Nature Medicine
- 12, 441 - 445 (2006)
Published online: 26 March 2006; | doi:10.1038/nm1387
Role of matrix metalloproteinases in delayed cortical responses after strokeBing-Qiao Zhao1, 2, Sophia Wang1, 2, Hahn-Young Kim1, 2, 5, Hannah Storrie4, Bruce R Rosen3, David J Mooney4, Xiaoying Wang1, 2 & Eng H Lo1, 21
Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital, MGH East 149-2401, Charlestown, Massachusetts 02129, USA. 2
Program in Neuroscience, Harvard Medical School, Boston, Massachusetts 02114, USA. 3
Aninthoula Martinos Center for Biomedical Imaging, MGH East 2, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, USA. 4
Division of Engineering and Applied Science, Pierce Hall, Harvard University, Cambridge, Massachusetts 02138, USA. 5
Current address: Department of Neurology, Konkuk University, Seoul, Korea.
Correspondence should be addressed to Eng H Lo Lo@helix.mgh.harvard.edu Matrix metalloproteinases (MMPs) are zinc-endopeptidases with multifactorial actions in central nervous system (CNS) physiology and pathology1. Accumulating data suggest that MMPs have a deleterious role in stroke. By degrading neurovascular matrix, MMPs promote injury of the blood-brain barrier, edema and hemorrhage2,
3,
4. By disrupting cell-matrix signaling and homeostasis, MMPs trigger brain cell death5,
6. Hence, there is a movement toward the development of MMP inhibitors for acute stroke therapy. But MMPs may have a different role during delayed phases after stroke. Because MMPs modulate brain matrix, they may mediate beneficial plasticity and remodeling during stroke recovery. Here, we show that MMPs participate in delayed cortical responses after focal cerebral ischemia in rats. MMP-9 is upregulated in peri-infarct cortex at 7–14 days after stroke and is colocalized with markers of neurovascular remodeling. Treatment with MMP inhibitors at 7 days after stroke suppresses neurovascular remodeling, increases ischemic brain injury and impairs functional recovery at 14 days. MMP processing of bioavailable VEGF may be involved because inhibition of MMPs reduces endogenous VEGF signals, whereas additional treatment with exogenous VEGF prevents MMP inhibitor–induced worsening of infarction. These data suggest that, contrary to MMP inhibitor therapies for acute stroke, strategies that modulate MMPs may be needed for promoting stroke recovery.
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