title: 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.affiliation: UMR-CNRS 6185, Centre Cyceron, University of Caen, Caen, France.
authors.forename: Samuel
authors.initials: S
authors.lastname: Valable
authors.forename: Joan
authors.initials: J
authors.lastname: Montaner
authors.forename: Anita
authors.initials: A
authors.lastname: Bellail
authors.forename: Vincent
authors.initials: V
authors.lastname: Berezowski
authors.forename: Julien
authors.initials: J
authors.lastname: Brillault
authors.forename: Romeo
authors.initials: R
authors.lastname: Cecchelli
authors.forename: Didier
authors.initials: D
authors.lastname: Divoux
authors.forename: Eric T
authors.initials: ET
authors.lastname: Mackenzie
authors.forename: Myriam
authors.initials: M
authors.lastname: Bernaudin
authors.forename: Simon
authors.initials: S
authors.lastname: Roussel
authors.forename: Edwige
authors.initials: E
authors.lastname: Petit
mesh_terms: D042683:Angiopoietin-1 / Q000008:administration & dosage*; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism* / Q000473:pathology; D002545:Brain Ischemia / Q000378:metabolism* / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D004357:Drug Synergism; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051379:Mice; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology; D009416:Nerve Regeneration / Q000187:drug effects; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010539:Permeability / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000008:administration & dosage*
chemical_list: D042683:Angiopoietin-1; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D020780:Matrix Metalloproteinase 9