title: Matrix metalloproteinase-13 participates in neuroprotection and neurorepair after cerebral ischemia in mice.
abstract: New neuroreparative and neuroprotective therapies are being sought to treat stroke patients. One approach is the remodeling of extracellular matrix, which participates in both brain injury and neurovascular repair when matrix metalloproteinases (MMPs) are thought to be key players. Our aim was to investigate the role of MMP-13 (collagenase-3) in the acute (24h and 3days) and delayed (2weeks) phases of stroke. Permanent and transient cerebral ischemia models involving the cortex were induced in MMP-13 knock-out (KO) and wild-type (WT) mice. In the transient model, MMP-13 deficiency reduced the amount of TTC-stained infarct tissue, reduced hemorrhagic events and improved functional outcomes (p<0.01). At two weeks, normal neuroblast (DCX+) migration from the subventricular zone toward the peri-infarct area was observed. However, MMP-13 deficiency significantly reduced the number of newborn neuroblasts (DCX+/BrdU+) in the cortical peri-infarct area (p<0.01). This result occurred in parallel with aberrant cortical vascular remodeling: post-stroke peri-infarct vessel density increased in the WT mice (p<0.01) but this increase was blocked in the MMP-13 KO mice. Prior to these vascular alterations, the levels of pro-angiogenic factors, including G-CSF, VEGF-A and angiopoietin-2, were lower in the ischemic cortex of MMP-13 KO mice than in WT mice (p<0.05). In vitro, gene-silencing of MMP-13 in endothelial progenitor cells (EPCs) confirmed the reduced ability of these cells to build tubulogenic networks in Matrigel™ substrate. Together, our results indicate that MMP-13 is a central protease in infarct development and cortical remodeling during post-stroke neurorepair, which is critical for optimal angiogenic and neurogenic responses.
authors.affiliation: Neurovascular Research Laboratory, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Passeig Vall d'Hebron 119-129, 08035 Barcelona, Spain.
authors.forename: Feifei
authors.initials: F
authors.lastname: Ma
authors.affiliation: Neurovascular Research Laboratory, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Passeig Vall d'Hebron 119-129, 08035 Barcelona, Spain.
authors.forename: Pablo
authors.initials: P
authors.lastname: Martínez-San Segundo
authors.affiliation: Neurovascular Research Laboratory, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Passeig Vall d'Hebron 119-129, 08035 Barcelona, Spain.
authors.forename: Verónica
authors.initials: V
authors.lastname: Barceló
authors.affiliation: Neurovascular Research Laboratory, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Passeig Vall d'Hebron 119-129, 08035 Barcelona, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Morancho
authors.affiliation: Neurovascular Research Laboratory, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Passeig Vall d'Hebron 119-129, 08035 Barcelona, Spain.
authors.forename: Marina
authors.initials: M
authors.lastname: Gabriel-Salazar
authors.affiliation: Neurovascular Research Laboratory, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Passeig Vall d'Hebron 119-129, 08035 Barcelona, Spain.
authors.forename: Dolors
authors.initials: D
authors.lastname: Giralt
authors.affiliation: Neurovascular Research Laboratory, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Passeig Vall d'Hebron 119-129, 08035 Barcelona, Spain.
authors.forename: Joan
authors.initials: J
authors.lastname: Montaner
authors.affiliation: Neurovascular Research Laboratory, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Passeig Vall d'Hebron 119-129, 08035 Barcelona, Spain. Electronic address: anna.rosell@vhir.org.
authors.forename: Anna
authors.initials: A
authors.lastname: Rosell
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D000089662:Doublecortin Protein; D020244:Infarction, Middle Cerebral Artery / Q000378:metabolism; D002546:Ischemic Attack, Transient / Q000201:enzymology*; D053509:Matrix Metalloproteinase 13 / Q000235:genetics / Q000378:metabolism*; D018345:Mice, Knockout; D055495:Neurogenesis / Q000502:physiology; D000066829:Neuroprotection / Q000502:physiology*; D020521:Stroke / Q000201:enzymology*
chemical_list: C000714847:Dcx protein, mouse; D000089662:Doublecortin Protein; D053509:Matrix Metalloproteinase 13; C507081:Mmp13 protein, mouse
keywords: Angiogenesis; Cerebral ischemia; MMP-13; Neurogenesis; Neurorepair