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

Silvia Fischer, Matthias Clauss, Marion Wiesnet, Dieter Renz, Wolfgang Schafer, Gerhard F. Karliczek

Research output: Contribution to journalArticlepeer-review

165 Scopus citations


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 N(G)-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.

Original languageEnglish (US)
Pages (from-to)C812-C820
JournalAmerican Journal of Physiology - Cell Physiology
Issue number4 45-4
StatePublished - 1999
Externally publishedYes


  • Blood-brain barrier
  • Endothelial barrier function
  • Hyperpermeability
  • Nitric oxide
  • Vascular endothelial growth factor

ASJC Scopus subject areas

  • Physiology
  • Cell Biology

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