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This Article Full Text Full Text (PDF) All Versions of this Article: 297/1/C207    most recent 00579.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Lee, S. H. Articles by Han, H. J. PubMed PubMed Citation Articles by Lee, S. H. Articles by Han, H. J.

GROWTH, DIFFERENTIATION, AND APOPTOSIS

Arachidonic acid potentiates hypoxia-induced VEGF expression in mouse embryonic stem cells: involvement of Notch, Wnt, and HIF-1

Department of Veterinary Physiology, Biotherapy Human Resources Center (BK 21), College of Veterinary Medicine, Chonnam National University, Gwangju, Korea

Submitted 12 November 2008 ; accepted in final form 31 March 2009

Recent investigations suggest that hypoxia increases the release of fatty acids, which participate in the regulation of cytokine synthesis and cell growth. Therefore, in this study, we examined the effect of arachidonic acid (AA) on hypoxia-induced vascular endothelial growth factor (VEGF) expression and its related signaling pathways in mouse embryonic stem (ES) cells. Hypoxia increased the level of [³H]AA release and VEGF expression. AA treatment concurrent with hypoxia further increased the PGE₂ production and VEGF expression level, which was inhibited by the suppression of cPLA₂ and cyclooxygenase 2 (COX-2) pathways. Hypoxia increased the level of Notch-1 and Wnt-1/β-catenin expression, which was blocked by the inhibition of COX-2, and inhibition of Notch-1 by -secretase inhibitor blocked Wnt-1 activation. Moreover, the hypoxia-induced increase of hypoxia-inducible factor 1 (HIF-1) expression induced Notch-1 activation and was regulated by Wnt-1 activation. The expression of each signaling molecule induced an increase in VEGF expression that was greater in hypoxia with AA than in hypoxia alone. The inhibition of VEGF expression using VEGF-targeted small interfering RNA decreased the hypoxia-induced increase in cell cycle regulatory protein expression, DNA synthesis, and cell number, suggesting that hypoxia-induced VEGF expression stimulates proliferation of mouse ES cells. In conclusion, AA potentiates hypoxia-induced VEGF expression in mouse ES cells through the Notch-1, Wnt-1, and HIF-1 pathways.

hypoxia-inducible factor 1; vascular endothelial growth factor; prostaglandin E₂; cyclooxygenase 2; cell cycle regulatory protein