Hypothermia abolishes hypoxia-induced hyperpermeability in brain microvessel endothelial cells

The effect of mild (32 degrees C) and deep (22 degrees C) hypothermia on hy poxia-induced hyperpermeability was examined using an in vitro model of bra in derived microvascular endothelial cells (BMEC). It was shown that hypoxi a-induced hyperpermeability to inulin across the BMEC monolayer was complet ely abolished at 32 degrees C and 22 degrees C for up to 24 h of hypoxia. D uring normoxia, no influence of hypothermia on BMEC monolayer permeability was observed. The hypoxia-induced decrease of the cyclic AMP level after 6 h was abolished at 32 degrees C as well as at 22 degrees C of hypoxia. But after 24 h of hypoxia, hypothermia did no longer prevent the hypoxia-induce d decrease of the cAMP level, which suggests that the effect of hypothermia on hypoxia-induced hyperpermeability is not caused by maintenance of the c AMP level. Because vascular endothelial growth factor (VEGF) has been shown to be the mediator of hypoxia-induced permeability changes of BMEC via the release of nitric oxide (NO), the effect of hypothermia on the VEGF expres sion was evaluated. During normoxia, hypothermia did not change the VEGF ex pression significantly but the hypoxia-induced increase in VEGF mRNA and pr otein expression was completely abolished at 32 degrees C and 22 degrees C respectively. Accordingly, the hypoxia-induced increase of the cGMP level w as depressed by hypothermia, which demonstrates that also the amount of NO released during hypoxia is decreased at lower temperatures. Results suggest that deep as well as mild hypothermia decreased hypoxia-induced hyperperme ability by lowering the expression of the permeability-increasing protein V EGF and with it the release of NO. (C) 1999 Elsevier Science B.V. All right s reserved.