Hypoglycemia-induced VEGF expression is mediated by intracellular Ca2+ andprotein kinase C signaling pathway in HepG2 human hepatoblastoma cells

Vascular endothelial growth factor (VEGF) is a potent angiogenic factor tha t plays a central role in angiogenesis. In this study, we investigated the mechanism of VEGF expression in HepG2 human hepatoblastoma cells under hypo glycemia. The shortage of glucose significantly enhanced VEGF mRNA expressi on in a time-dependent manner as well as increased DNA-binding activity of AP-1 that plays an important role in VEGF transcription. In addition, treat ment of a potent PKC inhibitor, H-7 in glucose-deprived HepG2 cells suppres sed hypoglycemia-elevated VEGF expression as well as the increased AP-1 DNA -binding activity. Moreover, we observed that Ca2+ levels remarkably increa sed under low glucose condition. Consistently, an intracellular Ca2+ chelat or, BAPTA/AM significantly decreased hypoglycemia-induced VEGF expression a nd AP-1 DNA-binding activity. Therefore, these results indicate that increa se of intracellular Ca2+ lever induces the activation of PKC, which induce the activation of AP-1 leading to the increase of VEGF in glucose-deprived environment. Furthermore, it provides one link in regulation of VEGF with h ypoglycemia as well as information to understand how hypoglycemia induces V EGF expression and subsequently leads to tumor angiogenesis.