VEGF-induced BBB permeability is associated with an MMP-9 activity increase in cerebral ischemia: Both effects decreased by Ang-1

Samuel Valable, Joan Montaner, Anita Bellail, Vincent Berezowski, Julien Brillault, Romeo Cecchelli, Didier Divoux, Eric T. MacKenzie, Myriam Bernaudin, Simon Roussel, Edwige Petit

Research output: Contribution to journalArticle

149 Scopus citations

Abstract

After cerebral ischemia, angiogenesis, by supplying for the deficient perfusion, may be a beneficial process for limiting neuronal death and promoting tissue repair. In this study, we showed that the combination of Ang-1 and vascular endothelial growth factor (VEGF) provides a more adapted therapeutic strategy than the use of VEGF alone. Indeed, we showed on a focal ischemia model that an early administration of VEGF exacerbates ischemic damage, because of its effects on blood-brain barrier (BBB) permeability. In contrast, a coapplication of Ang-1 and VEGF leads to a significant reduction of the ischemic and edema volumes by 50% and 42%, respectively, in comparison with VEGF-treated mice. We proposed that Ang-1 blocks the BBB permeability effect of VEGF in association with a modulation of matrix metalloproteinase (MMP) activity. Indeed, we showed on both ischemic in vivo and BBB in vitro models that VEGF enhances BBB damage and MMP-9 activity and that Ang-1 counteracts both effects. However, we also showed a synergic angiogenic effect of Ang-1 and VEGF in the brain. Taken together, these results allow to propose that, in cerebral ischemia, the combination of Ang-1 and VEGF could be used early to promote the formation of mature neovessels without inducing side effects on BBB permeability.

Original languageEnglish (US)
Pages (from-to)1491-1504
Number of pages14
JournalJournal of Cerebral Blood Flow and Metabolism
Volume25
Issue number11
DOIs
StatePublished - Nov 2005
Externally publishedYes

Keywords

  • Ang-1
  • BBB
  • Cerebral ischemia
  • MMP-9
  • VEGF

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine

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    Valable, S., Montaner, J., Bellail, A., Berezowski, V., Brillault, J., Cecchelli, R., Divoux, D., MacKenzie, E. T., Bernaudin, M., Roussel, S., & Petit, E. (2005). VEGF-induced BBB permeability is associated with an MMP-9 activity increase in cerebral ischemia: Both effects decreased by Ang-1. Journal of Cerebral Blood Flow and Metabolism, 25(11), 1491-1504. https://doi.org/10.1038/sj.jcbfm.9600148