Hypoxia-inducible factor-1-dependent and -independent regulation of insulin-like growth factor-1-stimulated vascular endothelial growth factor secretion

J Pharmacol Exp Ther. 2006 Aug;318(2):666-75. doi: 10.1124/jpet.106.104158. Epub 2006 May 8.


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 phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR (mammalian target of rapamycin)-dependent, whereas VEGF secretion was only partially reduced by inhibition of PI3K/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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Anti-Bacterial Agents / pharmacology
  • Cell Line
  • Cobalt / pharmacology
  • Gene Expression Regulation / drug effects
  • Humans
  • Hypoxia / metabolism
  • Hypoxia-Inducible Factor 1 / biosynthesis
  • Hypoxia-Inducible Factor 1 / physiology*
  • Immunoblotting
  • Immunohistochemistry
  • Insulin-Like Growth Factor I / pharmacology*
  • Ligands
  • Phosphatidylinositol 3-Kinases / physiology
  • Promoter Regions, Genetic / genetics
  • RNA, Messenger / biosynthesis
  • Signal Transduction / drug effects
  • Sirolimus / pharmacology
  • Stimulation, Chemical
  • Transfection
  • Vascular Endothelial Growth Factor A / biosynthesis
  • Vascular Endothelial Growth Factor A / genetics
  • Vascular Endothelial Growth Factor A / metabolism*


  • Anti-Bacterial Agents
  • Hypoxia-Inducible Factor 1
  • Ligands
  • RNA, Messenger
  • Vascular Endothelial Growth Factor A
  • Cobalt
  • Insulin-Like Growth Factor I
  • Phosphatidylinositol 3-Kinases
  • cobaltous chloride
  • Sirolimus