403

Submitted 15 December 2003 ; accepted in final form 5 May 2004

Hypoxia-induced physiological stress plays a central role in various neovascular diseases of the eye. Increased expression of hypoxia-inducible factor 1 (HIF-1) and subsequent formation of HIF-1 dimers active at the vascular endothelial growth factor (VEGF) promoter lead to expression of this potent angiogenic factor in the retina, including retinal pigment epithelial (RPE) cells. We previously demonstrated that insulin-like growth factor I (IGF-I) stimulates VEGF and IGF binding protein (IGFBP)-3 secretion in RPE cells. In this study we examined IGF-I-induced HIF-1 expression, VEGF and IGFBP-3 secretion, and the autocrine actions of VEGF and IGFBP-3 on these processes in the spontaneously transformed RPE cell line ARPE-19. Cells were treated with CoCl₂, IGF-I, recombinant human (rh)IGFBP-3, and rhVEGF. Immunoblot analysis revealed IGF-I-induced upregulation of total HIF-1 protein, whereas luciferase reporter assays of HIF-1 transcriptional activity demonstrated accumulation of HIF-1 correlated with the formation of functional HIF-1 heterodimers. Western and ligand blot analyses of RPE cell conditioned medium confirmed that IGF-I stimulated VEGF and IGFBP-3 secretion. rhVEGF stimulated IGFBP-3 secretion in an IGF-I- and HIF-1-independent manner, whereas rhIGFBP-3 attenuated IGF-I-induced VEGF secretion. These findings demonstrate the multifaceted autocrine regulation of IGF-I-induced VEGF secretion by IGFBP-3 secreted in response to both IGF-I and, to a lesser extent, VEGF. These results provide evidence for HIF-1-dependent and -independent mechanisms by which IGF-I regulates VEGF and IGFBP-3 secretion.

angiogenesis; hypoxia-inducible factor 1; hypoxia; insulin-like growth factor binding protein; vascular endothelial growth factor

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