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Role of matrix metalloproteinases in delayed cortical responses after stroke

Nature Medicine volume 12, pages 441–445 (2006)Cite this article

Abstract

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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Figure 1: Increased expression of cortical MMP-9 during stroke recovery.
Figure 2: MMP activity after stroke, as measured by in situ zymography.
Figure 3: Upregulation of RECA-1 and Egr1 within peri-infarct cortical areas precedes cell death.
Figure 4: Worsening of delayed stroke outcomes by inhibition of MMPs.

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Acknowledgements

This work was supported in part by US National Institutes of Health grants R01-NS37074, R01-NS40529, R01-NS48422, R01-EB02066, P50-NS10828 (to E.H.L.), R01-EBO2066 (to B.R.R.), a Howard Hughes Medical Research Training Fellowship (to S.W.), and a Bugher award from the American Heart Association (to E.H.L.).

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Author notes

  1. Hahn-Young Kim

    Present address: Department of Neurology, Konkuk University, Seoul, Korea

Authors and Affiliations

  1. Departments of Radiology and Neurology, Neuroprotection Research Laboratory, Massachusetts General Hospital, MGH East, Charlestown, 149-2401, 02129, Massachusetts, USA

    Bing-Qiao Zhao, Sophia Wang, Hahn-Young Kim, Xiaoying Wang & Eng H Lo

  2. Program in Neuroscience, Harvard Medical School, Boston, 02114, Massachusetts, USA

    Bing-Qiao Zhao, Sophia Wang, Hahn-Young Kim, Xiaoying Wang & Eng H Lo

  3. Aninthoula Martinos Center for Biomedical Imaging, MGH East 2, Massachusetts General Hospital and Harvard Medical School, Charlestown, 02129, Massachusetts, USA

    Bruce R Rosen

  4. Division of Engineering and Applied Science, Pierce Hall, Harvard University, Cambridge, 02138, Massachusetts, USA

    Hannah Storrie & David J Mooney

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Correspondence to Eng H Lo.

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Supplementary information

Supplementary Fig. 1

MMP-9 expression at 24 h after stroke. (PDF 194 kb)

Supplementary Fig. 2

Neuroprotection in MMP-9 knockout neuronal cultures. (PDF 29 kb)

Supplementary Fig. 3

Increased cortical infarction after delayed MMP inhibition. (PDF 107 kb)

Supplementary Fig. 4

RECA-1 staining of vascular remodeling in peri-infarct cortex. (PDF 120 kb)

Supplementary Methods (PDF 19 kb)

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Zhao, BQ., Wang, S., Kim, HY. et al. Role of matrix metalloproteinases in delayed cortical responses after stroke. Nat Med 12, 441–445 (2006). https://doi.org/10.1038/nm1387

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