Differential downregulation of vascular endothelial growth factor by dexamethasone in normoxic and hypoxic rat glioma cells

Vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) is a mitogen and chemotactic factor for endothelial cells in vitro and an a ngiogenesis and vascular permeability factor in vivo. Due to its properties , VEGF is a candidate for both angiogenesis and vascular permeability/oedem a induction which typically occur in glioblastomas. In this study we test t he hypothesis that the antioedema effect of dexamethasone is mediated by do wnregulation of VEGF or VEGF receptor expression. VEGF mRNA and protein lev els of two rat glioma cells lines, C6 and GS-9L, were determined after incu bation with dexamethasone under normoxic and hypoxic conditions. In normoxi c C6 and GS9L cells, we observed 50-60% downregulation of VEGF mRNA by dexa methasone (P = 0.015 and P = 0.01, respectively). This effect was dependent on glucocorticoid-receptor (GR) function. The inhibitory effect of dexamet hasone on VEGF gene expression by tumour cells was markedly reduced by hypo xia which suggests that the upregulation of VEGF driven by hypoxia overcome s the effect of the dexamethasone, Dexamethasone did not. alter VEGFR-2 mRN A levels in human umbilical endothelial cells. In a subcutaneous glioma tum our model, we observed only a 15% decrease in VEGF mRNA expression in dexam ethasone treated animals (n = 12) compared with controls animals (P = 0.24) . We conclude that dexamethasone may decrease brain tumour-associated oedem a by reduction of VEGF expression in tumour cells. However, the highly redu ced activity on hypoxic tumour cells suggests that dexamethasone efficacy m ay be limited by hypoxia in rapidly growing tumours.