UP-REGULATION OF VASCULAR ENDOTHELIAL GROWTH-FACTOR IN RESPONSE TO GLUCOSE DEPRIVATION

Vascular endothelial growth factor (VEGF), also known as a vascular pe rmeability factor (VPF), is an endothelial specific mitogen and is a p otent inducer of angiogenesis. Recently it has been reported that hypo xia induces VEGF mRNA expression in various cells. Since both oxygen a nd glucose are required for efficient production of energy, we examine d the effect of glucose deprivation on VEGF mRNA expression and VEGF p rotein production in U-937 (a human monocytic cell line) cells. Both t he mRNA expression and secretion of VEGF increased after exposure to l ow glucose. Addition of L-glucose, the L-stereoisomer of D-glucose, di d not prevent the up-regulation of VEGF expression. The conditioned me dium from glucose-deprived cells, followed by supplementation with glu cose, did not up-regulate VEGF mRNA expression in U-937 cells. The low glucose-induced VEGF mRNA expression returned to the control level af ter supplementation with D-glucose. Furthermore, oligomycin, a mitocho ndrial ATP synthase inhibitor, increased VEGF protein production. The results suggest that the up-regulation of VEGF mRNA in U-937 cells in response to glucose deprivation is not mediated by autocrine factors f rom the cells nor is the osmotic change of the medium mediated by the deficiency of glucose metabolism in the cells. Our results also sugges t that the intracellular ATP depletion due to glucose deprivation may be one of the causes for increased VEGF mRNA expression. We speculate that local hypoglycemia may act as an essential trigger for angiogenes is through the VEGF gene expression. ((C) Elsevier, Paris).