Skip to main content
SpringerLink
Log in
Book cover

Role of Proteases in Cellular Dysfunction pp 93–102Cite as

The Role of Matrix Metalloproteinases in Neurovascular Injury

  • Chapter
  • First Online:

  • 1291 Accesses

Part of the book series: Advances in Biochemistry in Health and Disease ((ABHD,volume 8))

Abstract

Cell–matrix homeostasis is vital in the CNS. In a large number of CNS disorders, abnormal activation of extracellular proteases may disrupt neuronal function by degrading neurovascular matrix integrity. This chapter surveys the role of a key family of extracellular proteases, the matrix metalloproteinases (MMPs), in stroke and brain injury. Blood–brain barrier (BBB) leakage and brain edema is a critical part of stroke pathophysiology. A large body of data in both experimental models as well as clinical patient populations suggests that MMPs may disrupt BBB permeability and interfere with cell–cell signaling between neuronal, glial, and vascular compartments. Hence, ongoing efforts are underway to validate MMPs as potential therapeutic targets as well as biomarkers in stroke. Because BBB perturbations may also occur in neurodegeneration, MMPs and associated neurovascular mechanisms may also be potential targets in a broader range of CNS disorders.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  1. Huber JD, Egleton RD, Davis TP (2001) Molecular physiology and pathophysiology of tight junctions in the blood-brain barrier. Trends Neurosci 24: 719-725

    Article  PubMed  CAS  Google Scholar 

  2. Petty MA, Lo EH (2002) Junctional complexes of the blood-brain barrier: permeability changes in neuroinflammation. Prog Neurobiol 68: 311-323

    Article  PubMed  CAS  Google Scholar 

  3. Abbott NJ, Ronnback L, Hansson E (2006) Astrocyte-endothelial interactions at the blood-brain barrier. Nat Rev Neurosci 7: 41-53

    Article  PubMed  CAS  Google Scholar 

  4. Winkler EA, Bell RD, Zlokovic BV (2011) Central nervous system pericytes in health and disease. Nat Neurosci 14: 1398-1405

    Article  PubMed  CAS  Google Scholar 

  5. Park JA, Choi KS, Kim SY et al (2003) Coordinated interaction of the vascular and nervous systems: from molecule-to cell-based approaches. Biochem Biophys Res Commun 311: 247-253

    Article  PubMed  CAS  Google Scholar 

  6. Lo EH, Broderick JP, Moskowitz MA (2004) tPA and proteolysis in the neurovascular unit. Stroke 35: 354-356

    Article  PubMed  Google Scholar 

  7. Lok J, Gupta P, Guo S et al (2007) Cell-cell signaling in the neurovascular unit. Neurochem Res 32: 2032-2045

    Article  PubMed  CAS  Google Scholar 

  8. Arai K, Jin G, Navaratna D et al (2009) Brain angiogenesis in developmental and pathological processes: neurovascular injury and angiogenic recovery after stroke. FEBS J 276: 4644-4652

    Article  PubMed  CAS  Google Scholar 

  9. Lee HS, Han J, Bai HJ et al (2009) Brain angiogenesis in developmental and pathological processes: regulation, molecular and cellular communication at the neurovascular interface. FEBS J 276: 4622-4635

    Article  PubMed  CAS  Google Scholar 

  10. Klatzo I (1967) Presidential address. Neuropathological aspects of brain edema. Neuropathol Exp Neurol 26: 1-14

    Article  CAS  Google Scholar 

  11. Klatzo I (1987) Pathophysiological aspects of brain edema. Acta Neuropathol 72: 236-9.

    Article  PubMed  CAS  Google Scholar 

  12. Huang ZG, Xue, D, Preston E et al (1999) Biphasic opening of the blood-brain barrier following transient focal ischemia: effects of hypothermia. Can J Neurol Sci 26: 298-304

    PubMed  CAS  Google Scholar 

  13. Cunningham LA, Wetzel M, Rosenberg GA (2005) Multiple roles for MMPs and TIMPs in cerebral ischemia. Glia 50: 329-339

    Article  PubMed  Google Scholar 

  14. Yong VW (2005) Metalloproteinases: mediators of pathology and regeneration in the CNS. Nat Rev Neurosci 6: 931-944

    Article  PubMed  CAS  Google Scholar 

  15. Simard JM, Kent TA, Chen M et al (2007) Brain oedema in focal ischaemia: molecular pathophysiology and theoretical implications. Lancet Neurol 6: 258-268.

    Article  PubMed  CAS  Google Scholar 

  16. Zlokovic BV (2008) The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron 57: 178-201

    Article  PubMed  CAS  Google Scholar 

  17. Neuwelt EA, Bauer B, Fahlke C et al (2011) Engaging neuroscience to advance translational research in brain barrier biology. Nat Rev Neurosci 12: 169-182

    Article  PubMed  CAS  Google Scholar 

  18. Romanic AM, White RF, Arleth AJ et al (1998) Matrix metalloproteinase expression increases after cerebral focal ischemia in rats: inhibition of matrix metalloproteinase-9 reduces infarct size. Stroke 29: 1020-1030

    Article  PubMed  CAS  Google Scholar 

  19. Gasche Y, Fujimura M, Morita-Fujimura Y et al (1999) 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

    Google Scholar 

  20. Heo JH, Lucero J, Abumiya T, et al (1999) Matrix metalloproteinases increase very early during experimental focal cerebral ischemia. J Cereb Blood Flow Metab 19: 624-633

    Article  PubMed  CAS  Google Scholar 

  21. Asahi M, Asahi K, Jung JC et al (2000) Role for matrix metalloproteinase 9 after focal cerebral ischemia: effects of gene knockout and enzyme inhibition with BB-94. J Cereb Blood Flow Metab 20: 1681-1689

    Article  PubMed  CAS  Google Scholar 

  22. Wang X, Jung J, Asahi M et al (2000) Effects of matrix metalloproteinase-9 gene knock-out on morphological and motor outcomes after traumatic brain injury. J Neurosci 20: 7037-7042

    PubMed  CAS  Google Scholar 

  23. Asahi M, Wang X, Mori T et al (2001) Effects of matrix metalloproteinase-9 gene knock-out on the proteolysis of blood-brain barrier and white matter components after cerebral ischemia. J Neurosci 21: 7724-7732

    PubMed  CAS  Google Scholar 

  24. Lee SR, Tsuji K, Lee SR et al (2004) Role of matrix metalloproteinases in delayed neuronal damage after transient global cerebral ischemia. J Neurosci 24: 671-678

    Article  PubMed  CAS  Google Scholar 

  25. Tejima E, Guo S, Murata, Y et al (2009) Neuroprotective effects of overexpressing tissue inhibitor of metalloproteinase TIMP-1. J Neurotrauma 26: 1935-1941

    Article  PubMed  Google Scholar 

  26. Rosenberg GA, Estrada EY, Dencoff JE et al (1995) Tumor necrosis factor-alpha-induced gelatinase B causes delayed opening of the blood-brain barrier: an expanded therapeutic window. Brain Res 703: 151-155

    Article  PubMed  CAS  Google Scholar 

  27. Gu Z, Kaul M, Yan B et al (2002) S-nitrosylation of matrix metalloproteinases: signaling pathway to neuronal cell death. Science 297: 1186-1190

    Article  PubMed  CAS  Google Scholar 

  28. Lee SR, Lo EH (2004) Induction of caspase-mediated cell death by matrix metalloproteinases in cerebral endothelial cells after hypoxia-reoxygenation. J Cereb Blood Flow Metab 24: 720-727

    Article  PubMed  CAS  Google Scholar 

  29. Gu Z, Cui J, Brown S et al (2005) 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

    Article  PubMed  CAS  Google Scholar 

  30. Fukuda S, Fini CA, Mabuchi T et al (2004) Focal cerebral ischemia induces active proteases that degrade microvascular matrix. Stroke 35: 998-1004

    Article  PubMed  CAS  Google Scholar 

  31. Sakai T, Johnson KJ, Murozono et al (2001) Plasma fibronectin supports neuronal survival and reduces brain injury following transient focal cerebral ischemia but is not essential for skin-wound healing and hemostasis. Nat Med 7: 324-330

    Google Scholar 

  32. Dugas JC, Mandemakers W, Rogers M et al (2008) A novel purification method for CNS projection neurons leads to the identification of brain vascular cells as a source of trophic support for corticospinal motor neurons. J Neurosci 28: 8294-8305

    Article  PubMed  CAS  Google Scholar 

  33. Guo S, Kim WJ, Lok J et al (2008) Neuroprotection via matrix-trophic coupling between cerebral endothelial cells and neurons. Proc Natl Acad Sci U S A 105: 7582-7587

    Article  PubMed  CAS  Google Scholar 

  34. Arai K, Lo EH (2009) An oligovascular niche: cerebral endothelial cells promote the survival and proliferation of oligodendrocyte precursor cells. J Neurosci 29: 4351-4355

    Article  PubMed  CAS  Google Scholar 

  35. Arai K, Lo EH (2010) Astrocytes protect oligodendrocyte precursor cells via MEK/ERK and PI3K/Akt signaling. J Neurosci Res 88: 758-763

    PubMed  CAS  Google Scholar 

  36. Zhao BQ, Tejima E, Lo EH (2007) Neurovascular proteases in brain injury, hemorrhage and remodeling after stroke. Stroke 38: 748-752

    Article  PubMed  CAS  Google Scholar 

  37. Rosell A, Lo EH (2008) Multiphasic roles for matrix metalloproteinases after stroke. Curr Opin Pharmacol 8: 82-89

    Article  PubMed  CAS  Google Scholar 

  38. Canete Soler R, Gui YH, Linask KK, Muschel RJ (1995) MMP-9 (gelatinase B) mRNA is expressed during mouse neurogenesis and may be associated with vascularization. Brain Res Dev Brain Res 88: 37-52

    Article  PubMed  CAS  Google Scholar 

  39. Bergers G, Brekken R, McMahon G et al (2000) Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat Cell Biol 2: 737-744

    Article  PubMed  CAS  Google Scholar 

  40. Meighan SE, Meighan PC, Choudhury P et al (2006) Effects of extracellular matrix-degrading proteases matrix metalloproteinases 3 and 9 on spatial learning and synaptic plasticity. J Neurochem 96: 1227-12241

    Article  PubMed  CAS  Google Scholar 

  41. Nagy V, Bozdagi O, Matynia A et al (2006) Matrix metalloproteinase-9 is required for hippocampal late-phase long-term potentiation and memory. J Neurosci 26: 1923-1934

    Article  PubMed  CAS  Google Scholar 

  42. Arvidsson A, Collin T, Kirik D et al (2002) Neuronal replacement from endogenous precursors in the adult brain after stroke. Nat Med 8: 963-970

    Article  PubMed  CAS  Google Scholar 

  43. Lee SR, Kim HY, Rogowska J et al (2006) Involvement of matrix metalloproteinase in neuroblast cell migration from the subventricular zone after stroke. J Neurosci 26: 3491-3495

    Article  PubMed  CAS  Google Scholar 

  44. Zhao BQ, Wang S, Kim HY et al (2006) Role of matrix metalloproteinases in delayed cortical responses after stroke. Nat Med 12: 441-445

    Article  PubMed  CAS  Google Scholar 

  45. Sood RR, Taheri S, Candelario-Jalil E et al (2008) Early beneficial effect of matrix metalloproteinase inhibition on blood-brain barrier permeability as measured by magnetic resonance imaging countered by impaired long-term recovery after stroke in rat brain. J Cereb Blood Flow Metab 28: 431-438

    Article  PubMed  CAS  Google Scholar 

  46. Goussev S, Hsu JY, Lin Y et al (2003) Differential temporal expression of matrix metalloproteinases after spinal cord injury: relationship to revascularization and wound healing. J Neurosurg 99: 188-197

    Article  PubMed  CAS  Google Scholar 

  47. Hsu JY, McKeon R, Goussev S et al (2006) Matrix metalloproteinase-2 facilitates wound healing events that promote functional recovery after spinal cord injury. J Neurosci 26: 9841-9850

    Article  PubMed  CAS  Google Scholar 

  48. Montaner J, Alvarez-Sabin J, Molina CA et al (2001) Matrix metalloproteinase expression after human cardioembolic stroke: temporal profile and relation to neurological impairment. Stroke 32: 1759-1766

    Article  PubMed  CAS  Google Scholar 

  49. Montaner J, Alvarez-Sabin J, Molina CA et al (2001) Matrix metalloproteinase expression is related to hemorrhagic transformation after cardioembolic stroke. Stroke 32: 2762-2767

    Article  PubMed  CAS  Google Scholar 

  50. Sumii T, Lo EH (2002) Involvement of matrix metalloproteinase in thrombolysis-associated hemorrhagic transformation after embolic focal ischemia in rats. Stroke 33: 831-836

    Article  PubMed  CAS  Google Scholar 

  51. Montaner J, Molina CA, Monasterio et al (2003) Matrix metalloproteinase-9 pretreatment level predicts intracranial hemorrhagic complications after thrombolysis in human stroke. Circulation 107: 598-603

    Google Scholar 

  52. Ning M, Furie KL, Koroshetz WJ et al (2006) Association between tPA therapy and raised early matrix metalloproteinase-9 in acute stroke. Neurology 66: 1550-1555

    Article  PubMed  CAS  Google Scholar 

  53. Tang Y, Xu H, Du X et al (2006) Gene expression in blood changes rapidly in neutrophils and monocytes after ischemic stroke in humans: a microarray study. J Cereb Blood Flow Metab 2: 1089-1102

    Article  Google Scholar 

  54. Barr TL, Conley Y, Ding J, Dillman A et al (2010) Genomic biomarkers and cellular pathways of ischemic stroke by RNA gene expression profiling. Neurology 75: 1009-1014

    Article  PubMed  CAS  Google Scholar 

  55. Tejima E, Zhao BQ, Tsuji K et al (2007) Astrocytic induction of matrix metalloproteinase-9 and edema in brain hemorrhage. J Cereb Blood Flow Metab 27: 460-468

    Article  PubMed  CAS  Google Scholar 

  56. Gidday JM, Gasche YG, Copin JC et al (2005) Leukocyte-derived matrix metalloproteinase-9 mediates blood-brain barrier breakdown and is proinflammatory after transient focal cerebral ischemia. Am J Physiol Heart Circ Physiol 289: H558-H568

    Article  PubMed  CAS  Google Scholar 

  57. Rosell A, Cuadrado E, Ortega-Aznar A et al (2008) MMP-9-positive neutrophil infiltration is associated to blood-brain barrier breakdown and basal lamina type IV collagen degradation during hemorrhagic transformation after human ischemic stroke. Stroke 39: 1121112-6

    Article  Google Scholar 

  58. Wang X, Lee SR, Arai K et al (2003) Lipoprotein receptor-mediated induction of matrix metalloproteinase by tissue plasminogen activator. Nat Med 9: 1313-1317

    Article  PubMed  CAS  Google Scholar 

  59. Fagan SC, Cronic LE, Hess DC (2011) Minocycline Development for Acute Ischemic Stroke. Transl Stroke Res 2: 202-208

    Article  PubMed  CAS  Google Scholar 

  60. Murata Y, Rosell A, Scannevin RH et al (2008) Extension of the thrombolytic time window with minocycline in experimental stroke. Stroke 39: 3372-3377

    Article  PubMed  CAS  Google Scholar 

  61. Fagan SC, Waller JL, Nichols FT et al (2010) Minocycline to improve neurologic outcome in stroke (MINOS): a dose-finding study. Stroke 41: 2283-2287

    Article  PubMed  CAS  Google Scholar 

  62. Switzer JA, Hess DC, Ergul A et al (2011) Matrix metalloproteinase-9 in an exploratory trial of intravenous minocycline for acute ischemic stroke. Stroke 42: 2633-2635

    Article  PubMed  CAS  Google Scholar 

  63. Gordon PH, Moore DH, Miller RG et al (2007) Efficacy of minocycline in patients with amyotrophic lateral sclerosis: a phase III randomised trial. Lancet Neurol 6: 1045-1053

    Article  PubMed  CAS  Google Scholar 

  64. Chou SH, Feske SK, Simmons SL et al (2011) Elevated Peripheral Neutrophils and Matrix Metalloproteinase 9 as Biomarkers of Functional Outcome Following Subarachnoid Hemorrhage. Transl Stroke Res 2: 600-607

    Article  PubMed  CAS  Google Scholar 

  65. Chou SH, Lee PS, Konigsberg RG et al (2011) Plasma-type gelsolin is decreased in human blood and cerebrospinal fluid after subarachnoid hemorrhage. Stroke 42: 3624-3627

    Article  PubMed  CAS  Google Scholar 

  66. Guo ZD, Zhang XD, Wu HT et al (2011) Matrix metalloproteinase 9 inhibition reduces early brain injury in cortex after subarachnoid hemorrhage. Acta Neurochir Suppl 110: 81-84

    PubMed  Google Scholar 

  67. Lorenzl S, Albers DS, Narr S et al (2002) Expression of MMP-2, MMP-9, and MMP-1 and their endogenous counterregulators TIMP-1 and TIMP-2 in postmortem brain tissue of Parkinson’s disease. Exp Neurol 178: 13-20

    Article  PubMed  CAS  Google Scholar 

  68. Kim YS, Choi DH, Block ML et al (2007) A pivotal role of matrix metalloproteinase-3 activity in dopaminergic neuronal degeneration via microglial activation. FASEB J 21: 179-187

    Article  PubMed  CAS  Google Scholar 

  69. Guo S, Wang S, Kim WJ et al (2006) Effects of apoE isoforms on beta-amyloid-induced matrix metalloproteinase-9 in rat astrocytes. Brain Res 1111: 222-226

    Article  PubMed  CAS  Google Scholar 

  70. Yin KJ, Cirrito JR, Yan P et al (2006) Matrix metalloproteinases expressed by astrocytes mediate extracellular amyloid-beta peptide catabolism. J Neurosci 26: 10939-10948

    Article  PubMed  CAS  Google Scholar 

  71. Garcia-Alloza M, Prada C, Lattarulo C et al (2009) Matrix metalloproteinase inhibition reduces oxidative stress associated with cerebral amyloid angiopathy in vivo in transgenic mice. J Neurochem 109: 1636-1647

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

Supported in part by grants from NIH, the Claflin Foundation, and the Rappaport Foundation. This chapter is based on ideas previously discussed in Rosell et al., Curr Opin Pharmacol 2008, and Seo et al., Curr Pharm Des 2012.

Author information

Authors and Affiliations

  1. Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Ji Hae Seo, Shuzhen Guo, Josephine Lok, Deepti Navaratna, Changhong Xing & Eng H. Lo

  2. Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Ji Hae Seo, Shuzhen Guo, Josephine Lok, Deepti Navaratna, Changhong Xing & Eng H. Lo

  3. Department of Pediatrics, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Ji Hae Seo, Shuzhen Guo, Josephine Lok, Deepti Navaratna, Changhong Xing & Eng H. Lo

Authors
  1. Ji Hae Seo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shuzhen Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Josephine Lok
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Deepti Navaratna
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Changhong Xing
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Eng H. Lo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Eng H. Lo .

Editor information

Editors and Affiliations

  1. St. Boniface Hosp. Research, Univ. of Ma Institute of Cardiovascular Sciences, Winnipeg, Manitoba, Canada

    Naranjan S. Dhalla

  2. Dept of Biochemistry and Biophysics, University of Kalyani, Kalyani, West Bengal, India

    Sajal Chakraborti

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer Science+Business Media New York

About this chapter

Cite this chapter

Seo, J.H., Guo, S., Lok, J., Navaratna, D., Xing, C., Lo, E.H. (2014). The Role of Matrix Metalloproteinases in Neurovascular Injury. In: Dhalla, N., Chakraborti, S. (eds) Role of Proteases in Cellular Dysfunction. Advances in Biochemistry in Health and Disease, vol 8. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-9099-9_5

Download citation

Publish with us

Policies and ethics

Search

Navigation