Blood–Brain Barrier and Stroke

  • David Fernández-López
  • Zinaida S. VexlerEmail author
Part of the Topics in Medicinal Chemistry book series (TMC, volume 10)


Stroke disintegrates communications within a highly dynamic and regulated ensemble of cells that constitutes the blood–brain barrier (BBB), endothelial cells, astrocytic end feet that surround blood vessels, the basement membrane (BM)/extracellular matrix (ECM), and pericytes, inducing and propagating injury. We discuss the effects of experimental stroke on individual cell constituents of the BBB and how these changes affect structural and functional integrity of the BBB in relation to acute injury and repair. The age at the time of stroke, from the newborn period to adulthood and older, can markedly affect the particulars of deregulation, processes that we also discuss in this chapter.


Extracellular matrix Inflammation Microglia Middle cerebral artery occlusion Neonatal stroke 



The authors have been supported by RO1 NS55915 (Z.S.V), RO1 NS44025 (Z.S.V), R21 NS80015 (Z.S.V), NS35902 (Z.S.V), AHA GIA 0855235F (Z.S.V), Ramon Areces Foundation, Madrid, Spain (D.F.L), and AHA postdoctoral fellowship (D.F.L.).


  1. 1.
    Cummins PM (2012) Occludin: one protein, many forms. Mol Cell Biol 32:242–250Google Scholar
  2. 2.
    Asahi M, Wang X, Mori T, Sumii T, Jung JC, Moskowitz MA, Fini ME, Lo EH (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 21:7724–7732Google Scholar
  3. 3.
    Yang Y, Estrada EY, Thompson JF, Liu W, Rosenberg GA (2007) 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 27:697–709Google Scholar
  4. 4.
    Liu J, Jin X, Liu KJ, Liu W (2012) Matrix metalloproteinase-2-mediated occludin degradation and caveolin-1-mediated claudin-5 redistribution contribute to blood–brain barrier damage in early ischemic stroke stage. J Neurosci 32:3044–3057Google Scholar
  5. 5.
    Petty MA, Lo EH (2002) Junctional complexes of the blood–brain barrier: permeability changes in neuroinflammation. Prog Neurobiol 68:311–323Google Scholar
  6. 6.
    Dejana E, Giampietro C (2012) Vascular endothelial-cadherin and vascular stability. Curr Opin Hematol 19:218–223Google Scholar
  7. 7.
    Paolinelli R, Corada M, Orsenigo F, Dejana E (2011) The molecular basis of the blood brain barrier differentiation and maintenance. Is it still a mystery? Pharmacol Res 63:165–171Google Scholar
  8. 8.
    Wacker BK, Freie AB, Perfater JL, Gidday JM (2012) Junctional protein regulation by sphingosine kinase 2 contributes to blood–brain barrier protection in hypoxic preconditioning-induced cerebral ischemic tolerance. J Cereb Blood Flow Metab 32:1014–1023Google Scholar
  9. 9.
    Freeman LR, Keller JN (1822) Oxidative stress and cerebral endothelial cells: regulation of the blood–brain barrier and antioxidant based interventions. Biochim Biophys Acta 2012:822–829Google Scholar
  10. 10.
    Rizzo MT, Leaver HA (2010) Brain endothelial cell death: modes, signaling pathways, and relevance to neural development, homeostasis, and disease. Mol Neurobiol 42:52–63Google Scholar
  11. 11.
    Fernandez Lopez D, Faustino J, Daneman R, Zhou L, Lee SY, Derugin N, Wendland MF, Vexler ZS (2012) Blood–brain barrier permeability is increased after acute adult stroke but not neonatal stroke. J Neurosci 32:9588–9600Google Scholar
  12. 12.
    Armulik A, Genove G, Mae M, Nisancioglu MH, Wallgard E, Niaudet C, He L, Norlin J, Lindblom P, Strittmatter K, Johansson BR, Betsholtz C (2010) Pericytes regulate the blood–brain barrier. Nature 468:557–561Google Scholar
  13. 13.
    Daneman R, Zhou L, Kebede AA, Barres BA (2010) Pericytes are required for blood–brain barrier integrity during embryogenesis. Nature 468:562–566Google Scholar
  14. 14.
    Winkler EA, Bell RD, Zlokovic BV (2011) Central nervous system pericytes in health and disease. Nat Neurosci 14:1398–1405Google Scholar
  15. 15.
    Bonkowski D, Katyshev V, Balabanov RD, Borisov A, Dore-Duffy P (2011) The CNS microvascular pericyte: pericyte–astrocyte crosstalk in the regulation of tissue survival. Fluids Barriers CNS 8:8Google Scholar
  16. 16.
    Liu S, Agalliu D, Yu C, Fisher M (2012) The role of pericytes in blood–brain barrier function and stroke. Curr Pharm Des 18:3653–3662Google Scholar
  17. 17.
    Duz B, Oztas E, Erginay T, Erdogan E, Gonul E (2007) The effect of moderate hypothermia in acute ischemic stroke on pericyte migration: an ultrastructural study. Cryobiology 55:279–284Google Scholar
  18. 18.
    Gonul E, Duz B, Kahraman S, Kayali H, Kubar A, Timurkaynak E (2002) Early pericyte response to brain hypoxia in cats: an ultrastructural study. Microvasc Res 64:116–119Google Scholar
  19. 19.
    Fernandez-Klett F, Potas JR, Hilpert D, Blazej K, Radke J, Huck J, Engel O, Stenzel W, Genove G, Priller J (2013) Early loss of pericytes and perivascular stromal cell-induced scar formation after stroke. J Cereb Blood Flow Metab 33:428–439Google Scholar
  20. 20.
    Fukuda S, Fini CA, Mabuchi T, Koziol JA, Eggleston LL Jr, del Zoppo GJ (2004) Focal cerebral ischemia induces active proteases that degrade microvascular matrix. Stroke 35:998–1004Google Scholar
  21. 21.
    Takata F, Dohgu S, Matsumoto J, Takahashi H, Machida T, Wakigawa T, Harada E, Miyaji H, Koga M, Nishioku T, Yamauchi A, Kataoka Y (2011) 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 8:106Google Scholar
  22. 22.
    Skalli O, Pelte MF, Peclet MC, Gabbiani G, Gugliotta P, Bussolati G, Ravazzola M, Orci L (1989) Alpha-smooth muscle actin, a differentiation marker of smooth muscle cells, is present in microfilamentous bundles of pericytes. J Histochem Cytochem 37:315–321Google Scholar
  23. 23.
    Yemisci M, Gursoy-Ozdemir Y, Vural A, Can A, Topalkara K, Dalkara T (2009) Pericyte contraction induced by oxidative-nitrative stress impairs capillary reflow despite successful opening of an occluded cerebral artery. Nat Med 15:1031–1037Google Scholar
  24. 24.
    Dalkara T, Gursoy-Ozdemir Y, Yemisci M (2011) Brain microvascular pericytes in health and disease. Acta Neuropathol 122:1–9Google Scholar
  25. 25.
    Zechariah A, Elali A, Doeppner TR, Jin F, Hasan MR, Helfrich I, Mies G, Hermann DM (2013) Vascular endothelial growth factor promotes pericyte coverage of brain capillaries, improves cerebral blood flow during subsequent focal cerebral ischemia, and preserves the metabolic penumbra. Stroke 44(6):1690–1697Google Scholar
  26. 26.
    Rash JE, Yasumura T, Hudson CS, Agre P, Nielsen S (1998) Direct immunogold labeling of aquaporin-4 in square arrays of astrocyte and ependymocyte plasma membranes in rat brain and spinal cord. Proc Natl Acad Sci U S A 95:11981–11986Google Scholar
  27. 27.
    Nagelhus EA, Mathiisen TM, Ottersen OP (2004) Aquaporin-4 in the central nervous system: cellular and subcellular distribution and coexpression with kir4.1. Neuroscience 129:905–913Google Scholar
  28. 28.
    Neely JD, Amiry-Moghaddam M, Ottersen OP, Froehner SC, Agre P, Adams ME (2001) Syntrophin-dependent expression and localization of aquaporin-4 water channel protein. Proc Natl Acad Sci U S A 98:14108–14113Google Scholar
  29. 29.
    Zador Z, Stiver S, Wang V, Manley GT (2009) Role of aquaporin-4 in cerebral edema and stroke. Handb Exp Pharmacol 190:159–170Google Scholar
  30. 30.
    Zelaznik HN, Vaughn AJ, Green JT, Smith AL, Hoza B, Linnea K (2012) Motor timing deficits in children with attention-deficit/hyperactivity disorder. Hum Mov Sci 31:255–265Google Scholar
  31. 31.
    Manley GT, Binder DK, Papadopoulos MC, Verkman AS (2004) New insights into water transport and edema in the central nervous system from phenotype analysis of aquaporin-4 null mice. Neuroscience 129:983–991Google Scholar
  32. 32.
    Papadopoulos MC, Manley GT, Krishna S, Verkman AS (2004) Aquaporin-4 facilitates reabsorption of excess fluid in vasogenic brain edema. FASEB J 18:1291–1293Google Scholar
  33. 33.
    Tagaya M, Haring HP, Stuiver I, Wagner S, Abumiya T, Lucero J, Lee P, Copeland BR, Seiffert D, del Zoppo GJ (2001) Rapid loss of microvascular integrin expression during focal brain ischemia reflects neuron injury. J Cereb Blood Flow Metab 21:835–846Google Scholar
  34. 34.
    Steiner E, Enzmann GU, Lin S, Ghavampour S, Hannocks MJ, Zuber B, Ruegg MA, Sorokin L, Engelhardt B (2012) Loss of astrocyte polarization upon transient focal brain ischemia as a possible mechanism to counteract early edema formation. Glia 60:1646–1659Google Scholar
  35. 35.
    Ezan P, Andre P, Cisternino S, Saubamea B, Boulay AC, Doutremer S, Thomas MA, Quenech'du N, Giaume C, Cohen-Salmon M (2012) Deletion of astroglial connexins weakens the blood–brain barrier. J Cereb Blood Flow Metab 32:1457–1467Google Scholar
  36. 36.
    Engelhardt B, Sorokin L (2009) The blood–brain and the blood-cerebrospinal fluid barriers: function and dysfunction. Semin Immunopathol 31:497–511Google Scholar
  37. 37.
    Wang J, Milner R (2006) Fibronectin promotes brain capillary endothelial cell survival and proliferation through alpha5beta1 and alphavbeta3 integrins via map kinase signalling. J Neurochem 96:148–159Google Scholar
  38. 38.
    Willis CL, Leach L, Clarke GJ, Nolan CC, Ray DE (2004) Reversible disruption of tight junction complexes in the rat blood–brain barrier, following transitory focal astrocyte loss. Glia 48:1–13Google Scholar
  39. 39.
    Goetz JG, Joshi B, Lajoie P, Strugnell SS, Scudamore T, Kojic LD, Nabi IR (2008) Concerted regulation of focal adhesion dynamics by galectin-3 and tyrosine-phosphorylated caveolin-1. J Cell Biol 180:1261–1275Google Scholar
  40. 40.
    Gould DB, Phalan FC, Breedveld GJ, van Mil SE, Smith RS, Schimenti JC, Aguglia U, van der Knaap MS, Heutink P, John SW (2005) Mutations in col4a1 cause perinatal cerebral hemorrhage and porencephaly. Science 308:1167–1171Google Scholar
  41. 41.
    Labelle-Dumais C, Dilworth DJ, Harrington EP, de Leau M, Lyons D, Kabaeva Z, Manzini MC, Dobyns WB, Walsh CA, Michele DE, Gould DB (2011) Col4a1 mutations cause ocular dysgenesis, neuronal localization defects, and myopathy in mice and walker-warburg syndrome in humans. PLoS Genet 7:e1002062Google Scholar
  42. 42.
    Kuo DS, Labelle-Dumais C, Gould DB (2012) Col4a1 and col4a2 mutations and disease: insights into pathogenic mechanisms and potential therapeutic targets. Hum Mol Genet 21:R97–R110Google Scholar
  43. 43.
    Colognato H, Yurchenco PD (2000) Form and function: the laminin family of heterotrimers. Dev Dyn 218:213–234Google Scholar
  44. 44.
    Yu WM, Chen ZL, North AJ, Strickland S (2009) Laminin is required for schwann cell morphogenesis. J Cell Sci 122:929–936Google Scholar
  45. 45.
    Carlson KB, Singh P, Feaster MM, Ramnarain A, Pavlides C, Chen ZL, Yu WM, Feltri ML, Strickland S (2011) Mesenchymal stem cells facilitate axon sorting, myelination, and functional recovery in paralyzed mice deficient in Schwann cell-derived laminin. Glia 59:267–277Google Scholar
  46. 46.
    Han Q, Li B, Feng H, Xiao Z, Chen B, Zhao Y, Huang J, Dai J (2011) The promotion of cerebral ischemia recovery in rats by laminin-binding BDNF. Biomaterials 32:5077–5085Google Scholar
  47. 47.
    Rosenberg GA, Estrada EY, Dencoff JE (1998) Matrix metalloproteinases and TIMPs are associated with blood–brain barrier opening after reperfusion in rat brain. Stroke 29:2189–2195Google Scholar
  48. 48.
    Rosenberg GA, Yang Y (2007) Vasogenic edema due to tight junction disruption by matrix metalloproteinases in cerebral ischemia. Neurosurg Focus 22:E4Google Scholar
  49. 49.
    McColl BW, Rose N, Robson FH, Rothwell NJ, Lawrence CB. Increased brain microvascular mmp-9 and incidence of haemorrhagic transformation in obese mice after experimental stroke. J Cereb Blood Flow Metab.30:267-272Google Scholar
  50. 50.
    Asahi M, Asahi K, Jung JC, del Zoppo GJ, Fini ME, Lo EH (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 20:1681–1689Google Scholar
  51. 51.
    Asahi M, Sumii T, Fini ME, Itohara S, Lo EH (2001) Matrix metalloproteinase 2 gene knockout has no effect on acute brain injury after focal ischemia. Neuroreport 12:3003–3007Google Scholar
  52. 52.
    Suofu Y, Clark JF, Broderick JP, Kurosawa Y, Wagner KR, Lu A (2012) Matrix metalloproteinase-2 or -9 deletions protect against hemorrhagic transformation during early stage of cerebral ischemia and reperfusion. Neuroscience 212:180–189Google Scholar
  53. 53.
    McColl BW, Rothwell NJ, Allan SM (2008) Systemic inflammation alters the kinetics of cerebrovascular tight junction disruption after experimental stroke in mice. J Neurosci 28:9451–9462Google Scholar
  54. 54.
    Gidday JM, Gasche YG, Copin JC, Shah AR, Perez RS, Shapiro SD, Chan PH, Park TS (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–H568Google Scholar
  55. 55.
    Zhao BQ, Wang S, Kim HY, Storrie H, Rosen BR, Mooney DJ, Wang X, Lo EH (2006) Role of matrix metalloproteinases in delayed cortical responses after stroke. Nat Med 12:441–445Google Scholar
  56. 56.
    Cunningham LA, Wetzel M, Rosenberg GA (2005) Multiple roles for MMPs and TIMPs in cerebral ischemia. Glia 50:329–339Google Scholar
  57. 57.
    Iadecola C, Anrather J (2011) The immunology of stroke: from mechanisms to translation. Nat Med 17:796–808Google Scholar
  58. 58.
    Osborn L, Hession C, Tizard R, Vassallo C, Luhowskyj S, Chi-Rosso G, Lobb R (1989) Direct expression cloning of vascular cell adhesion molecule 1, a cytokine-induced endothelial protein that binds to lymphocytes. Cell 59:1203–1211Google Scholar
  59. 59.
    Stanimirovic DB, Wong J, Shapiro A, Durkin JP (1997) Increase in surface expression of ICAM-1, VCAM-1 and e-selectin in human cerebromicrovascular endothelial cells subjected to ischemia-like insults. Acta Neurochir Suppl 70:12–16Google Scholar
  60. 60.
    Lindsberg PJ, Sairanen T, Strbian D, Kaste M (2012) Current treatment of basilar artery occlusion. Ann N Y Acad Sci 1268:35–44Google Scholar
  61. 61.
    Ransohoff RM, Kivisakk P, Kidd G (2003) Three or more routes for leukocyte migration into the central nervous system. Nat Rev Immunol 3:569–581Google Scholar
  62. 62.
    Datta YH, Ewenstein BM (2001) Regulated secretion in endothelial cells: biology and clinical implications. Thromb Haemost 86:1148–1155Google Scholar
  63. 63.
    del Zoppo GJ, Hallenbeck JM (2000) Advances in the vascular pathophysiology of ischemic stroke. Thromb Res 98:73–81Google Scholar
  64. 64.
    Williams MR, Azcutia V, Newton G, Alcaide P, Luscinskas FW (2011) Emerging mechanisms of neutrophil recruitment across endothelium. Trends Immunol 32:461–469Google Scholar
  65. 65.
    Yamasaki Y, Matsuo Y, Matsuura N, Onodera H, Itoyama Y, Kogure K (1995) Transient increase of cytokine-induced neutrophil chemoattractant, a member of the interleukin-8 family, in ischemic brain areas after focal ischemia in rats. Stroke 26:318–322, discussion 322-313Google Scholar
  66. 66.
    Baggiolini M (2001) Chemokines in pathology and medicine. J Intern Med 250:91–104Google Scholar
  67. 67.
    Gerard C, Rollins BJ (2001) Chemokines and disease. Nat Immunol 2:108–115Google Scholar
  68. 68.
    Kochanek PM, Hallenbeck JM (1992) Polymorphonuclear leukocytes and monocytes/macrophages in the pathogenesis of cerebral ischemia and stroke. Stroke 23:1367–1379Google Scholar
  69. 69.
    del Zoppo GJ, Schmid-Schonbein GW, Mori E, Copeland BR, Chang CM (1991) Polymorphonuclear leukocytes occlude capillaries following middle cerebral artery occlusion and reperfusion in baboons. Stroke 22:1276–1283Google Scholar
  70. 70.
    Garcia JH, Liu KF, Yoshida Y, Lian J, Chen S, del Zoppo GJ (1994) Influx of leukocytes and platelets in an evolving brain infarct (Wistar rat). Am J Pathol 144:188–199Google Scholar
  71. 71.
    Matsuo Y, Kihara T, Ikeda M, Ninomiya M, Onodera H, Kogure K (1995) Role of neutrophils in radical production during ischemia and reperfusion of the rat brain: effect of neutrophil depletion on extracellular ascorbyl radical formation. J Cereb Blood Flow Metab 15:941–947Google Scholar
  72. 72.
    Zhang L, Zhang ZG, Zhang RL, Lu M, Krams M, Chopp M (2003) Effects of a selective CD11b/CD18 antagonist and recombinant human tissue plasminogen activator treatment alone and in combination in a rat embolic model of stroke. Stroke 34:1790–1795Google Scholar
  73. 73.
    Yamasaki Y, Matsuo Y, Zagorski J, Matsuura N, Onodera H, Itoyama Y, Kogure K (1997) New therapeutic possibility of blocking cytokine-induced neutrophil chemoattractant on transient ischemic brain damage in rats. Brain Res 759:103–111Google Scholar
  74. 74.
    Dunstan CA, Salafranca MN, Adhikari S, Xia Y, Feng L, Harrison JK (1996) Identification of two rat genes orthologous to the human interleukin-8 receptors. J Biol Chem 271:32770–32776Google Scholar
  75. 75.
    Murphy PM, Tiffany HL (1991) Cloning of complementary DNA encoding a functional human interleukin-8 receptor. Science 253:1280–1283Google Scholar
  76. 76.
    Holmes WE, Lee J, Kuang WJ, Rice GC, Wood WI (1991) Structure and functional expression of a human interleukin-8 receptor. Science 253:1278–1280Google Scholar
  77. 77.
    Gu L, Tseng SC, Rollins BJ (1999) Monocyte chemoattractant protein-1. Chem Immunol 72:7–29Google Scholar
  78. 78.
    Mahad DJ, Ransohoff RM (2003) The role of MCP-1 (CCL2) and CCR2 in multiple sclerosis and experimental autoimmune encephalomyelitis (EAE). Semin Immunol 15:23–32Google Scholar
  79. 79.
    Huo Y, Weber C, Forlow SB, Sperandio M, Thatte J, Mack M, Jung S, Littman DR, Ley K (2001) The chemokine KC, but not monocyte chemoattractant protein-1, triggers monocyte arrest on early atherosclerotic endothelium. J Clin Invest 108:1307–1314Google Scholar
  80. 80.
    Glabinski AR, Tani M, Strieter RM, Tuohy VK, Ransohoff RM (1997) Synchronous synthesis of alpha- and beta-chemokines by cells of diverse lineage in the central nervous system of mice with relapses of chronic experimental autoimmune encephalomyelitis. Am J Pathol 150:617–630Google Scholar
  81. 81.
    Horuk R, Martin AW, Wang Z, Schweitzer L, Gerassimides A, Guo H, Lu Z, Hesselgesser J, Perez HD, Kim J, Parker J, Hadley TJ, Peiper SC (1997) Expression of chemokine receptors by subsets of neurons in the central nervous system. J Immunol 158:2882–2890Google Scholar
  82. 82.
    Giovannelli A, Limatola C, Ragozzino D, Mileo AM, Ruggieri A, Ciotti MT, Mercanti D, Santoni A, Eusebi F (1998) CXC chemokines interleukin-8 (IL-8) and growth-related gene product alpha (groalpha) modulate purkinje neuron activity in mouse cerebellum. J Neuroimmunol 92:122–132Google Scholar
  83. 83.
    Wiekowski MT, Chen SC, Zalamea P, Wilburn BP, Kinsley DJ, Sharif WW, Jensen KK, Hedrick JA, Manfra D, Lira SA (2001) Disruption of neutrophil migration in a conditional transgenic model: evidence for CXCR2 desensitization in vivo. J Immunol 167:7102–7110Google Scholar
  84. 84.
    Tani M, Fuentes ME, Peterson JW, Trapp BD, Durham SK, Loy JK, Bravo R, Ransohoff RM, Lira SA (1996) Neutrophil infiltration, glial reaction, and neurological disease in transgenic mice expressing the chemokine N51/KC in oligodendrocytes. J Clin Invest 98:529–539Google Scholar
  85. 85.
    Belayev L, Busto R, Zhao W, Ginsberg MD (1996) Quantitative evaluation of blood–brain barrier permeability following middle cerebral artery occlusion in rats. Brain Res 739:88–96Google Scholar
  86. 86.
    Zhang RL, Chopp M, Chen H, Garcia JH (1994) Temporal profile of ischemic tissue damage, neutrophil response, and vascular plugging following permanent and transient (2 h) middle cerebral artery occlusion in the rat. J Neurol Sci 125:3–10Google Scholar
  87. 87.
    Jiang N, Chopp M, Chahwala S (1998) Neutrophil inhibitory factor treatment of focal cerebral ischemia in the rat. Brain Res 788:25–34Google Scholar
  88. 88.
    Emerich DF, Dean RL 3rd, Bartus RT (2002) The role of leukocytes following cerebral ischemia: pathogenic variable or bystander reaction to emerging infarct? Exp Neurol 173:168–181Google Scholar
  89. 89.
    Mori E, del Zoppo GJ, Chambers JD, Copeland BR, Arfors KE (1992) Inhibition of polymorphonuclear leukocyte adherence suppresses no-reflow after focal cerebral ischemia in baboons. Stroke 23:712–718Google Scholar
  90. 90.
    Tonai T, Shiba K, Taketani Y, Ohmoto Y, Murata K, Muraguchi M, Ohsaki H, Takeda E, Nishisho T (2001) A neutrophil elastase inhibitor (ono-5046) reduces neurologic damage after spinal cord injury in rats. J Neurochem 78:1064–1072Google Scholar
  91. 91.
    Afshar-Kharghan V, Thiagarajan P (2006) Leukocyte adhesion and thrombosis. Curr Opin Hematol 13:34–39Google Scholar
  92. 92.
    Akopov SE, Simonian NA, Grigorian GS (1996) Dynamics of polymorphonuclear leukocyte accumulation in acute cerebral infarction and their correlation with brain tissue damage. Stroke 27:1739–1743Google Scholar
  93. 93.
    Tang Y, Xu H, Du X, Lit L, Walker W, Lu A, Ran R, Gregg JP, Reilly M, Pancioli A, Khoury JC, Sauerbeck LR, Carrozzella JA, Spilker J, Clark J, Wagner KR, Jauch EC, Chang DJ, Verro P, Broderick JP, Sharp FR (2006) Gene expression in blood changes rapidly in neutrophils and monocytes after ischemic stroke in humans: a microarray study. J Cereb Blood Flow Metab 26:1089–1102Google Scholar
  94. 94.
    Krams M, Lees KR, Hacke W, Grieve AP, Orgogozo JM, Ford GA (2003) Acute stroke therapy by inhibition of neutrophils (ASTIN): an adaptive dose-response study of uk-279,276 in acute ischemic stroke. Stroke 34:2543–2548Google Scholar
  95. 95.
    Harlan JM, Winn RK (2002) Leukocyte-endothelial interactions: clinical trials of anti-adhesion therapy. Crit Care Med 30:S214–S219Google Scholar
  96. 96.
    Catania A, Lipton JM (1998) Peptide modulation of fever and inflammation within the brain. Ann N Y Acad Sci 856:62–68Google Scholar
  97. 97.
    Gliem M, Mausberg AK, Lee JI, Simiantonakis I, van Rooijen N, Hartung HP, Jander S (2012) Macrophages prevent hemorrhagic infarct transformation in Murine stroke models. Ann Neurol 71:743–752Google Scholar
  98. 98.
    Fantin A, Vieira JM, Gestri G, Denti L, Schwarz Q, Prykhozhij S, Peri F, Wilson SW, Ruhrberg C (2010) Tissue macrophages act as cellular chaperones for vascular anastomosis downstream of VEGF-mediated endothelial tip cell induction. Blood 116:829–840Google Scholar
  99. 99.
    Hurtado O, Lizasoain I, Fernandez-Tome P, Alvarez-Barrientos A, Leza JC, Lorenzo P, Moro MA (2002) TACE/ADAM17-TNF-alpha pathway in rat cortical cultures after exposure to oxygen–glucose deprivation or glutamate. J Cereb Blood Flow Metab 22:576–585Google Scholar
  100. 100.
    Swanson RA, Ying W, Kauppinen TM (2004) Astrocyte influences on ischemic neuronal death. Curr Mol Med 4:193–205Google Scholar
  101. 101.
    Stephenson D, Yin T, Smalstig EB, Hsu MA, Panetta J, Little S, Clemens J (2000) Transcription factor nuclear factor-kappa B is activated in neurons after focal cerebral ischemia. J Cereb Blood Flow Metab 20:592–603Google Scholar
  102. 102.
    Smith JA, Das A, Ray SK, Banik NL (2012) Role of pro-inflammatory cytokines released from microglia in neurodegenerative diseases. Brain Res Bull 87:10–20Google Scholar
  103. 103.
    Defilippi P, Silengo L, Tarone G (1992) Alpha 6.Beta 1 integrin (laminin receptor) is down-regulated by tumor necrosis factor alpha and interleukin-1 beta in human endothelial cells. J Biol Chem 267:18303–18307Google Scholar
  104. 104.
    Defilippi P, Bozzo C, Geuna M, Rossino P, Silengo L, Tarone G (1992) Modulation of extracellular matrix receptors (integrins) on human endothelial cells by cytokines. EXS 61:193–197Google Scholar
  105. 105.
    Chaitanya GV, Cromer W, Wells S, Jennings M, Mathis JM, Minagar A, Alexander JS (2012) Metabolic modulation of cytokine-induced brain endothelial adhesion molecule expression. Microcirculation 19:155–165Google Scholar
  106. 106.
    Gottschall PE, Deb S (1996) Regulation of matrix metalloproteinase expressions in astrocytes, microglia and neurons. Neuroimmunomodulation 3:69–75Google Scholar
  107. 107.
    Simi A, Tsakiri N, Wang P, Rothwell NJ (2007) Interleukin-1 and inflammatory neurodegeneration. Biochem Soc Trans 35:1122–1126Google Scholar
  108. 108.
    Lambertsen KL, Clausen BH, Babcock AA, Gregersen R, Fenger C, Nielsen HH, Haugaard LS, Wirenfeldt M, Nielsen M, Dagnaes-Hansen F, Bluethmann H, Faergeman NJ, Meldgaard M, Deierborg T, Finsen B (2009) Microglia protect neurons against ischemia by synthesis of tumor necrosis factor. J Neurosci 29:1319–1330Google Scholar
  109. 109.
    Chen Y, Hallenbeck JM, Ruetzler C, Bol D, Thomas K, Berman NE, Vogel SN (2003) Overexpression of monocyte chemoattractant protein 1 in the brain exacerbates ischemic brain injury and is associated with recruitment of inflammatory cells. J Cereb Blood Flow Metab 23:748–755Google Scholar
  110. 110.
    Dimitrijevic OB, Stamatovic SM, Keep RF, Andjelkovic AV (2006) Effects of the chemokine CCL2 on blood–brain barrier permeability during ischemia-reperfusion injury. J Cereb Blood Flow Metab 26:797–810Google Scholar
  111. 111.
    Dimitrijevic OB, Stamatovic SM, Keep RF, Andjelkovic AV (2007) Absence of the chemokine receptor CCR2 protects against cerebral ischemia/reperfusion injury in mice. Stroke 38:1345–1353Google Scholar
  112. 112.
    Stamatovic SM, Dimitrijevic OB, Keep RF, Andjelkovic AV (2006) Protein kinase Calpha-Rhoa cross-talk in CCL2-induced alterations in brain endothelial permeability. J Biol Chem 281:8379–8388Google Scholar
  113. 113.
    Min KJ, Jou I, Joe E (2003) Plasminogen-induced IL-1beta and TNF-alpha production in microglia is regulated by reactive oxygen species. Biochem Biophys Res Commun 312:969–974Google Scholar
  114. 114.
    Davalos D, Ryu JK, Merlini M, Baeten KM, Le Moan N, Petersen MA, Deerinck TJ, Smirnoff DS, Bedard C, Hakozaki H, Gonias Murray S, Ling JB, Lassmann H, Degen JL, Ellisman MH, Akassoglou K (2012) Fibrinogen-induced perivascular microglial clustering is required for the development of axonal damage in neuroinflammation. Nat Commun 3:1227Google Scholar
  115. 115.
    Nimmerjahn A, Kirchhoff F, Helmchen F (2005) Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308:1314–1318Google Scholar
  116. 116.
    Faustino J, Wang X, Jonhson C, Klibanov A, Derugin N, Wendland M, Vexler ZS (2011) Microglial cells contribute to endogenous brain defenses after acute neonatal focal stroke. J Neurosci 31:12992–13001Google Scholar
  117. 117.
    Fernandez-Lopez D, Faustino J, Derugin N, Vexler ZS (2013) Acute and chronic vascular responses to experimental focal arterial stroke in the neonate rat. Transl Stroke Res 4:179–188Google Scholar
  118. 118.
    Bauer J, Ruuls SR, Huitinga I, Dijkstra CD (1996) The role of macrophage subpopulations in autoimmune disease of the central nervous system. Histochem J 28:83–97Google Scholar
  119. 119.
    Angelov DN, Walther M, Streppel M, Guntinas-Lichius O, van Dam AM, Stennert E, Neiss WF (1998) ED2-positive perivascular phagocytes produce interleukin-1beta during delayed neuronal loss in the facial nucleus of the rat. J Neurosci Res 54:820–827Google Scholar
  120. 120.
    Angelov DN, Walther M, Streppel M, Guntinas-Lichius O, Neiss WF (1998) The cerebral perivascular cells. Adv Anat Embryol Cell Biol 147:1–87Google Scholar
  121. 121.
    Becher B, Bechmann I, Greter M (2006) Antigen presentation in autoimmunity and cns inflammation: how T lymphocytes recognize the brain. J Mol Med (Berl) 84:532–543Google Scholar
  122. 122.
    Polfliet MM, van de Veerdonk F, Dopp EA, van Kesteren-Hendrikx EM, van Rooijen N, Dijkstra CD, van den Berg TK (2002) The role of perivascular and meningeal macrophages in experimental allergic encephalomyelitis. J Neuroimmunol 122:1–8Google Scholar
  123. 123.
    Lindsberg PJ, Strbian D, Karjalainen-Lindsberg ML (2010) Mast cells as early responders in the regulation of acute blood–brain barrier changes after cerebral ischemia and hemorrhage. J Cereb Blood Flow Metab 30:689–702Google Scholar
  124. 124.
    Strbian D, Karjalainen-Lindsberg ML, Kovanen PT, Tatlisumak T, Lindsberg PJ (2007) Mast cell stabilization reduces hemorrhage formation and mortality after administration of thrombolytics in experimental ischemic stroke. Circulation 116:411–418Google Scholar
  125. 125.
    Strbian D, Karjalainen-Lindsberg ML, Tatlisumak T, Lindsberg PJ (2006) Cerebral mast cells regulate early ischemic brain swelling and neutrophil accumulation. J Cereb Blood Flow Metab 26:605–612Google Scholar
  126. 126.
    Zhang RL, Zhang ZG, Chopp M (2005) Neurogenesis in the adult ischemic brain: generation, migration, survival, and restorative therapy. Neuroscientist 11:408–416Google Scholar
  127. 127.
    Beck H, Plate KH (2009) Angiogenesis after cerebral ischemia. Acta Neuropathol 117:481–496Google Scholar
  128. 128.
    Greenberg DA, Jin K (2005) From angiogenesis to neuropathology. Nature 438:954–959Google Scholar
  129. 129.
    Distler JH, Hirth A, Kurowska-Stolarska M, Gay RE, Gay S, Distler O (2003) Angiogenic and angiostatic factors in the molecular control of angiogenesis. Q J Nucl Med 47:149–161Google Scholar
  130. 130.
    Abumiya T, Lucero J, Heo JH, Tagaya M, Koziol JA, Copeland BR, del Zoppo GJ (1999) Activated microvessels express vascular endothelial growth factor and integrin alpha(V)beta3 during focal cerebral ischemia. J Cereb Blood Flow Metab 19:1038–1050Google Scholar
  131. 131.
    Zhang ZG, Zhang L, Jiang Q, Zhang R, Davies K, Powers C, Bruggen N, Chopp M (2000) Vegf enhances angiogenesis and promotes blood–brain barrier leakage in the ischemic brain. J Clin Invest 106:829–838Google Scholar
  132. 132.
    Sun Y, Jin K, Xie L, Childs J, Mao XO, Logvinova A, Greenberg DA (2003) Vegf-induced neuroprotection, neurogenesis, and angiogenesis after focal cerebral ischemia. J Clin Invest 111:1843–1851Google Scholar
  133. 133.
    Li B, Sharpe EE, Maupin AB, Teleron AA, Pyle AL, Carmeliet P, Young PP (2006) VEGF and PLGF promote adult vasculogenesis by enhancing EPC recruitment and vessel formation at the site of tumor neovascularization. FASEB J 20:1495–1497Google Scholar
  134. 134.
    Lee SR, Kim HY, Rogowska J, Zhao BQ, Bhide P, Parent JM, Lo EH (2006) Involvement of matrix metalloproteinase in neuroblast cell migration from the subventricular zone after stroke. J Neurosci 26:3491–3495Google Scholar
  135. 135.
    Arvidsson A, Collin T, Kirik D, Kokaia Z, Lindvall O (2002) Neuronal replacement from endogenous precursors in the adult brain after stroke. Nat Med 8:963–970Google Scholar
  136. 136.
    Parent JM, Vexler ZS, Gong C, Derugin N, Ferriero DM (2002) Rat forebrain neurogenesis and striatal neuron replacement after focal stroke. Ann Neurol 52:802–813Google Scholar
  137. 137.
    Carmichael ST (2006) Cellular and molecular mechanisms of neural repair after stroke: making waves. Ann Neurol 59:735–742Google Scholar
  138. 138.
    Ohab JJ, Fleming S, Blesch A, Carmichael ST (2006) A neurovascular niche for neurogenesis after stroke. J Neurosci 26:13007–13016Google Scholar
  139. 139.
    Wang L, Zhang Z, Wang Y, Zhang R, Chopp M (2004) Treatment of stroke with erythropoietin enhances neurogenesis and angiogenesis and improves neurological function in rats. Stroke 35:1732–1737Google Scholar
  140. 140.
    Shimamura M, Sato N, Sata M, Kurinami H, Takeuchi D, Wakayama K, Hayashi T, Iida H, Morishita R (2007) Delayed postischemic treatment with fluvastatin improved cognitive impairment after stroke in rats. Stroke 38:3251–3258Google Scholar
  141. 141.
    Xiong Y, Mahmood A, Chopp M (2010) Angiogenesis, neurogenesis and brain recovery of function following injury. Curr Opin Investig Drugs 11:298–308Google Scholar
  142. 142.
    Li L, Jiang Q, Zhang L, Ding G, Gang Zhang Z, Li Q, Ewing JR, Lu M, Panda S, Ledbetter KA, Whitton PA, Chopp M (2007) Angiogenesis and improved cerebral blood flow in the ischemic boundary area detected by MRI after administration of sildenafil to rats with embolic stroke. Brain Res 1132:185–192Google Scholar
  143. 143.
    Battista D, Ferrari CC, Gage FH, Pitossi FJ (2006) Neurogenic niche modulation by activated microglia: transforming growth factor beta increases neurogenesis in the adult dentate gyrus. Eur J Neurosci 23:83–93Google Scholar
  144. 144.
    Watanabe H, Abe H, Takeuchi S, Tanaka R (2000) Protective effect of microglial conditioning medium on neuronal damage induced by glutamate. Neurosci Lett 289:53–56Google Scholar
  145. 145.
    Lu YZ, Lin CH, Cheng FC, Hsueh CM (2005) Molecular mechanisms responsible for microglia-derived protection of sprague-dawley rat brain cells during in vitro ischemia. Neurosci Lett 373:159–164Google Scholar
  146. 146.
    Butovsky O, Ziv Y, Schwartz A, Landa G, Talpalar AE, Pluchino S, Martino G, Schwartz M (2006) Microglia activated by IL-4 or IFN-gamma differentially induce neurogenesis and oligodendrogenesis from adult stem/progenitor cells. Mol Cell Neurosci 31:149–160Google Scholar
  147. 147.
    Lobov IB, Rao S, Carroll TJ, Vallance JE, Ito M, Ondr JK, Kurup S, Glass DA, Patel MS, Shu W, Morrisey EE, McMahon AP, Karsenty G, Lang RA (2005) WNT7b mediates macrophage-induced programmed cell death in patterning of the vasculature. Nature 437:417–421Google Scholar
  148. 148.
    Tammela T, Zarkada G, Wallgard E, Murtomaki A, Suchting S, Wirzenius M, Waltari M, Hellstrom M, Schomber T, Peltonen R, Freitas C, Duarte A, Isoniemi H, Laakkonen P, Christofori G, Yla-Herttuala S, Shibuya M, Pytowski B, Eichmann A, Betsholtz C, Alitalo K (2008) Blocking VEGFR-3 suppresses angiogenic sprouting and vascular network formation. Nature 454:656–660Google Scholar
  149. 149.
    Colton CA (2009) Heterogeneity of microglial activation in the innate immune response in the brain. J Neuroimmune Pharmacol 4:399–418Google Scholar
  150. 150.
    Chen J, Li Y, Katakowski M, Chen X, Wang L, Lu D, Lu M, Gautam SC, Chopp M (2003) Intravenous bone marrow stromal cell therapy reduces apoptosis and promotes endogenous cell proliferation after stroke in female rat. J Neurosci Res 73:778–786Google Scholar
  151. 151.
    Zacharek A, Chen J, Cui X, Li A, Li Y, Roberts C, Feng Y, Gao Q, Chopp M (2007) Angiopoietin1/TIE2 and VEGF/FLK1 induced by MSC treatment amplifies angiogenesis and vascular stabilization after stroke. J Cereb Blood Flow Metab 27:1684–1691Google Scholar
  152. 152.
    Zhang J, Li Y, Chen J, Yang M, Katakowski M, Lu M, Chopp M (2004) Expression of insulin-like growth factor 1 and receptor in ischemic rats treated with human marrow stromal cells. Brain Res 1030:19–27Google Scholar
  153. 153.
    Horie N, Pereira MP, Niizuma K, Sun G, Keren-Gill H, Encarnacion A, Shamloo M, Hamilton SA, Jiang K, Huhn S, Palmer TD, Bliss TM, Steinberg GK (2011) Transplanted stem cell-secreted vascular endothelial growth factor effects poststroke recovery, inflammation, and vascular repair. Stem Cells 29:274–285Google Scholar
  154. 154.
    Daadi MM, Davis AS, Arac A, Li Z, Maag AL, Bhatnagar R, Jiang K, Sun G, Wu JC, Steinberg GK (2010) Human neural stem cell grafts modify microglial response and enhance axonal sprouting in neonatal hypoxic-ischemic brain injury. Stroke 41:516–523Google Scholar
  155. 155.
    Bliss TM, Andres RH, Steinberg GK (2010) Optimizing the success of cell transplantation therapy for stroke. Neurobiol Dis 37:275–283Google Scholar
  156. 156.
    Shen LH, Li Y, Gao Q, Savant-Bhonsale S, Chopp M (2008) Down-regulation of neurocan expression in reactive astrocytes promotes axonal regeneration and facilitates the neurorestorative effects of bone marrow stromal cells in the ischemic rat brain. Glia 56:1747–1754Google Scholar
  157. 157.
    van Velthoven CT, Kavelaars A, van Bel F, Heijnen CJ (2011) Mesenchymal stem cell transplantation changes the gene expression profile of the neonatal ischemic brain. Brain Behav Immun 25:1342–1348Google Scholar
  158. 158.
    Saunders NR, Daneman R, Dziegielewska KM, Liddelow SA (2013) Transporters of the blood–brain and blood–CSF interfaces in development and in the adult. Mol Aspects Med 34:742–752Google Scholar
  159. 159.
    Saunders NR, Habgood MD, Dziegielewska KM (1999) Barrier mechanisms in the brain. II. Immature brain. Clin Exp Pharmacol Physiol 26:85–91Google Scholar
  160. 160.
    Kniesel U, Risau W, Wolburg H (1996) Development of blood–brain barrier tight junctions in the rat cortex. Brain Res Dev Brain Res 96:229–240Google Scholar
  161. 161.
    Engelhardt B (2003) Development of the blood–brain barrier. Cell Tissue Res 314:119–129Google Scholar
  162. 162.
    Anthony DC, Bolton SJ, Fearn S, Perry VH (1997) Age-related effects of interleukin-1 beta on polymorphonuclear neutrophil-dependent increases in blood–brain barrier permeability in rats. Brain 120(Pt 3):435–444Google Scholar
  163. 163.
    Bona E, Andersson AL, Blomgren K, Gilland E, Puka-Sundvall M, Gustafson K, Hagberg H (1999) Chemokine and inflammatory cell response to hypoxia-ischemia in immature rats. Pediatr Res 45:500–509Google Scholar
  164. 164.
    Hudome S, Palmer C, Roberts RL, Mauger D, Housman C, Towfighi J (1997) The role of neutrophils in the production of hypoxic-ischemic brain injury in the neonatal rat. Pediatr Res 41:607–616Google Scholar
  165. 165.
    Denker S, Ji S, Lee SY, Dingman A, Derugin N, Wendland M, Vexler ZS (2007) Macrophages are comprised of resident brain microglia not infiltrating peripheral monocytes acutely after neonatal stroke. J Neurochem 100:893–904Google Scholar
  166. 166.
    Iwai M, Cao G, Yin W, Stetler RA, Liu J, Chen J (2007) Erythropoietin promotes neuronal replacement through revascularization and neurogenesis after neonatal hypoxia/ischemia in rats. Stroke 38:2795–2803Google Scholar
  167. 167.
    Ogunshola OO, Stewart WB, Mihalcik V, Solli T, Madri JA, Ment LR (2000) Neuronal VEGF expression correlates with angiogenesis in postnatal developing rat brain. Brain Res Dev Brain Res 119:139–153Google Scholar
  168. 168.
    Robertson PL, Du Bois M, Bowman PD, Goldstein GW (1985) Angiogenesis in developing rat brain: an in vivo and in vitro study. Brain Res 355:219–223Google Scholar
  169. 169.
    Hayashi T, Noshita N, Sugawara T, Chan PH (2003) Temporal profile of angiogenesis and expression of related genes in the brain after ischemia. J Cereb Blood Flow Metab 23:166–180Google Scholar
  170. 170.
    Marti HJ, Bernaudin M, Bellail A, Schoch H, Euler M, Petit E, Risau W (2000) Hypoxia-induced vascular endothelial growth factor expression precedes neovascularization after cerebral ischemia. Am J Pathol 156:965–976Google Scholar
  171. 171.
    Ghabriel MN, Zhu C, Hermanis G, Allt G (2000) Immunological targeting of the endothelial barrier antigen (EBA) in vivo leads to opening of the blood–brain barrier. Brain Res 878:127–135Google Scholar
  172. 172.
    Lu H, Demny S, Zuo Y, Rea W, Wang L, Chefer SI, Vaupel DB, Yang Y, Stein EA (2010) Temporary disruption of the rat blood–brain barrier with a monoclonal antibody: a novel method for dynamic manganese-enhanced MRI. Neuroimage 50:7–14Google Scholar
  173. 173.
    Saubamea B, Cochois-Guegan V, Cisternino S, Scherrmann JM. Heterogeneity in the rat brain vasculature revealed by quantitative confocal analysis of endothelial barrier antigen and p-glycoprotein expression. J Cereb Blood Flow Metab. 2011Google Scholar
  174. 174.
    Rosenstein JM, Krum JM, Sternberger LA, Pulley MT, Sternberger NH (1992) Immunocytochemical expression of the endothelial barrier antigen (EBA) during brain angiogenesis. Brain Res Dev Brain Res 66:47–54Google Scholar
  175. 175.
    Sternberger NH, Sternberger LA (1987) Blood–brain barrier protein recognized by monoclonal antibody. Proc Natl Acad Sci U S A 84:8169–8173Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  1. 1.Department of NeurologyUniversity of California San FranciscoSan FranciscoUSA

Personalised recommendations