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Am J Physiol Cell Physiol 276: C812-C820, 1999;
0363-6143/99 $5.00
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Vol. 276, Issue 4, C812-C820, April 1999

Hypoxia induces permeability in brain microvessel endothelial cells via VEGF and NO

Silvia Fischer1, Matthias Clauss2, Marion Wiesnet3, Dieter Renz1, Wolfgang Schaper3, and Gerhard F. Karliczek1

Departments of 1 Anesthesiology and Intensive Care, 2 Molecular Cell Biology, and 3 Experimental Cardiology, Max Planck Institute for Physiological and Clinical Research, 61231 Bad Nauheim, Germany

In this study, an in vitro model of the blood-brain barrier, consisting of porcine brain-derived microvascular endothelial cells (BMEC), was used to evaluate the mechanism of hypoxia-induced hyperpermeability. We show that hypoxia-induced permeability in BMEC was completely abolished by a neutralizing antibody to vascular endothelial growth factor (VEGF). In contrast, under normoxic conditions, addition of VEGF up to 100 ng/ml did not alter monolayer barrier function. Treatment with either hypoxia or VEGF under normoxic conditions induced a twofold increase in VEGF binding sites and VEGF receptor 1 (Flt-1) mRNA expression in BMEC. Hypoxia-induced permeability also was prevented by the nitric oxide (NO) synthase inhibitor NG-monomethyl-L-arginine, suggesting that NO is involved in hypoxia-induced permeability changes, which was confirmed by measurements of the cGMP level. During normoxia, treatment with VEGF (5 ng/ml) increased permeability as well as cGMP content in the presence of several antioxidants. These results suggest that hypoxia-induced permeability in vitro is mediated by the VEGF/VEGF receptor system in an autocrine manner and is essentially dependent on reducing conditions stabilizing the second messenger NO as the mediator of changes in barrier function of BMEC.

blood-brain barrier; endothelial barrier function; hyperpermeability; nitric oxide; vascular endothelial growth factor


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