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

J Cereb Blood Flow Metab. 2005 Nov;25(11):1491-504. doi: 10.1038/sj.jcbfm.9600148.


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.

MeSH terms

  • Angiopoietin-1 / administration & dosage*
  • Animals
  • Blood-Brain Barrier / metabolism*
  • Blood-Brain Barrier / pathology
  • Brain Ischemia / metabolism*
  • Brain Ischemia / pathology
  • Cell Death / drug effects
  • Drug Synergism
  • Humans
  • Matrix Metalloproteinase 9 / metabolism*
  • Mice
  • Neovascularization, Pathologic / metabolism
  • Neovascularization, Pathologic / pathology
  • Nerve Regeneration / drug effects
  • Neurons / metabolism
  • Neurons / pathology
  • Permeability / drug effects
  • Vascular Endothelial Growth Factor A / administration & dosage*


  • Angiopoietin-1
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • Matrix Metalloproteinase 9