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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on May 8, 2006; DOI: 10.1124/jpet.106.104158

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Mark G Slomiany
Steven A Rosenzweig
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Received for publication March 8, 2006.
Revised April 25, 2006.
Accepted for publication May 4, 2006.

Hypoxia inducible factor-1 (HIF-1) dependent and independent regulation of insulin-like growth factor-1 (IGF-1) stimulated vascular endothelial growth factor (VEGF) secretion

Mark G Slomiany 1 Steven A Rosenzweig 1*

1 Medical University of South Carolina

* Address correspondence to: E-mail: rosenzsa{at}musc.edu

Abstract

Hypoxia-induced stress plays a central role in retinal vascular disease and cancer. Increased hypoxia-inducible factor-1{alpha} (Hif-1{alpha}) expression leads to HIF-1 formation and the production of vascular endothelial growth factor (VEGF). Cytokines, including insulin-like growth factor-1 (IGF-1) also stimulate VEGF secretion. In this study, we examined the relationship between IGF-1-signaling, Hif-1{alpha} protein turnover and VEGF secretion in the ARPE-19 retinal pigment epithelial cell line. Northern analysis revealed that IGF-1 stimulated Hif-1{alpha} message expression, whereas the hypoxia-mimetic CoCl2 did not. CoCl2 treatment increased Hif-1{alpha} 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 PI 3-K/Akt/mTOR dependent, while VEGF secretion was only partially reduced by inhibition of PI 3-K/Akt/mTOR and HIF-1 activities. Analysis of VEGF promoter truncation mutants indicated that sensitivity to CoCl2 was hypoxia response element (HRE) dependent with the region upstream of the HRE conferring IGF-1 sensitivity. In conclusion, IGF-1 regulates VEGF expression and secretion via HIF-1-dependent and -independent pathways.


Key words: HIF-1, IGF-1, IGFBP, VEGF, angiogenesis, choroidal neovascularization




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