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Cerebral Ischemic Reperfusion Injuries (CIRI) pp 1–14Cite as

Gelatinase-Mediated Impairment of Microvascular Beds in Cerebral Ischemia and Reperfusion Injury

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Part of the book series: Springer Series in Translational Stroke Research ((SSTSR))

Abstract

Stroke is one of the leading causes of death, and acute ischemic stroke (AIS) is the most common form. Tissue plasminogen activator (tPA) is the only FDA-approved drug for recanalization in AIS with narrow therapeutic window. In this chapter, we will discuss the activation of gelatinases (MMP-2/9), one of the major mediators in cerebral ischemia and reperfusion injury (CIRI) with exogenous tPA in AIS. First, we briefly overview the structure of microvascular beds and the homeostasis of neurovascular unit associated with the extracellular matrix (ECM). Then we review the gelatinase-mediated degradation of ECM and the impairment of microvascular beds in AIS. Moreover, we discuss the self-perpetuating loop of gelatinase activation in CIRI with exogenous tPA. At last, we literature available approaches showing protective functions through blocking the vicious circle of gelatinase activation, which may hold great promise in combined treatment with tPA in AIS.

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References

  1. Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V, et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the global burden of disease study 2010. Lancet. 2012;380:2095–128.

    Article  PubMed  Google Scholar 

  2. Feigin VL, Forouzanfar MH, Krishnamurthi R, Mensah GA, Connor M, Bennett DA, et al. Global and regional burden of stroke during 1990–2010: findings from the global burden of disease study 2010. Lancet. 2014;383:245–54.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, et al. Heart disease and stroke statistics—2015 update: a report from the American Heart Association. Circulation. 2015;131:e29–322.

    Article  PubMed  Google Scholar 

  4. Lloyd-Jones D, Adams R, Carnethon M, De Simone G, Ferguson TB, Flegal K, et al. Heart disease and stroke statistics—2009 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2009;119:480–6.

    Article  PubMed  Google Scholar 

  5. Liu L, Wang D, Wong KS, Wang Y. Stroke and stroke care in china: huge burden, significant workload, and a national priority. Stroke. 2011;42:3651–4.

    Article  PubMed  Google Scholar 

  6. He J, Gu D, Wu X, Reynolds K, Duan X, Yao C, et al. Major causes of death among men and women in china. N Engl J Med. 2005;353:1124–34.

    Article  PubMed  CAS  Google Scholar 

  7. Zhou M, Wang H, Zhu J, Chen W, Wang L, Liu S, et al. Cause-specific mortality for 240 causes in china during 1990–2013: a systematic subnational analysis for the global burden of disease study 2013. Lancet. 2016;387:251–72.

    Article  PubMed  Google Scholar 

  8. Toyoda K, Koga M, Hayakawa M, Yamagami H. Acute reperfusion therapy and stroke care in Asia after successful endovascular trials. Stroke. 2015;46:1474–81.

    Article  PubMed  CAS  Google Scholar 

  9. Wang W, Jiang B, Sun H, Ru X, Sun D, Wang L, et al. Prevalence, incidence and mortality of stroke in china: results from a nationwide population-based survey of 480,687 adults. Circulation. 2017;135(8):759–71.

    Article  PubMed  Google Scholar 

  10. van der Worp HB, van Gijn J. Clinical practice. Acute ischemic stroke. N Engl J Med. 2007;357:572–9.

    Article  PubMed  Google Scholar 

  11. Rha JH, Saver JL. The impact of recanalization on ischemic stroke outcome: a meta-analysis. Stroke. 2007;38:967–73.

    Article  PubMed  Google Scholar 

  12. Del Zoppo GJ, Saver JL, Jauch EC, Adams HP Jr, American Heart Association Stroke Council. Expansion of the time window for treatment of acute ischemic stroke with intravenous tissue plasminogen activator: a science advisory from the American Heart Association/American Stroke Association. Stroke. 2009;40:2945–8.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Jauch EC, Saver JL, Adams HP Jr, Bruno A, Connors JJ, Demaerschalk BM, et al. Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2013;44:870–947.

    Article  PubMed  Google Scholar 

  14. Saver JL, Fonarow GC, Smith EE, Reeves MJ, Grau-Sepulveda MV, Pan W, et al. Time to treatment with intravenous tissue plasminogen activator and outcome from acute ischemic stroke. JAMA. 2013;309:2480–8.

    Article  PubMed  CAS  Google Scholar 

  15. Su EJ, Fredriksson L, Geyer M, Folestad E, Cale J, Andrae J, et al. Activation of pdgf-cc by tissue plasminogen activator impairs blood-brain barrier integrity during ischemic stroke. Nat Med. 2008;14:731–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Wang L, Fan W, Cai P, Fan M, Zhu X, Dai Y, et al. Recombinant adamts13 reduces tissue plasminogen activator-induced hemorrhage after stroke in mice. Ann Neurol. 2013;73:189–98.

    Article  PubMed  CAS  Google Scholar 

  17. Chevilley A, Lesept F, Lenoir S, Ali C, Parcq J, Vivien D. Impacts of tissue-type plasminogen activator (tpa) on neuronal survival. Front Cell Neurosci. 2015;9:415.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Lo EH, Broderick JP, Moskowitz MA. Tpa and proteolysis in the neurovascular unit. Stroke. 2004;35:354–6.

    Article  PubMed  Google Scholar 

  19. Wang X, Rosell A, Lo EH. Targeting extracellular matrix proteolysis for hemorrhagic complications of tpa stroke therapy. CNS Neurol Disord Drug Targets. 2008;7:235–42.

    Article  PubMed  CAS  Google Scholar 

  20. Yong VW. Metalloproteinases: mediators of pathology and regeneration in the cns. Nat Rev Neurosci. 2005;6:931–44.

    Article  PubMed  CAS  Google Scholar 

  21. Rosenberg GA. Matrix metalloproteinases and their multiple roles in neurodegenerative diseases. Lancet Neurol. 2009;8:205–16.

    Article  PubMed  CAS  Google Scholar 

  22. Van Wart HE, Birkedal-Hansen H. The cysteine switch: a principle of regulation of metalloproteinase activity with potential applicability to the entire matrix metalloproteinase gene family. Proc Natl Acad Sci U S A. 1990;87:5578–82.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Asahi M, Asahi K, Jung JC, del Zoppo GJ, Fini ME, Lo EH. Role for matrix metalloproteinase 9 after focal cerebral ischemia: effects of gene knockout and enzyme inhibition with bb-94. J Cereb Blood Flow Metab. 2000;20:1681–9.

    Article  PubMed  CAS  Google Scholar 

  24. Turner RJ, Sharp FR. Implications of mmp9 for blood brain barrier disruption and hemorrhagic transformation following ischemic stroke. Front Cell Neurosci. 2016;10:56.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Dong X, Song YN, Liu WG, Guo XL. Mmp-9, a potential target for cerebral ischemic treatment. Curr Neuropharmacol. 2009;7:269–75.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Chaturvedi M, Kaczmarek L. Mmp-9 inhibition: a therapeutic strategy in ischemic stroke. Mol Neurobiol. 2014;49:563–73.

    Article  PubMed  CAS  Google Scholar 

  27. Sweeney MD, Ayyadurai S, Zlokovic BV. Pericytes of the neurovascular unit: key functions and signaling pathways. Nat Neurosci. 2016;19:771–83.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Dirnagl U. Pathobiology of injury after stroke: the neurovascular unit and beyond. Ann N Y Acad Sci. 2012;1268:21–5.

    Article  PubMed  Google Scholar 

  29. Ballabh P, Braun A, Nedergaard M. The blood-brain barrier: an overview: structure, regulation, and clinical implications. Neurobiol Dis. 2004;16:1–13.

    Article  PubMed  CAS  Google Scholar 

  30. Hawkins BT, Davis TP. The blood-brain barrier/neurovascular unit in health and disease. Pharmacol Rev. 2005;57:173–85.

    Article  CAS  PubMed  Google Scholar 

  31. Zlokovic BV. Remodeling after stroke. Nat Med. 2006;12:390–1.

    Article  CAS  PubMed  Google Scholar 

  32. Kniesel U, Wolburg H. Tight junctions of the blood-brain barrier. Cell Mol Neurobiol. 2000;20:57–76.

    Article  CAS  PubMed  Google Scholar 

  33. Stamatovic SM, Keep RF, Andjelkovic AV. Brain endothelial cell-cell junctions: how to “open” the blood brain barrier. Curr Neuropharmacol. 2008;6:179–92.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Dorfel MJ, Huber O. Modulation of tight junction structure and function by kinases and phosphatases targeting occludin. J Biomed Biotechnol. 2012;2012:807356.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Ni Y, Sun GY, Lee JC. TNFα alters occludin and cerebral endothelial permeability: role of p38MAPK. PLoS One. 2017;12(2):e0170346.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Winkler EA, Bell RD, Zlokovic BV. Central nervous system pericytes in health and disease. Nat Neurosci. 2011;14:1398–405.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Cai W, Liu H, Zhao J, Chen LY, Chen J, Lu Z, et al. Pericytes in brain injury and repair after ischemic stroke. Transl Stroke Res. 2017;8(2):107–21.

    Article  CAS  PubMed  Google Scholar 

  38. Armulik A, Genove G, Mae M, Nisancioglu MH, Wallgard E, Niaudet C, et al. Pericytes regulate the blood-brain barrier. Nature. 2010;468:557–61.

    Article  CAS  PubMed  Google Scholar 

  39. Attwell D, Mishra A, Hall CN, O’Farrell FM, Dalkara T. What is a pericyte? J Cereb Blood Flow Metab. 2016;36:451–5.

    Article  CAS  PubMed  Google Scholar 

  40. Lassmann H, Zimprich F, Vass K, Hickey WF. Microglial cells are a component of the perivascular glia limitans. J Neurosci Res. 1991;28:236–43.

    Article  PubMed  CAS  Google Scholar 

  41. Mathiisen TM, Lehre KP, Danbolt NC, Ottersen OP. The perivascular astroglial sheath provides a complete covering of the brain microvessels: an electron microscopic 3d reconstruction. Glia. 2010;58:1094–103.

    Article  PubMed  Google Scholar 

  42. Baeten KM, Akassoglou K. Extracellular matrix and matrix receptors in blood-brain barrier formation and stroke. Dev Neurobiol. 2011;71:1018–39.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Barber AJ, Lieth E. Agrin accumulates in the brain microvascular basal lamina during development of the blood-brain barrier. Dev Dyn. 1997;208:62–74.

    Article  PubMed  CAS  Google Scholar 

  44. Lukes A, Mun-Bryce S, Lukes M, Rosenberg GA. Extracellular matrix degradation by metalloproteinases and central nervous system diseases. Mol Neurobiol. 1999;19:267–84.

    Article  PubMed  CAS  Google Scholar 

  45. Fukuda S, Fini CA, Mabuchi T, Koziol JA, Eggleston LL Jr, del Zoppo GJ. Focal cerebral ischemia induces active proteases that degrade microvascular matrix. Stroke. 2004;35:998–1004.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Yurchenco PD, Amenta PS, Patton BL. Basement membrane assembly, stability and activities observed through a developmental lens. Matrix Biol. 2004;22:521–38.

    Article  PubMed  CAS  Google Scholar 

  47. Agrawal S, Anderson P, Durbeej M, van Rooijen N, Ivars F, Opdenakker G, et al. Dystroglycan is selectively cleaved at the parenchymal basement membrane at sites of leukocyte extravasation in experimental autoimmune encephalomyelitis. J Exp Med. 2006;203:1007–19.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Baumann E, Preston E, Slinn J, Stanimirovic D. Post-ischemic hypothermia attenuates loss of the vascular basement membrane proteins, agrin and sparc, and the blood-brain barrier disruption after global cerebral ischemia. Brain Res. 2009;1269:185–97.

    Article  PubMed  CAS  Google Scholar 

  49. Cardoso FL, Brites D, Brito MA. Looking at the blood-brain barrier: molecular anatomy and possible investigation approaches. Brain Res Rev. 2010;64:328–63.

    Article  CAS  PubMed  Google Scholar 

  50. Miner JH, Li C, Mudd JL, Go G, Sutherland AE. Compositional and structural requirements for laminin and basement membranes during mouse embryo implantation and gastrulation. Development. 2004;131:2247–56.

    Article  PubMed  CAS  Google Scholar 

  51. Hallmann R, Horn N, Selg M, Wendler O, Pausch F, Sorokin LM. Expression and function of laminins in the embryonic and mature vasculature. Physiol Rev. 2005;85:979–1000.

    Article  CAS  PubMed  Google Scholar 

  52. Chen ZL, Haegeli V, Yu H, Strickland S. Cortical deficiency of laminin gamma1 impairs the akt/gsk-3beta signaling pathway and leads to defects in neurite outgrowth and neuronal migration. Dev Biol. 2009;327:158–68.

    Article  PubMed  CAS  Google Scholar 

  53. Coles EG, Gammill LS, Miner JH, Bronner-Fraser M. Abnormalities in neural crest cell migration in laminin alpha5 mutant mice. Dev Biol. 2006;289:218–28.

    Article  PubMed  CAS  Google Scholar 

  54. Cui J, Chen S, Zhang C, Meng F, Wu W, Hu R, et al. Inhibition of mmp-9 by a selective gelatinase inhibitor protects neurovasculature from embolic focal cerebral ischemia. Mol Neurodegener. 2012;7:21.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Gu Z, Cui J, Brown S, Fridman R, Mobashery S, Strongin AY, 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. 2005;25:6401–8.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  56. Sorokin L, Girg W, Gopfert T, Hallmann R, Deutzmann R. Expression of novel 400-kda laminin chains by mouse and bovine endothelial cells. Eur J Biochem. 1994;223:603–10.

    Article  PubMed  CAS  Google Scholar 

  57. Sixt M, Engelhardt B, Pausch F, Hallmann R, Wendler O, Sorokin LM. Endothelial cell laminin isoforms, laminins 8 and 10, play decisive roles in t cell recruitment across the blood-brain barrier in experimental autoimmune encephalomyelitis. J Cell Biol. 2001;153:933–46.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Tilling T, Engelbertz C, Decker S, Korte D, Huwel S, Galla HJ. Expression and adhesive properties of basement membrane proteins in cerebral capillary endothelial cell cultures. Cell Tissue Res. 2002;310:19–29.

    Article  PubMed  CAS  Google Scholar 

  59. Menezes MJ, McClenahan FK, Leiton CV, Aranmolate A, Shan X, Colognato H. The extracellular matrix protein laminin alpha2 regulates the maturation and function of the blood-brain barrier. J Neurosci. 2014;34:15260–80.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  60. Yao Y, Chen ZL, Norris EH, Strickland S. Astrocytic laminin regulates pericyte differentiation and maintains blood brain barrier integrity. Nat Commun. 2014;5:3413.

    Article  PubMed  CAS  Google Scholar 

  61. Gautam J, Zhang X, Yao Y. The role of pericytic laminin in blood brain barrier integrity maintenance. Sci Rep. 2016;6:36450.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. Frisch SM, Francis H. Disruption of epithelial cell-matrix interactions induces apoptosis. J Cell Biol. 1994;124:619–26.

    Article  PubMed  CAS  Google Scholar 

  63. Gu Z, Kaul M, Yan B, Kridel SJ, Cui J, Strongin A, et al. S-nitrosylation of matrix metalloproteinases: signaling pathway to neuronal cell death. Science. 2002;297:1186–90.

    Article  PubMed  CAS  Google Scholar 

  64. Li L, Liu F, Welser-Alves JV, McCullough LD, Milner R. Upregulation of fibronectin and the alpha5beta1 and alphavbeta3 integrins on blood vessels within the cerebral ischemic penumbra. Exp Neurol. 2012;233:283–91.

    Article  PubMed  CAS  Google Scholar 

  65. Chen ZL, Yao Y, Norris EH, Kruyer A, Jno-Charles O, Akhmerov A, et al. Ablation of astrocytic laminin impairs vascular smooth muscle cell function and leads to hemorrhagic stroke. J Cell Biol. 2013;202:381–95.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Wagner S, Tagaya M, Koziol JA, Quaranta V, del Zoppo GJ. Rapid disruption of an astrocyte interaction with the extracellular matrix mediated by integrin alpha 6 beta 4 during focal cerebral ischemia/reperfusion. Stroke. 1997;28:858–65.

    Article  PubMed  CAS  Google Scholar 

  67. Tagaya M, Haring HP, Stuiver I, Wagner S, Abumiya T, Lucero J, et al. Rapid loss of microvascular integrin expression during focal brain ischemia reflects neuron injury. J Cereb Blood Flow Metab. 2001;21:835–46.

    Article  PubMed  CAS  Google Scholar 

  68. Milner R, Hung S, Wang X, Spatz M, del Zoppo GJ. The rapid decrease in astrocyte-associated dystroglycan expression by focal cerebral ischemia is protease-dependent. J Cereb Blood Flow Metab. 2008;28:812–23.

    Article  PubMed  CAS  Google Scholar 

  69. Chen ZL, Strickland S. Neuronal death in the hippocampus is promoted by plasmin-catalyzed degradation of laminin. Cell. 1997;91:917–25.

    Article  PubMed  CAS  Google Scholar 

  70. Lakhan SE, Kirchgessner A, Tepper D, Leonard A. Matrix metalloproteinases and blood-brain barrier disruption in acute ischemic stroke. Front Neurol. 2013;4:32.

    PubMed  PubMed Central  CAS  Google Scholar 

  71. del Zoppo GJ. The neurovascular unit, matrix proteases, and innate inflammation. Ann N Y Acad Sci. 2010;1207:46–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  72. Kawakita K, Kawai N, Kuroda Y, Yasashita S, Nagao S. Expression of matrix metalloproteinase-9 in thrombin-induced brain edema formation in rats. J Stroke Cerebrovasc Dis. 2006;15:88–95.

    Article  PubMed  Google Scholar 

  73. Li L, Tao Y, Tang J, Chen Q, Yang Y, Feng Z, et al. A cannabinoid receptor 2 agonist prevents thrombin-induced blood-brain barrier damage via the inhibition of microglial activation and matrix metalloproteinase expression in rats. Transl Stroke Res. 2015;6:467–77.

    Article  PubMed  CAS  Google Scholar 

  74. Hadass O, Tomlinson BN, Gooyit M, Chen S, Purdy JJ, Walker JM, et al. Selective inhibition of matrix metalloproteinase-9 attenuates secondary damage resulting from severe traumatic brain injury. PLoS One. 2013;8:e76904.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. Horstmann S, Kalb P, Koziol J, Gardner H, Wagner S. Profiles of matrix metalloproteinases, their inhibitors, and laminin in stroke patients: influence of different therapies. Stroke. 2003;34:2165–70.

    Article  PubMed  Google Scholar 

  76. Switzer JA, Hess DC, Ergul A, Waller JL, Machado LS, Portik-Dobos V, et al. Matrix metalloproteinase-9 in an exploratory trial of intravenous minocycline for acute ischemic stroke. Stroke. 2011;42:2633–5.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Castellanos M, Leira R, Serena J, Pumar JM, Lizasoain I, Castillo J, et al. Plasma metalloproteinase-9 concentration predicts hemorrhagic transformation in acute ischemic stroke. Stroke. 2003;34:40–6.

    Article  PubMed  CAS  Google Scholar 

  78. Asahi M, Wang X, Mori T, Sumii T, Jung JC, Moskowitz MA, et al. Effects of matrix metalloproteinase-9 gene knock-out on the proteolysis of blood-brain barrier and white matter components after cerebral ischemia. J Neurosci. 2001;21:7724–32.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  79. Wang J, Tsirka SE. Neuroprotection by inhibition of matrix metalloproteinases in a mouse model of intracerebral haemorrhage. Brain. 2005;128:1622–33.

    Article  PubMed  Google Scholar 

  80. Alluri H, Wilson RL, Anasooya Shaji C, Wiggins-Dohlvik K, Patel S, Liu Y, et al. Melatonin preserves blood-brain barrier integrity and permeability via matrix metalloproteinase-9 inhibition. PLoS One. 2016;11:e0154427.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. Hu X, De Silva TM, Chen J, Faraci FM. Cerebral vascular disease and neurovascular injury in ischemic stroke. Circ Res. 2017;120:449–71.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  82. Underly RG, Levy M, Hartmann DA, Grant RI, Watson AN, Shih AY. Pericytes as inducers of rapid, matrix metalloproteinase-9-dependent capillary damage during ischemia. J Neurosci. 2017;37:129–40.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. Yang Y, Estrada EY, Thompson JF, Liu W, Rosenberg GA. Matrix metalloproteinase-mediated disruption of tight junction proteins in cerebral vessels is reversed by synthetic matrix metalloproteinase inhibitor in focal ischemia in rat. J Cereb Blood Flow Metab. 2007;27:697–709.

    Article  PubMed  CAS  Google Scholar 

  84. Mishiro K, Ishiguro M, Suzuki Y, Tsuruma K, Shimazawa M, Hara H. A broad-spectrum matrix metalloproteinase inhibitor prevents hemorrhagic complications induced by tissue plasminogen activator in mice. Neuroscience. 2012;205:39–48.

    Article  PubMed  CAS  Google Scholar 

  85. Yang Y, Thompson JF, Taheri S, Salayandia VM, McAvoy TA, Hill JW, et al. Early inhibition of mmp activity in ischemic rat brain promotes expression of tight junction proteins and angiogenesis during recovery. J Cereb Blood Flow Metab. 2013;33:1104–14.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. del Zoppo GJ, von Kummer R, Hamann GF. Ischaemic damage of brain microvessels: inherent risks for thrombolytic treatment in stroke. J Neurol Neurosurg Psychiatry. 1998;65:1–9.

    Article  PubMed  Google Scholar 

  87. Del Zoppo GJ, Milner R, Mabuchi T, Hung S, Wang X, Koziol JA. Vascular matrix adhesion and the blood-brain barrier. Biochem Soc Trans. 2006;34:1261–6.

    Article  PubMed  Google Scholar 

  88. Dore-Duffy P, Owen C, Balabanov R, Murphy S, Beaumont T, Rafols JA. Pericyte migration from the vascular wall in response to traumatic brain injury. Microvasc Res. 2000;60:55–69.

    Article  PubMed  CAS  Google Scholar 

  89. Liu S, Agalliu D, Yu C, Fisher M. The role of pericytes in blood-brain barrier function and stroke. Curr Pharm Des. 2012;18:3653–62.

    Article  PubMed  CAS  Google Scholar 

  90. Fernandez-Klett F, Priller J. Diverse functions of pericytes in cerebral blood flow regulation and ischemia. J Cereb Blood Flow Metab. 2015;35:883–7.

    Article  PubMed  PubMed Central  Google Scholar 

  91. Hall CN, Reynell C, Gesslein B, Hamilton NB, Mishra A, Sutherland BA, et al. Capillary pericytes regulate cerebral blood flow in health and disease. Nature. 2014;508:55–60.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  92. Dawson DA, Ruetzler CA, Hallenbeck JM. Temporal impairment of microcirculatory perfusion following focal cerebral ischemia in the spontaneously hypertensive rat. Brain Res. 1997;749:200–8.

    Article  PubMed  CAS  Google Scholar 

  93. Yemisci M, Gursoy-Ozdemir Y, Vural A, Can A, Topalkara K, Dalkara T. Pericyte contraction induced by oxidative-nitrative stress impairs capillary reflow despite successful opening of an occluded cerebral artery. Nat Med. 2009;15:1031–7.

    Article  CAS  PubMed  Google Scholar 

  94. Nedelmann M, Ritschel N, Doenges S, Langheinrich AC, Acker T, Reuter P, et al. Combined contrast-enhanced ultrasound and rt-pa treatment is safe and improves impaired microcirculation after reperfusion of middle cerebral artery occlusion. J Cereb Blood Flow Metab. 2010;30:1712–20.

    Article  PubMed  PubMed Central  Google Scholar 

  95. An H, Ford AL, Vo K, Eldeniz C, Ponisio R, Zhu H, et al. Early changes of tissue perfusion after tissue plasminogen activator in hyperacute ischemic stroke. Stroke. 2011;42:65–72.

    Article  PubMed  Google Scholar 

  96. Al Ahmad A, Gassmann M, Ogunshola OO. Maintaining blood-brain barrier integrity: pericytes perform better than astrocytes during prolonged oxygen deprivation. J Cell Physiol. 2009;218:612–22.

    Article  PubMed  CAS  Google Scholar 

  97. Daneman R, Zhou L, Agalliu D, Cahoy JD, Kaushal A, Barres BA. The mouse blood-brain barrier transcriptome: a new resource for understanding the development and function of brain endothelial cells. PLoS One. 2010;5:e13741.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  98. Takata F, Dohgu S, Matsumoto J, Takahashi H, Machida T, Wakigawa T, et al. Brain pericytes among cells constituting the blood-brain barrier are highly sensitive to tumor necrosis factor-alpha, releasing matrix metalloproteinase-9 and migrating in vitro. J Neuroinflammation. 2011;8:106.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  99. Rosenberg GA, Estrada EY, Dencoff JE. Matrix metalloproteinases and timps are associated with blood-brain barrier opening after reperfusion in rat brain. Stroke. 1998;29:2189–95.

    Article  PubMed  CAS  Google Scholar 

  100. Jin R, Yang G, Li G. Molecular insights and therapeutic targets for blood-brain barrier disruption in ischemic stroke: critical role of matrix metalloproteinases and tissue-type plasminogen activator. Neurobiol Dis. 2010;38:376–85.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  101. Heo JH, Lucero J, Abumiya T, Koziol JA, Copeland BR, del Zoppo GJ. Matrix metalloproteinases increase very early during experimental focal cerebral ischemia. J Cereb Blood Flow Metab. 1999;19:624–33.

    Article  PubMed  CAS  Google Scholar 

  102. Shi Y, Zhang L, Pu H, Mao L, Hu X, Jiang X, et al. Rapid endothelial cytoskeletal reorganization enables early blood-brain barrier disruption and long-term ischaemic reperfusion brain injury. Nat Commun. 2016;7:10523.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  103. Benchenane K, Berezowski V, Fernandez-Monreal M, Brillault J, Valable S, Dehouck MP, et al. Oxygen glucose deprivation switches the transport of tpa across the blood-brain barrier from an lrp-dependent to an increased lrp-independent process. Stroke. 2005;36:1065–70.

    Article  PubMed  CAS  Google Scholar 

  104. Niego B, Medcalf RL. Plasmin-dependent modulation of the blood-brain barrier: a major consideration during tpa-induced thrombolysis? J Cereb Blood Flow Metab. 2014;34:1283–96.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  105. Aoki T, Sumii T, Mori T, Wang X, Lo EH. Blood-brain barrier disruption and matrix metalloproteinase-9 expression during reperfusion injury: mechanical versus embolic focal ischemia in spontaneously hypertensive rats. Stroke. 2002;33:2711–7.

    Article  PubMed  Google Scholar 

  106. Tsuji K, Aoki T, Tejima E, Arai K, Lee SR, Atochin DN, et al. Tissue plasminogen activator promotes matrix metalloproteinase-9 upregulation after focal cerebral ischemia. Stroke. 2005;36:1954–9.

    Article  PubMed  CAS  Google Scholar 

  107. Wang X, Lee SR, Arai K, Lee SR, Tsuji K, Rebeck GW, et al. Lipoprotein receptor-mediated induction of matrix metalloproteinase by tissue plasminogen activator. Nat Med. 2003;9:1313–7.

    Article  PubMed  CAS  Google Scholar 

  108. Murata Y, Rosell A, Scannevin RH, Rhodes KJ, Wang X, Lo EH. Extension of the thrombolytic time window with minocycline in experimental stroke. Stroke. 2008;39:3372–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  109. Yepes M, Sandkvist M, Moore EG, Bugge TH, Strickland DK, Lawrence DA. Tissue-type plasminogen activator induces opening of the blood-brain barrier via the ldl receptor-related protein. J Clin Invest. 2003;112:1533–40.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  110. Montaner J, Molina CA, Monasterio J, Abilleira S, Arenillas JF, Ribo M, et al. Matrix metalloproteinase-9 pretreatment level predicts intracranial hemorrhagic complications after thrombolysis in human stroke. Circulation. 2003;107:598–603.

    Article  PubMed  CAS  Google Scholar 

  111. Jovin TG, Chamorro A, Cobo E, de Miquel MA, Molina CA, Rovira A, et al. Thrombectomy within 8 hours after symptom onset in ischemic stroke. N Engl J Med. 2015;372:2296–306.

    Article  CAS  PubMed  Google Scholar 

  112. Rodrigues FB, Neves JB, Caldeira D, Ferro JM, Ferreira JJ, Costa J. Endovascular treatment versus medical care alone for ischaemic stroke: systematic review and meta-analysis. BMJ. 2016;353:i1754.

    Article  PubMed  PubMed Central  Google Scholar 

  113. Ciccone A, Valvassori L, SYNTHESIS Expansion Investigators. Endovascular treatment for acute ischemic stroke. N Engl J Med. 2013;368:2433–4.

    Article  PubMed  CAS  Google Scholar 

  114. Miao Z, Huo X, Gao F, Liao X, Wang C, Peng Y, et al. Endovascular therapy for Acute ischemic Stroke Trial (EAST): study protocol for a prospective, multicentre control trial in China. Stroke Vasc Neurol. 2016;1:e000022.

    Google Scholar 

  115. Pires PW, Rogers CT, McClain JL, Garver HS, Fink GD, Dorrance AM. Doxycycline, a matrix metalloprotease inhibitor, reduces vascular remodeling and damage after cerebral ischemia in stroke-prone spontaneously hypertensive rats. Am J Physiol Heart Circ Physiol. 2011;301:H87–97.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  116. Fagan SC, Cronic LE, Hess DC. Minocycline development for acute ischemic stroke. Transl Stroke Res. 2011;2:202–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  117. Chen W, Hartman R, Ayer R, Marcantonio S, Kamper J, Tang J, et al. Matrix metalloproteinases inhibition provides neuroprotection against hypoxia-ischemia in the developing brain. J Neurochem. 2009;111:726–36.

    Article  PubMed  CAS  Google Scholar 

  118. Lapchak PA, Chapman DF, Zivin JA. Metalloproteinase inhibition reduces thrombolytic (tissue plasminogen activator)-induced hemorrhage after thromboembolic stroke. Stroke. 2000;31:3034–40.

    Article  PubMed  CAS  Google Scholar 

  119. Lampl Y, Boaz M, Gilad R, Lorberboym M, Dabby R, Rapoport A, et al. Minocycline treatment in acute stroke: an open-label, evaluator-blinded study. Neurology. 2007;69:1404–10.

    Article  PubMed  CAS  Google Scholar 

  120. Kohler E, Prentice DA, Bates TR, Hankey GJ, Claxton A, van Heerden J, et al. Intravenous minocycline in acute stroke: a randomized, controlled pilot study and meta-analysis. Stroke. 2013;44:2493–9.

    Article  PubMed  CAS  Google Scholar 

  121. Gooyit M, Suckow MA, Schroeder VA, Wolter WR, Mobashery S, Chang M. Selective gelatinase inhibitor neuroprotective agents cross the blood-brain barrier. ACS Chem Neurosci. 2012;3:730–6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  122. Stroke Council American Heart Association, American Stroke Association. Statins after ischemic stroke and transient ischemic attack: an advisory statement from the Stroke Council, American Heart Association and American Stroke Association. Stroke. 2004;35:1023.

    Google Scholar 

  123. McFarland AJ, Anoopkumar-Dukie S, Arora DS, Grant GD, McDermott CM, Perkins AV, et al. Molecular mechanisms underlying the effects of statins in the central nervous system. Int J Mol Sci. 2014;15:20607–37.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  124. Reuter B, Rodemer C, Grudzenski S, Meairs S, Bugert P, Hennerici MG, et al. Effect of simvastatin on mmps and timps in human brain endothelial cells and experimental stroke. Transl Stroke Res. 2015;6:156–9.

    Article  PubMed  CAS  Google Scholar 

  125. Shang J, Yamashita T, Kono S, Morihara R, Nakano Y, Fukui Y, et al. Effects of pretreatment with warfarin or rivaroxaban on neurovascular unit dissociation after tissue plasminogen activator thrombolysis in ischemic rat brain. J Stroke Cerebrovasc Dis. 2016;25:1997–2003.

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Interdisciplinary Neuroscience Program, University of Missouri School of Medicine, Columbia, MO, USA

    Shanyan Chen & Hailong Song

  2. Department of Pathology and Anatomical Sciences, University of Missouri School of Medicine, Columbia, MO, USA

    Shanyan Chen, Hailong Song, Jiankun Cui, Grace Y. Sun & Zezong Gu

  3. Harry S. Truman Memorial Veterans’ Hospital Research Service, Columbia, MO, USA

    Jiankun Cui & Zezong Gu

  4. Department of Neurology, University of Missouri School of Medicine, Columbia, MO, USA

    Joel I. Shenker

  5. Department of Neurosurgery, Southwest Hospital, Third Military Medical University, Chongqing, China

    Yujie Chen & Hua Feng

  6. Department of Biochemistry, University of Missouri School of Medicine, Columbia, MO, USA

    Grace Y. Sun

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  1. Shanyan Chen
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  8. Zezong Gu
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Correspondence to Zezong Gu .

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Editors and Affiliations

  1. Department of Vascular Neurosurgery, PLA Rocket Force General Hospital, Beijing, China

    Weijian Jiang

  2. Department of Neurology, University of California Irvine, Irvine, California, USA

    Wengui Yu

  3. Department of Neurosurgery, Tangdu Hospital of Air Force Medical University, Xi’an, China

    Yan Qu

  4. Department of Neurosurgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China

    Zhongsong Shi

  5. Department of Neurology, The First Affiliated Hospital School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China

    Benyan Luo

  6. Department of Anesthesiology, Loma Linda University, Loma Linda, California, USA

    John H. Zhang

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Chen, S. et al. (2018). Gelatinase-Mediated Impairment of Microvascular Beds in Cerebral Ischemia and Reperfusion Injury. In: Jiang, W., Yu, W., Qu, Y., Shi, Z., Luo, B., Zhang, J. (eds) Cerebral Ischemic Reperfusion Injuries (CIRI). Springer Series in Translational Stroke Research. Springer, Cham. https://doi.org/10.1007/978-3-319-90194-7_1

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