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

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.

• Authors: Samuel Valable, Joan Montaner, Anita Bellail, Vincent Berezowski, Julien Brillault, Romeo Cecchelli, Didier Divoux, Eric T Mackenzie, Myriam Bernaudin, Simon Roussel, Edwige Petit
• Journal: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism (J Cereb Blood Flow Metab) Vol. 25 Issue 11 Pg. 1491-504 (Nov 2005) ISSN: 0271-678X [Print] United States
• PMID: 15902195 (Publication Type: Journal Article)

Chemical References

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

Topics

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