In vitro effects of dexamethasone on hypoxia-induced hyperpermeability andexpression of vascular endothelial growth factor

Clinically, dexamethasone is known to reduce cerebral edema. To further inv estigate the mechanism of this neuroprotection, an in vitro model of brain- derived microvessel endothelial cells (BME cells) was used to investigate t he effect of dexamethasone on hypoxia-induced hyperpermeability. Furthermor e, the expression of vascular endothelial growth factor (VEGF), which is kn own to be the mediator of hypoxia-induced hyperpermeability, was evaluated. Dexamethasone (40 mug/ml = 100 muM) decreased hypoxia-induced permeability and VEGF expression significantly during time periods of more than 3 h. Th e time dependence of the dexamethasone effect correlated with a changed mec hanism by which hypoxia induced VEGF expression. This was deduced because h ypoxia-induced hyperpermeability and VEGF mRNA level were decreased in the presence of an antisense oligonucleotide coding for a region which binds a mRNA stabilizing protein, but only up to 3 h of hypoxia. Furthermore, durin g this time period the half-life of VEGF mRNA was increased. Results sugges t that dexamethasone: only decreases transcriptional-induced VEGF expressio n and that this may be related to the efficacy of dexamethasone to treat br ain edema. (C) 2001 Elsevier Science B.V. All rights reserved.