Journal
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM
Volume 25, Issue 11, Pages 1491-1504Publisher
SAGE PUBLICATIONS INC
DOI: 10.1038/sj.jcbfm.9600148
Keywords
Ang-1; BBB; cerebral ischemia; MMP-9; VEGF
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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 bloodbrain 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 131313 permeability effect of VEGF in association with a modulation of matrix metal loproteinase (MMP) activity. Indeed, we showed on both ischemic in vivo and 131313 in vitro models that VEGF enhances 131313 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.
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