Role of matrix metalloproteinases in delayed cortical responses after stroke (original) (raw)

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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References

  1. Yong, V.W. Metalloproteinases: mediators of pathology and regeneration in the CNS. Nat. Rev. Neurosci. 6, 931–944 (2005).
    Article CAS Google Scholar
  2. Asahi, M. et al. Effects of matrix metalloproteinase 9 gene knockout on the proteolysis of blood-brain barrier and white matter components after cerebral ischemia. J. Neurosci. 21, 7724–7732 (2001).
    Article CAS Google Scholar
  3. Wang, X. et al. Lipoprotein receptor-mediated induction of matrix metalloproteinase by tissue plasminogen activator. Nat. Med. 9, 1313–1317 (2003).
    Article CAS Google Scholar
  4. Lo, E.H., Dalkara, T. & Moskowitz, M.A. Mechanisms, challenges and opportunities in stroke. Nat. Rev. Neurosci. 4, 399–415 (2003).
    Article CAS Google Scholar
  5. Lee, S.R. & Lo, E.H. Induction of caspase-mediated cell death by matrix metalloproteinases in cerebral endothelial cells after hypoxia-reoxygenation. J. Cereb. Blood Flow Metab. 24, 720–727 (2004).
    Article CAS Google Scholar
  6. Gu, Z. et al. A highly specific inhibitor of matrix metalloproteinase-9 rescues laminin from proteolysis and neurons from apoptosis in transient focal cerebral ischemia. J. Neurosci. 25, 6401–6408 (2005).
    Article CAS Google Scholar
  7. Gasche, Y. et al. Early appearance of activated matrix metalloproteinase-9 after focal cerebral ischemia in mice: a possible role in blood-brain barrier dysfunction. J. Cereb. Blood Flow Metab. 19, 1020–1028 (1999).
    Article CAS Google Scholar
  8. Heo, J.H. et al. Matrix metalloproteinases increase very early during experimental focal cerebral ischemia. J. Cereb. Blood Flow Metab. 19, 624–633 (1999).
    Article CAS Google Scholar
  9. Mun-Bryce, S. & Rosenberg, G.A. Matrix metalloproteinases in cerebrovascular disease. J. Cereb. Blood Flow Metab. 18, 1163–1172 (1998).
    Article CAS Google Scholar
  10. Dijkhuizen, R.M. et al. Correlation between brain reorganization, ischemic damage, and neurologic status after transient focal cerebral ischemia in rats: a functional magnetic resonance imaging study. J. Neurosci. 23, 510–517 (2003).
    Article CAS Google Scholar
  11. Kim, Y.R. et al. Measurements of BOLD/CBV ratio show altered fMRI hemodynamics during stroke recovery in rats. J. Cereb. Blood Flow Metab. 25, 820–829 (2005).
    Article Google Scholar
  12. Reeves, T.M., Prins, M.L., Zhu, J., Povlishock, J.T. & Phillips, L.L. Matrix metalloproteinase inhibition alters functional and structural correlates of deafferentation-induced sprouting in the dentate gyrus. J. Neurosci. 23, 10182–10189 (2003).
    Article CAS Google Scholar
  13. Wallace, C.S. et al. Correspondence between sites of NGFI-A induction and sites of morphological plasticity following exposure to environmental complexity. Brain Res. Mol. Brain Res. 32, 211–220 (1995).
    Article CAS Google Scholar
  14. Jones, M.W. et al. A requirement for the immediate early gene Zif268 in the expression of late LTP and long-term memories. Nat. Neurosci. 4, 289–296 (2001).
    Article CAS Google Scholar
  15. Irving, E.A. et al. Identification of neuroprotective properties of anti-MAG antibody: a novel approach for the treatment of stroke? J. Cereb. Blood Flow Metab. 25, 98–107 (2005).
    Article CAS Google Scholar
  16. Omura, K. et al. Recovery of blood-nerve barrier in crush nerve injury – a quantitative analysis utlizing immunohistochemistry. Brain Res. 1001, 13–21 (2004).
    Article CAS Google Scholar
  17. Larsen, P.H., Wells, J.E., Stallcup, W.B., Opdenakker, G. & Yong, V.W. Matrix metalloproteinase-9 facilitates remyelination in part by processing the inhibitory NG2 proteoglycan. J. Neurosci. 23, 11127–11135 (2003).
    Article CAS Google Scholar
  18. Pang, P.T. et al. Cleavage of proBDNF by tPA/plasmin is essential for long-term hippocampal plasticity. Science 306, 487–491 (2004).
    Article CAS Google Scholar
  19. Bergers, G. et al. Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat. Cell Biol. 2, 737–744 (2000).
    Article CAS Google Scholar
  20. Zhang, Z.G. et al. VEGF enhances angiogenesis and promotes blood-brain barrier leakage in the ischemic brain. J. Clin. Invest. 106, 829–838 (2000).
    Article CAS Google Scholar
  21. Cramer, S.C. & Chopp, M. Recovery recapitulates ontogeny. Trends Neurosci. 23, 265–271 (2000).
    Article CAS Google Scholar
  22. Chmielnicki, E. & Goldman, S.A. Induced neurogenesis by endogenous progenitor cells in the adult mammalian brain. Prog. Brain Res. 138, 451–464 (2002).
    Article CAS Google Scholar
  23. Kaczmarek, L., Lapinska-Dzwonek, J. & Szymczak, S. Matrix metalloproteinases in the adult brain physiology: a link between c-Fos, AP-1 and remodeling of neuronal connections? EMBO J. 21, 6643–6648 (2002).
    Article CAS Google Scholar
  24. Pepper, M.S. Role of the matrix metalloproteinase and plasmminogen activator-plasmin systems in angiogenesis. Arterioscler. Thromb. Vasc. Biol. 21, 1104–1117 (2001).
    Article CAS Google Scholar
  25. Manoonkitiwongsa, P.S., Jackson-Friedman, C., Mcmillan, P.J., Schultz, R.L. & Lyden, P.D. Angiogenesis after stroke is correlated with increased numbers of macrophages: the clean-up hypothesis. J. Cereb. Blood Flow Metab. 21, 1223–1231 (2001).
    Article CAS Google Scholar
  26. Silva, E.A. & Mooney, D.J. Synthetic extracellular matrices for tissue engineering and regeneration. Curr. Top. Dev. Biol. 64, 181–205 (2004).
    Article CAS Google Scholar
  27. Montaner, J. et al. Matrix metalloproteinase expression after human cardioembolic stroke: temporal profile and relation to neurological impairment. Stroke 32, 1759–1766 (2001).
    Article CAS Google Scholar
  28. Montaner, J. et al. Matrix metalloproteinase-9 pretreatment level predicts intracranial hemorrhagic complications after thrombolysis in human stroke. Circulation 107, 598–603 (2003).
    Article CAS Google Scholar
  29. Lee, S.R., Tsuji, K., Lee, S.R. & Lo, E.H. Role of matrix metalloproteinases in delayed neuronal damage after transient global cerebral ischemia. J. Neurosci. 24, 671–678 (2004).
    Article CAS Google Scholar
  30. Taguchi, A. et al. Administration of CD34+ cells after stroke enhances neurogenesis via angiogenesis in a mouse model. J. Clin. Invest. 114, 330–338 (2004).
    Article CAS Google Scholar

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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

Authors

  1. Bing-Qiao Zhao
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  2. Sophia Wang
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  3. Hahn-Young Kim
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  4. Hannah Storrie
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  5. Bruce R Rosen
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  6. David J Mooney
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  7. Xiaoying Wang
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  8. Eng H Lo
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Correspondence toEng H Lo.

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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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