Cell and Tissue Research

, Volume 335, Issue 1, pp 75–96 | Cite as

Brain endothelial cells and the glio-vascular complex

  • Hartwig Wolburg
  • Susan Noell
  • Andreas Mack
  • Karen Wolburg-Buchholz
  • Petra Fallier-Becker


We present and discuss the role of endothelial and astroglial cells in managing the blood-brain barrier (BBB) and aspects of pathological alterations in the BBB. The impact of astrocytes, pericytes, and perivascular cells on the induction and maintenance of the gliovascular unit is largely unidentified so far. An understanding of the signaling pathways that lie between these cell types and the endothelium and that possibly are mediated by components of the basal lamina is just beginning to emerge. The metabolism for the maintenance of the endothelial barrier is intimately linked to and dependent on the microenvironment of the brain parenchyma. We report the structure and function of the endothelial cells of brain capillaries by describing structures involved in the regulation of permeability, including transporter systems, caveolae, and tight junctions. There is increasing evidence that caveolae are not only vehicles for endo- and transcytosis, but also important regulators of tight-junction-based permeability. Tight junctions separate the luminal from the abluminal membrane domains of the endothelial cell (“fence function”) and control the paracellular pathway (“gate function”) thus representing the most significant structure of the BBB. In addition, the extracellular matrix between astrocytes/pericytes and endothelial cells contains numerous molecules with inherent signaling properties that have to be considered if we are to improve our knowledge of the complex and closely regulated BBB.


Agrin Astrocytes Blood-brain barrier Extracellular matrix Tight junctions 


  1. Abbott NJ, Rönnbäck L, Hansson E (2006) Astrocyte-endothelial interactions at the blood-brain barrier. Nat Rev Neurosci 7:41–53PubMedCrossRefGoogle Scholar
  2. Agrawal S, Anderson P, Durbeej M, Van Rooijen N, Ivars F, Opdenakker G, Sorokin LM (2006) Dystroglycan is selectively cleaved at the parenchymal basement membrane at sites of leukocyte extravasation in experimental autoimmune encephalomyelitis. J Exp Med 203:1007–1019PubMedCrossRefGoogle Scholar
  3. Amantea D, Corasanti MT, Mercuri NB, Bernardi G, Bagetta G (2008) Brain regional and cellular localization of gelatinase activity in rat that have undergone transient middle cerebral artery occlusion. Neuroscience 152:8–17PubMedCrossRefGoogle Scholar
  4. Amiry-Moghaddam M, Ottersen OP (2003) The molecular basis of water transport in the brain. Nat Rev Neurosci 4:991–1001PubMedCrossRefGoogle Scholar
  5. Amiry-Moghaddam M, Xue R, Haug FM, Neely JD, Bhardwaj A, Agre P, Adams ME, Froehner SC, Mori S, Ottersen OP (2004) Alpha-syntrophin deletion removes the perivascular but not endothelial pool of aquaporin-4 at the blood-brain barrier and delays the development of brain edema in an experimental model of acute hyponatremia. FASEB J 18:542–544PubMedGoogle Scholar
  6. Anderson JM (1996) Cell signalling: MAGUK magic. Curr Biol 6:382–384PubMedCrossRefGoogle Scholar
  7. Antonetti DA, Barber AJ, Hollinger LA, Wolpert EB, Gardner TW (1999) Vascular endothelial growth factor induces rapid phosphorylation of tight junction proteins occludin and zonula occluden 1. A potential mechanism for vascular permeability in diabetic retinopathy and tumors. J Biol Chem 174:23463–23467CrossRefGoogle Scholar
  8. Badaut J, Regli L (2004) Distribution and possible roles of aquaporin 9 in the brain. Neuroscience 129:971–981PubMedCrossRefGoogle Scholar
  9. Badaut J, Lasbennes F, Magistretti PJ, Regli L (2002) Aquaporins in brain: distribution, physiology and pathophysiology. J Cereb Blood Flow Metab 22:367–378PubMedCrossRefGoogle Scholar
  10. Bader BL, Rayburn H, Crowley D, Hynes RO (1998) Extensive vasculogenesis, angiogenesis, and organogenesis precede lethality in mice lacking all αv integrins. Cell 95:507–519PubMedCrossRefGoogle Scholar
  11. Balda MS, Matter K (2000) The tight junction protein ZO-1 and an interacting transcription factor regulate ErbB-2 expression. EMBO J 19:2024–2033PubMedCrossRefGoogle Scholar
  12. Balda MS, Garrett MD, Matter K (2003) The ZO-1-associated Y-box factor ZONAB regulates epithelial cell proliferation and cell density. J Cell Biol 160:423–432PubMedCrossRefGoogle Scholar
  13. Ballabh P, Braun A, Nedergaard M (2004) The blood-brain barrier: an overview. Structure, regulation, and clinical implications. Neurobiol Dis 16:1–13PubMedCrossRefGoogle Scholar
  14. Banerjee S, Bhat MA (2007) Neuron-glial interactions in blood-brain barrier formation. Annu Rev Neurosci 30:235–258PubMedCrossRefGoogle Scholar
  15. Barakat S, Demeule M, Pilorget A, Régina A, Gingras D, Baggetto LG, Béliveau R (2007) Modulation of p-glycoprotein function by caveolin-1 phosporylation. J Neurochem 101:1–8PubMedCrossRefGoogle Scholar
  16. Barber AJ, Lieth E (1997) Agrin accumulates in the brain microvascular basal lamina during development of the blood-brain barrier. Dev Dyn 208:62–74PubMedCrossRefGoogle Scholar
  17. Bauer H, Sonnleitner U, Lametschwandtner A, Steiner M, Adam H, Bauer HC (1995) Ontogenic expression of the erythroid-type glucose transporter (Glut 1) in the telencephalon of the mouse: correlation to the tightening of the blood-brain barrier. Dev Brain Res 86:317–325CrossRefGoogle Scholar
  18. Bazzoni G, Dejana E (2004) Endothelial cell-tocell junctions: molecular organization and role in vascular homeostasis. Physiol Rev 84:869–901PubMedCrossRefGoogle Scholar
  19. Bechmann I, Galea I, Perry VH (2007) What is the blood-brain barrier (not)? Trends Immunol 28:5–11PubMedCrossRefGoogle Scholar
  20. Begley DJ (2004) ABC transporters and the blood-brain barrier. Curr Pharm Des 10:1295–1312PubMedCrossRefGoogle Scholar
  21. Begley DJ, Brightman MW (2003) Structural and functional aspects of the blood-brain barrier. Prog Drug Res 61:39–78PubMedGoogle Scholar
  22. Benfenati V, Nicchia GP, Svelto M, Rapisarda C, Frigeri A, Ferroni S (2007) Functional down-regulation of volume-regulated anion channels in AQP4 knockdown cultured rat cortical astrocytes. J Neurochem 1000:87–104CrossRefGoogle Scholar
  23. Berzin TM, Zipser BD, Rafii MS, Kuo-Leblanc V, Yancopoulos GD, Glass DJ, Fallon JR, Stopa EG (2000) Agrin and microvascular damage in Alzheimer’s disease. Neurobiol Aging 21:349–355PubMedCrossRefGoogle Scholar
  24. Bezakova G, Ruegg MA (2003) New insights into the roles of agrin. Nat Rev Mol Cell Biol 4:295–308PubMedCrossRefGoogle Scholar
  25. Blake DJ, Kröger S (2000) The neurobiology of Duchenne muscular dystrophy: learning lessons from muscle? Trends Neurosci 23:92–99PubMedCrossRefGoogle Scholar
  26. Blake DJ, Hawkes R, Benson MA, Beesley PW (1999) Different dystrophin-like complexes are expressed in neurons and glia. J Cell Biol 147:645–657PubMedCrossRefGoogle Scholar
  27. Bolz S, Farrell CL, Dietz K, Wolburg H (1996) Subcellular distribution of glucose transporter (GLUT-1) during development of the blood-brain barrier in rats. Cell Tissue Res 284:355–365PubMedCrossRefGoogle Scholar
  28. Brightman MW, Reese TS (1969) Junctions between intimately apposed cell membranes in the vertebrate brain. J Cell Biol 40:648–677PubMedCrossRefGoogle Scholar
  29. Brillault J, Berezowski V, Cecchelli R, Dehouck MP (2002) Intercommunications between brain capillary endothelial cells and glial cells increase the transcellular permeability of the blood-brain barrier during ischemia. J Neurochem 83:807–817PubMedCrossRefGoogle Scholar
  30. Burggraf D, Trinkl A, Burk J, Martens HK, Dichgans M, Hamann GF (2008) Vascular integrin immunoreactivity is selectively lost on capillaries during rat focal cerebral ischemia and reperfusion. Brain Res 1189:189–197PubMedCrossRefGoogle Scholar
  31. Calogero A, Pavoni E, Gramaglia T, D’Amati G, Ragona G, Brancaccio A, Petrucci TC (2006) Altered expression of α-dystroglycan subunit in human gliomas. Cancer Biol Ther 5:441–448PubMedCrossRefGoogle Scholar
  32. Cattelino A, Liebner S, Zanetti A, Gallini R, Balconi G, Corsi A, Bianco P, Wolburg H, Moore R, Oreda B, Kemler R, Dejana E (2003) The conditional inactivation of β-catenin gene in endothelial cells causes a defective vascular pattern and increased vascular fragility. J Cell Biol 162:1111–1122PubMedCrossRefGoogle Scholar
  33. Citi S, Sabanay H, Kendrick-Jones J, Geiger B (1989) Cingulin: characterization and localization. J Cell Sci 93:107–122PubMedGoogle Scholar
  34. Claude P (1978) Morphologic factors influencing transepithelial permeability. A model for the resistance of the zonula occludens. J Membr Biol 39:219–232PubMedCrossRefGoogle Scholar
  35. Connors NC, Kofuji P (2002) Dystrophin Dp71 is critical for the clustered localization of potassium channels in retinal glial cells. J Neurosci 22:4321–4327PubMedGoogle Scholar
  36. Connors NC, Adams ME, Froehner SC, Kofuji P (2004) The potassium channel Kir4.1 associates with the dystrophin glycoprotein complex via alpha-syntrophin in glia. J Biol Chem 279:28387–28392PubMedCrossRefGoogle Scholar
  37. Coomber BL, Stewart PA (1985) Morphometric analysis of CNS microvascular endothelium. Microvasc Res 30:99–115PubMedCrossRefGoogle Scholar
  38. Couty J-P, Rampon C, Leveque M, Laran-Chich M-P, Bourdoulous S, Greenwood J, Couraud P-O (2007) PECAM-1 engagement counteracts ICAM-1-induced signaling in brain vascular endothelial cells. J Neurochem 103:793–801PubMedCrossRefGoogle Scholar
  39. De Boer AG, Van der Sandt ICJ, Gaillard PJ (2003) The role of drug transporters at the blood-brain barrier. Annu Rev Pharmacol Toxicol 43:629–656PubMedCrossRefGoogle Scholar
  40. Deeken JF, Löscher W (2007) The blood-brain barrier and cancer: transporters, treatment, and Trojan horses. Clin Cancer Res 13:1663–1674PubMedCrossRefGoogle Scholar
  41. Dejana E (2004) Endothelial cell-cell junctions: happy together. Nat Rev Mol Cell Biol 5:261–270PubMedCrossRefGoogle Scholar
  42. Dejana E, Corada M, Lampugnani MG (1995) Endothelial cell-to-cell junctions. FASEB J 9:910–918PubMedGoogle Scholar
  43. De la Torre JC, Stefano GB (2000) Evidence that Alzheimer’s disease is a microvascular disorder: the role of constitutive nitric oxide. Brain Res Rev 34:119–136PubMedCrossRefGoogle Scholar
  44. Del Zoppo GJ, Milner R (2006) Integrin-matrix interactions in the cerebral microvasculature. Arterioscler Thromb Vasc Biol 26:1966–1975PubMedCrossRefGoogle Scholar
  45. Deli MA (2005) The role of blood-brain barrier in neurodegenerative diseases. In: Di Liegro I, Savettieri G (eds) Molecular bases of neurodegeneration. Research Signpost, Trivandrum, India, pp 137–161Google Scholar
  46. Demeule M, Jodoin J, Gingras D, Beliveau R (2000) P-glycoprotein is localized in caveolae in resistant cells and in brain capillaries. FEBS Lett 466:219–224PubMedCrossRefGoogle Scholar
  47. Dermietzel R, Spray DC, Nedergaard M (2006) Blood-brain barriers. From ontogeny to artificial interfaces. Wiley-VCH, WeinheimGoogle Scholar
  48. De Vries E, Prat A (2005) The blood-brain barrier and its microenvironment. Basic physiology to neurological disease. Taylor and Francis, New York LondonGoogle Scholar
  49. Dobrogowska DH, Vorbrodt AW (1999) Quantitative immunocytochemical study of blood-brain barrier glucose transporter (GLUT-1) in four regions of mouse brain. J Histochem Cytochem 47:1021–1029PubMedGoogle Scholar
  50. Dolman D, Drndarski S, Abbott NJ, Rattray M (2005) Induction of aquaporin 1 but aquaporin 4 messenger RNA in rat primary brain microvessel endothelial cells in culture. J Neurochem 93:825–833PubMedCrossRefGoogle Scholar
  51. Döring A, Wild M, Vestweber D, Deutsch U, Engelhardt B (2007) E- and P-selectin are not required for the development of experimental autoimmune encephalomyelitis in C57BL/6 and SJL mice. J Immunol 179:8470–8479PubMedGoogle Scholar
  52. Drab M, Verkade P, Elger M, Kasper M, Lohn M, Lauterbach B, Menne J, Lindschau C, Mende F, Luft FC, Schedl A, Haller H, Kurzchalia TV (2001) Loss of caveolae, vascular dysfunction, and pulmonary defects in caveolin-1 gene-disrupted mice. Science 293:2449–2452PubMedCrossRefGoogle Scholar
  53. Durbeej M, Henry MD, Campbell KP (1998) Dystroglycan in development and disease. Curr Biol 10:594–601Google Scholar
  54. Dziegielewska KM, Ek J, Habgood MD, Saunders NR (2001) Development of the choroid plexus. Microsc Res Tech 52:5–20PubMedCrossRefGoogle Scholar
  55. Ebnet K, Vestweber D (1999) Molecular mechanisms that control leukocyte extravasation: the selectins and the chemokines. Histochem Cell Biol 112:1–23PubMedCrossRefGoogle Scholar
  56. Ebnet K, Suzuki A, Ohno S, Vestweber D (2004) Junctional adhesion molecules (JAMs): more molecules with dual functions? J Cell Sci 117:19–29PubMedCrossRefGoogle Scholar
  57. Ehmsen J, Poon E, Davies K (2002) The dystrophin-associated protein complex. J Cell Sci 115:2801–2803PubMedGoogle Scholar
  58. Ehrlich P (1885) Das Sauerstoff-Bedürfnis des Organismus. Eine farbenanalytische Studie. PhD thesis. Herschwald, BerlinGoogle Scholar
  59. Engelhardt B (2003) Development of the blood-brain barrier. Cell Tissue Res 314:119–129PubMedCrossRefGoogle Scholar
  60. Engelhardt B, Wolburg H (2004) Transendothelial migration of leukocytes: through the front door or around the side of the house? Eur J Immunol 34:2955–2963PubMedCrossRefGoogle Scholar
  61. Esser S, Wolburg K, Wolburg H, Breier G, Kurzchalia T (1998) Vascular endothelial growth factor induces endothelial fenestrations in vitro. J Cell Biol 140:947–959PubMedCrossRefGoogle Scholar
  62. Farrell CL, Pardridge WM (1991) Blood-brain barrier glucose transporter is asymmetrically distributed on brain capillary endothelial lumenal and ablumenal membranes: an electron microscopic immunogold study. Proc Natl Acad Sci USA 88:5779–5783PubMedCrossRefGoogle Scholar
  63. Folkman J, D’Amore PA (1996) Blood vessel formation: what is its molecular basis? Cell 87:1153–1155PubMedCrossRefGoogle Scholar
  64. Förster C (2008) Tight junctions and the modulation of barrier function in disease. Histochem Cell Biol 130:55–70PubMedCrossRefGoogle Scholar
  65. Förster C, Waschke J, Burek M, Leers J, Drenckhahn D (2006) Glucocorticoid effects on mouse microvascular endothelial barrier permeability are brain specific. J Physiol (Lond) 573:413–425CrossRefGoogle Scholar
  66. Förster C, Kahles T, Kietz S, Drenckhahn D (2007) Dexamathasone induces the expression of metalloproteinase inhibitor TIMP-1 in the murine cerebral vascular endothelial cell line cEND. J Physiol (Lond) 580:937–949CrossRefGoogle Scholar
  67. Furuse M, Hirase T, Itoh M, Nagafuchi A, Yonemura S, Tsukita S, Tsukita S (1993) Occludin: a novel integral membrane protein localizing at tight junctions. J Cell Biol 123:1777–1788PubMedCrossRefGoogle Scholar
  68. Furuse M, Fujita K, Hiiragi T, Fujimoto K, Tsukita S (1998) Claudin-1 and -2: novel integral membrane proteins localizing at tight junctions. J Cell Biol 141:1539–1550PubMedCrossRefGoogle Scholar
  69. Furuse M, Sasaki H, Tsukita S (1999) Manner of interaction of heterogenous claudin species within and between tight junction strands. J Cell Biol 147:891–903PubMedCrossRefGoogle Scholar
  70. Gaillard PJ, Visser CC, De Boer AG (2006) Drug delivery to the brain by internalizing receptors at the blood-brain barrier. In: Dermietzel R, Spray DC, Nedergaard M (eds) Blood-brain interfaces: from ontogeny to artificial barriers. Wiley-VCH, Weinheim, pp 501–520Google Scholar
  71. Gao B, Saba TM, Tsan M-F (2002) Role of αvβ3-integrin in TNF-α-induced endothelial cell migration. Am J Physiol 283:C1196–C1205Google Scholar
  72. Ge S, Song L, Serwanski DR, Kuziel WA, Pachter JS (2008) Transcellular transport of CCL2 across brain microvascular endothelial cells. J Neurochem 104:1219–1232PubMedCrossRefGoogle Scholar
  73. Gee SH, Montanaro F, Lindenbaum MH, Carbonetto S (1994) Dystroglycan-α: a dystrophin-associated glyoprotein, is a functional agrin receptor. Cell 77:675–686PubMedCrossRefGoogle Scholar
  74. Gerhardt H, Liebner S, Redies C, Wolburg H (1999) N-Cadherin expression in endothelial cells during early angiogenesis in the eye and brain of the chicken: relation to blood-retina and blood-brain barrier development. Eur J Neurosci 11:1191–1201PubMedCrossRefGoogle Scholar
  75. Gerhardt H, Wolburg H, Redies C (2000) N-Cadherin mediates pericytic-endothelial interaction during brain angiogenesis in the chicken. Dev Dyn 218:472–479PubMedCrossRefGoogle Scholar
  76. Ghassemifar R, Lai C-M, Rakoczy PE (2006) VEGF differentially regulates transcription and translation of ZO-1α+ and ZO-1α- and mediates trans-epithelial resistance in cultured endothelial and epithelial cells. Cell Tissue Res 323:117–125PubMedCrossRefGoogle Scholar
  77. Gladson CL (1996) Expression of integrin alpha v beta 3 in small blood vessels of glioblastoma tumors. J Neuropathol Exp Neurol 55:1143–1149PubMedCrossRefGoogle Scholar
  78. Goldmann E (1913) Vitalfärbung am Zentralnervensystem. Beitrag zur Physio-Pathologie des Plexus chorioideus und der Hirnhäute. Abh Königl Preuss Akad Wiss Berlin 1:1–61Google Scholar
  79. Goldstein GW, Betz AL (1986) The blood-brain barrier. Sci Am 255:70–79CrossRefGoogle Scholar
  80. Gonzalez-Mariscal L, Betanzos A, Nava P, Jaramillo BE (2003) Tight junction proteins. Prog Biophys Mol Biol 81:1–44PubMedCrossRefGoogle Scholar
  81. Goodwin AM, Sullivan KM, D’Amore PA (2006) Cultured endothelial cells display endogenous activation of the canonical Wnt signalling pathway and express multiple ligands, receptors, and secreted modulators of Wnt signalling. Dev Dyn 235:3110–3120PubMedCrossRefGoogle Scholar
  82. Guadagno E, Moukhles H (2004) Laminin-induced aggregation of the inwardly rectifying poptassium channel, Kir4.1, and the water-permeable channel, AQP4, via a dystroglycan-containing complex in astrocytes. Glia 47:138–149PubMedCrossRefGoogle Scholar
  83. Guo M, Cox B, Mahale S, Davis W, Carranza A, Hayes K, Sprague S, Jimenez D, Ding Y (2008) Pre-ischemic exercise reduces matrix metalloproteinase-9 expression and ameliorates blood-brain barrier dysfunction in stroke. Neuroscience 151:340–351PubMedCrossRefGoogle Scholar
  84. Gurney KJ, Estrada EY, Rosenberg GA (2006) Blood-brain barrier disruption by stromelysin-1 facilitates neutrophil infiltration in neuroinflammation. Neurobiol Dis 23:87–96PubMedCrossRefGoogle Scholar
  85. Haenggi T, Fritschy J-M (2006) Role of dystrophin and utrophin for assembly and function of the dystrophin glycoprotein complex in non-muscle tissue. Cell Mol Life Sci 63:1614–1631PubMedCrossRefGoogle Scholar
  86. Haenggi T, Soontornmalai A, Schaub MC, Fritschy J-M (2004) The role of utrophin and Dp71 for assembly of different dystrophin-associated protein complexes (DPCs) in the choroid plexus and microvasculature of the brain. Neuroscience 129:403–413PubMedCrossRefGoogle Scholar
  87. Hallmann R, Mayer DN, Berg EL, Broermann R, Butcher EC (1995) Novel mouse endothelial cell surface marker is suppressed during differentation of the blood-brain barrier. Dev Dyn 202:325–332PubMedGoogle Scholar
  88. Hallmann R, Horn N, Selg M, Wendler O, Pausch F, Sorokin LM (2005) Expression and function of laminins in the embryonic and mature vasculature. Physiol Rev 85:979–1000PubMedCrossRefGoogle Scholar
  89. Hamazaki Y, Itoh M, Sasaki H, Furuse M, Tsukita S (2002) Multi-PDZ domain protein 1 (MUPP) is concentrated at tight junctions through its possible interaction with claudin-1 and junctional adhesion molecule. J Biol Chem 277:455–461PubMedCrossRefGoogle Scholar
  90. Haorah J, Ramirez SH, Schall K, Smith D, Pandya R, Persidsky Y (2007a) Oxidative stress activates protein tyrosine kinase and matrix metalloptroteinases leading to blood-brain barrier dysfunction. J Neurochem 101:566–576PubMedCrossRefGoogle Scholar
  91. Haorah J, Schall K, Ramirez SH, Persidsky Y (2007b) Activation of protein tyrosine kinases and matrix metalloproteinases causes blood-brain barrier injury: novel mechanism for neurodegeneration associated with alcohol abuse. Glia 56:78–88CrossRefGoogle Scholar
  92. Hawkins BT, Davis TP (2005) The blood-brain barrier/neurovascular unit in health and disease. Pharmacol Rev 57:173–185PubMedCrossRefGoogle Scholar
  93. Head BP, Insel PA (2007) Do caveolins regulate cells by actions outside of caveolae? Trends Cell Biol 17:51–57PubMedCrossRefGoogle Scholar
  94. Hellström M, Gerhardt H, Kalén M, Li X, Eriksson U, Wolburg H, Betsholtz C (2001) Lack of pericytes leads to endothelial hyperplasia and abnormal morphogenesis. J Cell Biol 153:543–553PubMedCrossRefGoogle Scholar
  95. Hodivala-Dilke KM, Reynolds AR, Reynolds LE (2003) Integrins in angiogenesis: multitalented molecules in a balancing act. Cell Tissue Res 314:131–144PubMedCrossRefGoogle Scholar
  96. Holt KH, Crosbie RH, Venzke DP, Campbell KP (2000) Biosynthesis of dystroglycan: processing of a precursor propeptide. FEBS Lett 468:79–83PubMedCrossRefGoogle Scholar
  97. Hosokawa H, Ninomiya H, Kitamura Y, Fujiwara K, Masaki T (2002) Vascular endothelial cells that express dystroglycan are involved in angiogenesis. J Cell Sci 115:1487–1496PubMedGoogle Scholar
  98. Hynes RO (2002) A reevaluation of integrins as regulators of angiogenesis. Nat Med 8:918–921PubMedCrossRefGoogle Scholar
  99. Iadecola C (2004) Neurovascular regulation in the normal brain and in Alzheimer’s disease. Nat Rev Neurosci 5:347–360PubMedCrossRefGoogle Scholar
  100. Inai T, Sengoku A, Hirose E, Iida H, Shibata Y (2008) Comparative characterization of mouse rectum CMT93-I and -II cells by expression of claudin isoforms and tight junction morphology and function. Histochem Cell Biol 129:223–232PubMedCrossRefGoogle Scholar
  101. Itoh M, Nagafuchi A, Yonemura S, Kitaniyasuda T, Tsukita S (1993) The 220 kD protein colocalizing with cadherins in non-epithelial cells is identical to ZO-1, a tight junction associated protein in epithelial cells—cDNA cloning and immunoelectron microscpy. J Cell Biol 121:491–502PubMedCrossRefGoogle Scholar
  102. Jodoin J, Demeule M, Fenart L, Cecchelli R, Farmer S, Linton KJ, Higgins CF, Béliveau R (2003) P-glycoprotein in blood-brain barrier endothelial cells: interaction and oligomerization with caveolins. J Neurochem 87:1010–1023PubMedCrossRefGoogle Scholar
  103. Johansson PA, Dziegielewska KM, Ek CJ, Habgood MD, Møllgard K, Potter A, Schuliga M, Saunders NR (2005) Aquaporin-1 in the choroid plexuses of developing mammalian brain. Cell Tissue Res 322:353–364PubMedCrossRefGoogle Scholar
  104. Jucker M, Tian M, Norton DD, Sherman C, Kusiak JW (1996) Laminin alpha 2 is a component of brain capillary basement membrane: reduced expression in dystrophic dy mice. Neurosci 71:1153–1161CrossRefGoogle Scholar
  105. Kaneko K, Yagui K, Tanaka A, Yoshihara K, Ishikawa K, Takahashi K, Bujo H, Sakurai K, Saito Y (2007) Aquaporin 1 is required for hypoxia-inducible angiogenesis in human retinal vascular endothelial cells. Microvasc Res (in press)Google Scholar
  106. Kanesaka T, Mori M, Hattori T, Oki T, Kuwabara S (2006) Serum matrix metalloproteinase-3 levels correlate with disease activity in relapsing-remitting multiple sclerosis. J Neurol Neurosurg Psychiatr 77:185–188PubMedCrossRefGoogle Scholar
  107. Kim GW, Lewén A, Copin J-C, Watson BD, Chan PH (2001) The cytosolic antioxidant, copper/zinc superoxide dismutase, attenuates blood-brain barrier disruption and oxidative cellular injury after photothrombotic cortical ischemia in mice. Neuroscience 105:1007–1018PubMedCrossRefGoogle Scholar
  108. Kniesel U, Risau W, Wolburg H (1996) Development of blood-brain barrier tight junctions in the rat cortex. Dev Brain Res 96:229–240CrossRefGoogle Scholar
  109. Kofuji P, Ceelen P, Zahs KR, Surbeck LW, Lester HA, Newman EA (2000) Genetic inactivation of an inwardly rectifying potassium channel (Kir4.1 subunit) in mice: phenotypic impact in retina. J Neurosci 20:5733–5740PubMedGoogle Scholar
  110. Krizbai IA, Bauer H, Bresgen N, Eckl PM, Farkas A, Szatmári E, Traweger A, Wejksza K, Bauer HC (2005) Effect of oxidative stress on the junctional proteins of cultured cerebral endothelial cells. Cell Mol Neurobiol 25:129–139PubMedCrossRefGoogle Scholar
  111. Lagrange P, Romero IA, Minn A, Revest PA (1999) Transendothelial permeability changes induced by free radicals in an in vitro model of the blood-brain barrier. Free Radic Biol Med 27:667–672PubMedCrossRefGoogle Scholar
  112. Labreque L, Royal I, Surprenant DS, Patterson C, Gingras D, Bélivuae R (2003) Regulation of vascular endothelial growth factor receptor-2 activity by caveolin-1 and plasma membrane cholesterol. Mol Biol Cell 14:334–347CrossRefGoogle Scholar
  113. Lee S-W, Kim W-J, Choi YK, Song HS, Son MJ, Gelman IH, Kim Y-J, Kim K-W (2003) SSeCKS regulates angiogenesis and tight junction formation in blood-brain barrier. Nat Med 9:900–906PubMedCrossRefGoogle Scholar
  114. Lidov HG, Byers TJ, Kunkel LM (1993) The distribution of dystrophin in the murine central nervous system: an immunocytochemical study. Neuroscience 54:167–187PubMedCrossRefGoogle Scholar
  115. Liebner S, Engelhardt B (2005) Development of the blood-brain barrier. In: De Vries E, Prat A (eds) The blood brain barrier and its microenvironment. Basic physiology to neurological disease. Taylor and Francis, New York London, pp 1–25Google Scholar
  116. Liebner S, Fischmann A, Rascher G, Duffner F, Grote E-H, Kalbacher H, Wolburg H (2000a) Claudin-1 and claudin-5 expression and tight junction morphology are altered in blood vessels of human glioblastoma multiforme. Acta Neuropathol 100:323–331PubMedCrossRefGoogle Scholar
  117. Liebner S, Gerhardt H, Wolburg H (2000b) Differential expression of endothelial β-catenin and plakoglobin during development and maturation of the blood-brain and the blood-retina barrier in the chicken. Dev Dyn 217:86–98PubMedCrossRefGoogle Scholar
  118. Lindahl P, Johansson BR, Leveen P, Betsholtz C (1997) Pericyte loss and microaneurysm formation in PDGF-B-deficient mice. Science 277:242–245PubMedCrossRefGoogle Scholar
  119. Luo Y, Radice GL (2005) N-cadherin acts upstream of VE-cadherin in controlling vascular morphogenesis. J Cell Biol 169:29–34PubMedCrossRefGoogle Scholar
  120. Maher F, Vannucci SJ, Simpson IA (1994) Glucose transporter proteins in brain. FASEB J 8:1003–1011PubMedGoogle Scholar
  121. Mandel LJ, Bacallao R, Zampighi G (1993) Uncoupling of the molecular “fence” and paracellular “gate” functions in epithelial tight junctions. Nature 361:552–555PubMedCrossRefGoogle Scholar
  122. Mann GE, Yudilevich DL, Sobrevia L (2003) Regulation of amino acid and glucose transporters in endothelial and smooth muscle cells. Physiol Rev 83:183–252PubMedGoogle Scholar
  123. Maretto S, Cordenonsi M, Dupont S, Braghetta P, Broccoli V, Hassan AB, Volpin D, Bressan GM, Piccolo S (2003) Mapping Wnt/β-catenin signaling during mouse development and in colorectal tumors. Proc Natl Acad Sci USA 100:3299–3304PubMedCrossRefGoogle Scholar
  124. Martinez-Estrada OM, Rodriguez-Millán E, González-de Vicente E, Reina M, Vilaró S, Fabre M (2003) Erythropoietin protects the in vitro blood-brain barrier against VEGF-induced permeability. Eur J Neurosci 18:2538–2544PubMedCrossRefGoogle Scholar
  125. Martinez-Palomo A, Meza I, Beaty G, Cereijido M (1980) Experimental modulation of occluding junctions in a cultured transporting epithelium. J Cell Biol 87:736–745PubMedCrossRefGoogle Scholar
  126. Masckauchán TNH, Agalliu D, Vorontchikhina M, Ahn A, Parmalee NL, Li C-M, Khoo A, Tycko B, Brown AMC, Kitajewski J (2006) Wnt5a signalling induces proliferation and survival of endothelial cells in vitro and expression of MMP-1 and Tie-2. Mol Biol Cell 17:5163–5172PubMedCrossRefGoogle Scholar
  127. Matter K, Balda MS (2003) Signalling to and from tight junctions. Nat Rev Mol Biol 4:225–236CrossRefGoogle Scholar
  128. Mayhan WG (2000) Cellular mechanisms by which tumor necrosis factor-alpha produces disruption of the blood-brain barrier. Brain Res 866:101–108PubMedCrossRefGoogle Scholar
  129. McCarty JH, Monahan-Earley RA, Brown LF, Keller M, Gerhardt H, Rubin K, Shani M, Dvorak HF, Wolburg H, Bader BL, Dvorak AM, Hynes RO (2002) Defective associations between blood vessels and brain parenchyma lead to cerebral hemorrhage in mice lacking αv integrins. Mol Cell Biol 22:7667–7677PubMedCrossRefGoogle Scholar
  130. McCaffrey G, Staatz WD, Quigley CA, Nametz N, Seelbach MJ, Campos CR, Brooks TA, Egleton RD, Davis TP (2007) Tight junctions contain oligomeric protein assembly critical for maintaining blood-brain barrier integrity in vivo. J Neurochem 103:2540–2555CrossRefGoogle Scholar
  131. Michel T (1999) Targeting and translocation of endothelial nitric oxide synthase. Braz J Med Biol Res 32:1361–1366PubMedCrossRefGoogle Scholar
  132. Miyamori H, Takino T, Kobayashi Y, Tokai H, Itoh Y, Seiki M, Sato H (2001) Claudin promotes activation of pro-matrix metalloproteinase-2 mediated by membrane-type matrix metalloproteinases. J Biol Chem 276:28204–28211PubMedCrossRefGoogle Scholar
  133. Møllgard K, Malinowska DH, Saunders NR (1980) Lack of correlation between tight junction morphology and permeability properties in the choroid plexus. Nature 264:293–294CrossRefGoogle Scholar
  134. Moore SA, Saito F, Chen J, Michele DE, Henry MD, Messing A, Cohn RD, Ross-Barta SE, Westra S, Williamson RA, Hoshi T, Campbell KP (2002) Deletion of brain dystroglycan recapitulates aspects of congenital muscular dystrophy. Nature 418:422–425PubMedCrossRefGoogle Scholar
  135. Morgan L, Shah B, Rivers LE, Barden L, Groom AJ, Chung R, Higazi D, Desmond H, Smith T, Staddon JM (2007) Inflammation and dephosphorylation of the tight junction protein occludin in an experimental model of multiple sclerosis. Neuroscience 147:664–673PubMedCrossRefGoogle Scholar
  136. Morita K, Furuse M, Fujimoto K, Tsukita S (1999a) Claudin multigene family encoding four-transmembrane domain protein components of tight junction strands. Proc Natl Acad Sci USA 96:511–516PubMedCrossRefGoogle Scholar
  137. Morita K, Sasaki H, Furuse M, Tsukita S (1999b) Endothelial claudin: claudin-5/TMVCF constitutes tight junction strands in endothelial cells. J Cell Biol 147:185–194PubMedCrossRefGoogle Scholar
  138. Mulligan SJ, MacVicar BA (2004) Calcium transients in astrocyte endfeet cause cerebrovascular constrictions. Nature 431:195–199PubMedCrossRefGoogle Scholar
  139. Nabi IR, Le PU (2003) Caveolae/raft-dependent endocytosis. J Cell Biol 161:673–677PubMedCrossRefGoogle Scholar
  140. Nag S (2003) The blood-brain barrier. Biology and research protocols. Humana, TotowaGoogle Scholar
  141. Nag S, Picard P, Stewart DJ (2001) Expression of nitric oxide synthases and nitrotyrosine during blood-brain barrier breakdown and repair after cold injury. Lab Invest 81:41–49PubMedGoogle Scholar
  142. Nag S, Venugopalan R, Stewart DJ (2007) Increased caveolin-1 expression precedes decreased expression of occludin and claudin-5 during blood-brain barrier breakdown. Acta Neuropathol 114:459–469PubMedCrossRefGoogle Scholar
  143. Nagelhus EA, Mathisen TM, Ottersen OP (2004) Aquaporin-4 in the central nervous system: cellular and subcellular distribution and coexpression with Kir4.1. Neuroscience 129:905–913PubMedCrossRefGoogle Scholar
  144. Nagy Z, Peters H, Hüttner I (1984) Fracture faces of cell junctions in cerebral endothelium during normal and hyperosmotic conditions. Lab Invest 50:313–322PubMedGoogle Scholar
  145. Nase G, Helm PJ, Enger R, Ottersen OP (2008) Water entry into astrocytes during brain edema formation. Glia 56:895–902PubMedCrossRefGoogle Scholar
  146. 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 USA 98:14108–14113PubMedCrossRefGoogle Scholar
  147. Neuhaus J (1990) Orthogonal arrays of particles in astroglial cells: quantitative analysis of their density, size, and correlation with intramembranous particles. Glia 3:241–251PubMedCrossRefGoogle Scholar
  148. Nicchia GP, Frigeri A, Liuzzi GM, Santocroce MP, Nico B, Procino G, Quondamatteo F, Herklen R, Roncali L, Svelto M (2000) Aquaporin-4-containing astrocytes sustain a temperature- and mercury-insensitive swelling in vitro. Glia 31:29–38PubMedCrossRefGoogle Scholar
  149. Nicchia GP, Nico B, Camassa LMA, Mola MG, Loh N, Dermietzel R, Spray DC, Svelto M, Frigeri A (2004) The role of aquaporin-4 in the blood-brain barrier development and integrity: studies in animal and cell culture models. Neuroscience 129:935–945PubMedCrossRefGoogle Scholar
  150. Nicchia GP, Cogotzi L, Rossi A, Basco D, Brancaccio A, Svelto M, Frigeri A (2008) Expression of multiple AQP4 pools in the plasma membrane and their association with the dystrophin complex. J Neurochem (in press)Google Scholar
  151. Nico B, Frigeri A, Nicchia GP, Quondamatteo F, Herken R, Errede M, Ribatti D, Svelto M, Roncali L (2001) Role of aquaporin-4 water channel in the development and integrity of the blood-brain barrier. J Cell Sci 114:1297–1307PubMedGoogle Scholar
  152. Nico B, Nicchia GP, Frigeri A, Corsi P, Mangieri D, Ribatti D, Svelto M, Roncali L (2004) Altered blood-brain barrier development in dystrophic mdx mice. Neuroscience 125:921–935PubMedCrossRefGoogle Scholar
  153. Nielsen S, Nagelhus EA, Amiry-Moghaddam M, Bourque C, Agre P, Ottersen OP (1997) Specialized membrane domains for water transport in glial cells: high-resolution immunogold cytochemistry of aquaporin-4 in rat brain. J Neurosci 17:171–180PubMedGoogle Scholar
  154. Nitkin RM, Smith MA, Magill C, Fallon JR, Yao Y-MM, Wallace BG, McMahan UJ (1987) Identification of agrin, a synaptic organizing protein from Torpedo electric organ. J Cell Biol 105:2471–2478PubMedCrossRefGoogle Scholar
  155. Nitta T, Hata M, Gotoh S, Seo Y, Sasaki H, Hashimoto N, Furuse M, Tsukita S (2003) Size-selective loosening of the blood-brain barrier in claudin-5-deficient mice. J Cell Biol 161:653–660PubMedCrossRefGoogle Scholar
  156. Noell S, Fallier-Becker P, Beyer C, Kröger S, Mack AF, Wolburg H (2007) Effects of agrin on the expression and distribution of the water channel protein aquaporin-4 and volume regulation in cultured astrocytes. Eur J Neurosci 26:2109–2118PubMedCrossRefGoogle Scholar
  157. Nusrat A, Parkos CA, Verkade P, Foley CS, Liang TW, Innis-Whitehouse W, Eastburn WK, Madara JL (2000) Tight junctions are membrane microdomains. J Cell Sci 113:1771–1781PubMedGoogle Scholar
  158. Ohnishi H, Nakahara T, Furuse K, Sasaki H, Tsukita S, Furuse M (2004) JACOP, a novel plaque protein localizing at the apical junctional complex with sequence similarity to cingulin. J Biol Chem 279:46014–46022PubMedCrossRefGoogle Scholar
  159. Omidi Y, Barar J, Ahmadian S, Heidari HR, Gumbleton M (2008) Characterization and astrocytic modulation of system L transporters in brain microvasculature endothelial cells. Cell Biochem Funct 26:381–391PubMedCrossRefGoogle Scholar
  160. Papadopoulos MC, Krishna S, Verkman AS (2002) Aquaporin water channels and brain edema. Mount Sinai J Med 69:242–248Google Scholar
  161. Parton RG, Richards AA (2003) Lipid rafts and caveolae as portals for endocytosis: new insights and common mechanisms. Traffic 4:724–738PubMedCrossRefGoogle Scholar
  162. Parton RG, Simons K (2007) The multiple faces of caveolae. Nat Rev Mol Cell Biol 8:185–194PubMedCrossRefGoogle Scholar
  163. Parton RG, Joggerst B, Simons K (1994) Regulated internalization of caveolae. J Cell Biol 127:1199–1215PubMedCrossRefGoogle Scholar
  164. Pawson T, Nash P (2003) Assembly of cell regulatory systems through protein interaction domains. Science 300:445–452PubMedCrossRefGoogle Scholar
  165. Peters A, Palay SL, Webster H (1991) The fine structure of the nervous system. Oxford University Press, New YorkGoogle Scholar
  166. Piontek J, Winkler L, Wolburg H, Müller SL, Zuleger N, Piehl C, Wiesner B, Krause G, Blasig IE (2008) Formation of tight junction: determinants of homophilic interaction between classic claudins. FASEB J 22:146–158PubMedCrossRefGoogle Scholar
  167. Qutub AA, Hunt CA (2005) Glucose transport to the brain: a systems model. Brain Res Rev 49:595–617PubMedCrossRefGoogle Scholar
  168. Rajasekaran AK, Hojo M, Huima T, Rodriguez-Boulan E (1996) Catenins and zonula occludens-1 form a complex during early stages in the assembly of tight junctions. J Cell Biol 132:451–464PubMedCrossRefGoogle Scholar
  169. Ramsauer M (2006) Pericytes and their contribution to the blood-brain barrier. In: Dermietzel R, Spray DC, Nedergaard M (eds) Blood-brain interfaces: from ontogeny to artificial barriers. Wiley-VCH, Weinheim, pp 109–127Google Scholar
  170. Ransohoff RM, Kivisääk P, Kidd G (2003) Three or more routes for leukocyte migration into the central nervous system. Nat Rev Immunol 3:569–581PubMedCrossRefGoogle Scholar
  171. Rascher G, Fischmann A, Kröger S, Duffner F, Grote E-H, Wolburg H (2002) Extracellular matrix and the blood-brain barrier in glioblastoma multiforme: spatial segregation of tenascin and agrin. Acta Neuropathol 104:85–91PubMedCrossRefGoogle Scholar
  172. Rascher-Eggstein G, Liebner S, Wolburg H (2004) The blood-brain barrier in the human glioma. In: Sharma HS, Westman J (eds) Blood-spinal cord and brain barriers in health and desease, vol 1. Academic Press, San Diego, pp 561-576CrossRefGoogle Scholar
  173. 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 USA 95:11981–11986PubMedCrossRefGoogle Scholar
  174. Reese TS, Karnovsky MJ (1967) Fine structural localization of a blood-brain barrier to exogenous peroxidase. J Cell Biol 34:207–217PubMedCrossRefGoogle Scholar
  175. Reichel A (2006) The role of blood-brain barrier studies in the pharmaceutical industry. Curr Drug Metab 7:183–203PubMedCrossRefGoogle Scholar
  176. Risau W, Hallmann R, Albrecht U (1986) Differentiation-dependent expression of protein in brain endothelium during development of the blood-brain barrier. Dev Biol 117:537–545PubMedCrossRefGoogle Scholar
  177. Roberts WG, Palade GE (1995) Increased microvascular permeability and endothelial fenestration induced by vascular endothelial growth factor. Cancer Res 57:765–772Google Scholar
  178. Rosenberg GA (2005) Matrix metalloproteinases and proteolytic opening of the blood-brain barrier in neuroinflammation. In: De Vries E, Prat A (eds) The blood-brain barrier and its microenvironment. Basic physiology to neurological disease. Taylor and Francis, New York London, pp 335–358Google Scholar
  179. Rosenberg GA, Yang Y (2007) Vasogenic edema due to tight junction disruption by matrix metalloproteinases in cerebral ischemia. Neurosurg Focus 22:E4PubMedCrossRefGoogle Scholar
  180. Rosenberg GA, Navratil M, Barone F, Feuerstein G (1996) Proteolytic cascade enzyme increase in focal cerebral ischemia in rat. J Cereb Blood Flow Metab 16:360–366PubMedCrossRefGoogle Scholar
  181. Ruiz-Ederra J, Zhang H, Verkman AS (2007) Evidence against functional interaction between aquaporin-4 water channels and Kir4.1 potassium channels in retinal Müller cells. J Biol Chem 282:21866–21872PubMedCrossRefGoogle Scholar
  182. Qin Y, Sato TN (1995) Mouse multidrug resistance 1a/3 gene is the earliest known endothelial cell differentiation marker during blood-brain barrier development. Dev Dyn 202:172–180PubMedGoogle Scholar
  183. Saadoun S, Papadopoulos MC, Davies DC, Krishna S, Bell BA (2002) Aquaporin-4 expression is increased in oedematous human brain tumours. J Neurol Neurosurg Psychiatry 72:262–265PubMedCrossRefGoogle Scholar
  184. Saitou M, Furuse M, Sasaki H, Schulzke J-D, Fromm M, Takano H, Noda T, Tsukita S (2000) Complex phenotype of mice lacking occludin, a component of tight junction strands. Mol Biol Cell 11:4131–4142PubMedGoogle Scholar
  185. Sakakibara A, Furuse M, Saitou M, Ando-Akatsuka Y, Tsukita S (1997) Possible involvement of phosphorylation of occludin in tight junction formation. J Cell Biol 137:1393–1401PubMedCrossRefGoogle Scholar
  186. Sameshima T, Nabeshima K, Toole BP, Yokogami K, Okada Y, Goya T, Koono M, Wakisaka S (2000) Glioma cell extracellular matrix metalloproteinase inducer (EMMPRIN) (CD147) stimulates production of membrane-type matrix metalloproteinases and activated gelatinase A in co-cultures with brain-derived fibroblasts. Cancer Lett 157:177–184PubMedCrossRefGoogle Scholar
  187. Saunders NR, Knott GW, Dziegielewska KM (2000) Barriers in the immature brain. Cell Mol Neurobiol 20:29–40PubMedCrossRefGoogle Scholar
  188. Schinkel AH, Smit JJM, Tellingen O van, Beijnen JH, Wagenaar E, Deemter L van, Mol CAAM, Walk MA van der, Robanus-Maandag EC, Riele HPJ te, Berns AJM, Borst P (1994) Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs. Cell 77:491–502PubMedCrossRefGoogle Scholar
  189. Schlosshauer B, Herzog K-H (1990) Neurothelin: an inducible cell surface glycoprotein of blood-brain barrier-specific endothelial cells and distinct neurons. J Cell Biol 110:1261–1274PubMedCrossRefGoogle Scholar
  190. Schreibelt G, Kooij G, Reijerkerk A, Van Doorn R, Gringhuis SI, Van der Pol S, Weksler BB, Romero IA, Couraud P-O, Piontek J, Blasig IE, Dijkstra CD, Ronken E, De Vries HE (2007a) Reactive oxygen species alter endothelial tight junction dynamics via rhoA, PI3 kinase, and PKB signalling. FASEB J 21:3666–3676PubMedCrossRefGoogle Scholar
  191. Schreibelt G, Van Horssen J, Van Rossum S, Dijkstra CD, Drukarch B, De Vries HE (2007b) Therapeutic potential and biological role of endogenous antioxidant enzymes in multiple sclerosis pathology. Brain Res Rev 56:322–330PubMedCrossRefGoogle Scholar
  192. Senger DR, Galli SJ, Dvorak AM, Perruzzi CA, Harvey VS, Dvorak HF (1983) Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 219:983–985PubMedCrossRefGoogle Scholar
  193. Seulberger H, Unger CM, Risau W (1992) HT7, Neurothelin, Basigin, gp42 and OX-47—many names for one developmentally regulated immuno-globulin-like surface glycoprotein on blood-brain barrier endothelium, epithelial tissue barriers and neurons. Neurosci Lett 140:93–97PubMedCrossRefGoogle Scholar
  194. Simard M, Nedergaard M (2004) The neurobiology of glia in the context of water and ion homeostasis. Neuroscience 129:877–896PubMedCrossRefGoogle Scholar
  195. Simionescu M, Gafencu A, Antohe F (2002) Transcytosis of plasma macromolecules in endothelial cells: a cell biological survey. Microsc Res Tech 57:269–288PubMedCrossRefGoogle Scholar
  196. Simpson IA, Vannucci SJ, DeJoseph MR, Hawkins RA (2001) Glucose transporters asymmetries in the bovine blood-brain barrier. J Biol Chem 276:12725–12729PubMedCrossRefGoogle Scholar
  197. Sixt M, Engelhardt B, Pausch F, Hallmann R, Wendler O, Sorokin LM (2001) 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 153:933–946PubMedCrossRefGoogle Scholar
  198. Smith MA, Hilgenberg LGW (2002) Agrin in the CNS: a protein in search of a function? NeuroReport 13:1485–1495PubMedCrossRefGoogle Scholar
  199. Smith MW, Gumbleton M (2006) Endocytosis at the blood-brain barrier: from basic understanding to drug delivery strategies. J Drug Targeting 14:191–214CrossRefGoogle Scholar
  200. Solé S, Petegnief V, Gorina R, Chamorro Á, Planas AM (2004) Activation of matrix metalloproteinase-3 and agrin cleavage in cerebral ischemia/reperfusion. J Neuropathol Exp Neurol 63:338–349PubMedGoogle Scholar
  201. Song L, Pachter JS (2004) Monocyte chemoattractant protein-1 alters expression of tight junction-associated proteins in brain microvascular endothelial cells. Microvasc Res 67:78–89PubMedCrossRefGoogle Scholar
  202. Song L, Ge S, Pachter JS (2007) Caveolin-1 regulates expression of junction-associated proteins in brain microvascular endothelial cells. Blood 109:1515–1523PubMedCrossRefGoogle Scholar
  203. Sorokin L, Girg W, Gopfert T, Hallmann R, Deutzmann R (1994) Expression of novel 400-kDa laminin chains by mouse and bovine endothelial cells. Eur J Biochem 223:603–610PubMedCrossRefGoogle Scholar
  204. Speake T, Freeman LJ, Brown PD (2003) Expression of aquaporin 1 and aquaporin 4 water channels in rat choroid plexus. Biochim Biophys Acta 1609:80–86PubMedCrossRefGoogle Scholar
  205. Staehelin LA (1974) Structure and function of intercellular junctions. Int Rev Cytol 39:191–283PubMedCrossRefGoogle Scholar
  206. Stan R-V (2002) Structure and function of endothelial caveolae. Microsc Res Tech 57:350–364PubMedCrossRefGoogle Scholar
  207. Stevenson BR, Siliciano JD, Mooseker MS, Goodenough DA (1986) Identification of ZO-1: a high molecular weight polypeptide associated with the tight junction (zonula occludens) in a variety of epithelia. J Cell Biol 103:755–766PubMedCrossRefGoogle Scholar
  208. Stewart PA, Wiley MJ (1981) Developing nervous tissue induces formation of blood-brain barrier characteristics in invading endothelial cells: a study using quail-chick transplantation chimeras. Dev Biol 84:183–192PubMedCrossRefGoogle Scholar
  209. Stone DM, Nikolics K (1995) Tissue- and age-specific expression patterns of alternatively spliced agrin mRNA transcripts in embryonic rat suggest novel developmental roles. J Neurosci 15:6767–6778PubMedGoogle Scholar
  210. Suzuki A, Yamanaka T, Hirose T, Manabe N, Mizuno K, Shimizu M, Akimoto K, Izumi T, Ohnishi T, Ohno S (2001) Atypical protein kinase C is involved in the evolutionarily conserved PAR protein complex and plays a critical role in establishing epithelia-specific junctional structures. J Cell Biol 152:1183–1196PubMedCrossRefGoogle Scholar
  211. Takano T, Tian G-F, Peng W, Lou N, Libionka W, Han X, Nedergaard M (2006) Astrocyte-mediated control of cerebral blood flow. Nat Neurosci 9:260–267PubMedCrossRefGoogle Scholar
  212. Takeichi M (2007) The cadherin superfamily in neuronal connections and interactions. Nat Rev Neurosci 8:11–20PubMedCrossRefGoogle Scholar
  213. Tian M, Jacobsen C, Gee SH, Campbell KP, Carbonetto S, Jucker M (1996) Dystroglycan in the cerebellum is a laminin α2 chain binding protein at the glial-vascular interface and is expressed in Purkinje cells. Eur J Neurosci 8:2739–2747PubMedCrossRefGoogle Scholar
  214. Traweger A, Fuchs R, Krizbai IA, Weiger TM, Bauer HC, Bauer H (2002) The tight junction specific protein occludin is a functional target of the E3 ubiquitin-protein ligase Itch. J Biol Chem 277:10201–10208PubMedCrossRefGoogle Scholar
  215. Traweger A, Lehner C, Farkas A, Krizbai IA, Tempfer H, Klement E, Guenther B, Bauer H-C, Bauer H (2008) Nuclear zonula occludens-2 alters gene expression and junctional stability in epithelial and endothelial cells. Differentiation 76:99–106PubMedGoogle Scholar
  216. Tsukita S, Furuse M (1999) Occludin and claudins in tight-junction strands: leading or supporting players? Trends Cell Biol 9:268–273PubMedCrossRefGoogle Scholar
  217. Tsukita S, Furuse M (2000) Pores in the wall: claudins constitute tight junction strands containing aqueous pores. J Cell Biol 149:13–16PubMedCrossRefGoogle Scholar
  218. Tsukita S, Furuse M, Itoh M (1999) Structural and signalling molecules come together at tight junctions. Curr Opin Cell Biol 11:628–633PubMedCrossRefGoogle Scholar
  219. Tsukita S, Furuse M, Itoh M (2001) Multifunctional strands in tight junctions. Nat Rev Mol Cell Biol 2:285–293PubMedCrossRefGoogle Scholar
  220. Tuma PL, Hubbard AL (2003) Transcytosis: crossing cellular barriers. Physiol Rev 83:871–932PubMedGoogle Scholar
  221. Turcotte S, Demeule M, Régina A, Fournier C, Jodoin J, Moghrabi A, Béliveau R (2006) The blood-brain barrier: roles of multidrug resistance transporter P-glycoprotein. In: Dermietzel R, Spray DC, Nedergaard M (eds) Blood-brain interfaces: from ontogeny to artificial barriers. Wiley-VCH, Weinheim, pp 431–462Google Scholar
  222. Ueda H, Baba T, Kashiwagi K, Iijima H, Ohno S (2000a) Dystrobrevin localization in photoreceptor axon terminals and at blood-ocular barrier sites. Invest Ophthalmol Vis Sci 41:3908–3914PubMedGoogle Scholar
  223. Ueda H, Baba T, Terada N, Kato Y, Fuji Y, Takayama I, Mei X, Ohno S (2000b) Immunolocalization of dystrobrevin in the astrocytic endfeet and endothelial cells in the rat cerebellum. Neurosci Letters 283:121–124CrossRefGoogle Scholar
  224. Usatyuk PV, Parinandi NL, Natarajan V (2006) Redox regulation of 4-hydroxy-2-nonenal-mediated endothelial barrier dysfunction by focal adhesion, adherens, and tight junction proteins. J Biol Chem 281:35554–35566PubMedCrossRefGoogle Scholar
  225. VanSaun M, Werle MJ (2000) Matrix metalloproteinase-3 removes agrin from synaptic basal lamina. J Neurobiol 43:140–149PubMedCrossRefGoogle Scholar
  226. Verbavatz J-M, Ma T, Gobin R, Verkman AS (1997) Absence of orthogonal arrays in kidney, brain and muscle from transgenic knockout mice lacking water channel aquaporin-4. J Cell Sci 110:2855–2860PubMedGoogle Scholar
  227. Virgintino D, Robertson D, Errede M, Benagiano V, Girolamo F, Maiorano E, Roncali L, Bertossi M (2002a) Expression of P-glycoprotein in human cerebral cortex microvessels. J Histochem Cytochem 50:1671–1676PubMedGoogle Scholar
  228. Virgintino D, Robertson D, Errede M, Benagiono V, Tauer U, Roncali L, Bertossi M (2002b) Expression of caveolin-1 in human brain microvessels. Neuroscience 115:145–152PubMedCrossRefGoogle Scholar
  229. Virgintino D, Girolamo F, Errede M, Capobianco C, Robertson D, Stallcup WB, Perris R, Roncali L (2007) An intimate interplay between precocious, migrating pericytes and endothelial cells governs human fetal brain angiogenesis. Angiogenesis 10:35–45PubMedCrossRefGoogle Scholar
  230. Virgintino D, Errede M, Girolamo F, Capobianco C, Robertson D, Vimercati A, Serio G, Di Benedetto A, Yonekawa Y, Frei K, Roncali L (2008) Fetal blood-brain barrier P-glycoprotein contributes to brain protection during human development. J Neuropathol Exp Neurol 67:50–61PubMedCrossRefGoogle Scholar
  231. Wakai S, Hirokawa N (1978) Development of the blood-brain barrier to horseradish peroxidase in the chick embryo. Cell Tissue Res 195:195–203PubMedCrossRefGoogle Scholar
  232. Warth A, Kröger S, Wolburg H (2004) Redistribution of aquaporin-4 in human glioblastoma correlates with loss of agrin immunoreactivity from brain capillary basal laminae. Acta Neuropathol 107:311–318PubMedCrossRefGoogle Scholar
  233. Warth A, Mittelbronn M, Wolburg H (2005) Redistribution of the water channel protein aquaporin-4 and the K+ channel protein Kir4.1 differs in low- and high-grade human brain tumors. Acta Neuropathol 109:418–426PubMedCrossRefGoogle Scholar
  234. Warth A, Mittelbronn M, Hülper P, Erdlenbruch B, Wolburg H (2007) Expression of the water channel protein aquaporin-9 in malignant brain tumors. Appl Immunohistochem Mol Morphol 15:193–198PubMedCrossRefGoogle Scholar
  235. Weber C, Fraemohs L, Dejana E (2007) The role of junctional adhesion molecules in vascular inflammation. Nat Rev Immunol 7:467–477PubMedCrossRefGoogle Scholar
  236. Winder SJ (2001) The complexities of dystroglycan. Trends Biochem Sci 26:118–124PubMedCrossRefGoogle Scholar
  237. Wolburg H (1995) Orthogonal arrays of intramembranous particles. A review with special reference to astrocytes. J Brain Res 36:239–258Google Scholar
  238. Wolburg H, Lippoldt A (2002) Tight junctions of the blood-brain barier: development, composition and regulation. Vasc Pharmacol 38:323–337CrossRefGoogle Scholar
  239. Wolburg H, Neuhaus J, Kniesel U, Krauss B, Schmid E-M, Öcalan M, Farrell C, Risau W (1994) Modulation of tight junction structure in blood-brain barrier endothelial cells. Effects of tissue culture, second messengers and cocultured astrocytes. J Cell Sci 107:1347–1357PubMedGoogle Scholar
  240. Wolburg H, Liebner S, Reichenbach A, Gerhardt H (1999) The pecten oculi of the chicken: a model system for vascular differentiation and barrier maturation. Int Rev Cytol 187:111–159PubMedCrossRefGoogle Scholar
  241. Wolburg H, Wolburg-Buchholz K, Kraus J, Rascher-Eggstein G, Liebner S, Hamm S, Duffner F, Grote E-H, Risau W, Engelhardt B (2003) Localization of claudin-3 in tight junctions of the blood-brain barrier is selectively lost during experimental autoimmune encephalomyelitis and human glioblastoma multiforme. Acta Neuropathol 105:586–592PubMedGoogle Scholar
  242. Wolburg H, Lippoldt A, Ebnet K (2006) Tight junctions and the blood-brain barrier. In: Gonzales-Mariscal L (ed) Tight junctions. Landes Bioscience/Springer Science, Georgetown New York, pp 175–195CrossRefGoogle Scholar
  243. Wolburg H, Wolburg-Buchholz K, Sam H, Horvát S, Deli MA, Mack AF (2008) Epithelial and endothelial barriers in the olfactory region of the nasal cavity of the rat. Histochem Cell Biol 130:127–140PubMedCrossRefGoogle Scholar
  244. Woodfin A, Voisin M-B, Nourshargh S (2007) PECAM-1: a multi-functional molecule in inflammation and vascular biology. Arterioscler Thromb Vasc Biol 27:2514–2523PubMedCrossRefGoogle Scholar
  245. Wu B, Crampton SP, Hughes CCW (2007) Wnt signaling induces MMP expression and regulates T cell transmigration. Immunity 26:227–239PubMedCrossRefGoogle Scholar
  246. Wu J, Helftenbein G, Koslowski M, Sahin U, Tureci Ö (2006) Identification of new claudin family members by a novel PSI-BLAST based approach with enhanced specificity. Proteins 65:808–815PubMedCrossRefGoogle Scholar
  247. Yang B, Brown D, Verkman AS (1996) The mercurial insensitive water channel (AQP-4) forms orthogonal arrays in stably transfected chinese hamster ovary cells. J Biol Chem 271:4577–4580PubMedCrossRefGoogle Scholar
  248. Yang Y, Estrada EY, Thompson JF, Liu W, Rosenberg GA (2007) Matrix metalloproteinase-mediated disruption of tight junction propteins in cerebral vessels is reversed by synthetic matrix metalloproteinase inhibitor in focal ischemia in rat. J Cereb Blood Flow Metab 27:698–709CrossRefGoogle Scholar
  249. Zaccaria ML, Di Tommaso F, Brancaccio A, Paggi P, Petrucci TC (2001) Dystroglycan distribution in adult mouse brain: a light and electron microscopy study. Neuroscience 104:311–324PubMedCrossRefGoogle Scholar
  250. Zozulya A, Weidenfeller C, Galla H-G (2008) Pericyte-endothelial cell interaction increases MMP-9 secretion at the blood-brain barrier in vitro. Brain Res 1189:1–11PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Hartwig Wolburg
    • 1
  • Susan Noell
    • 1
  • Andreas Mack
    • 1
  • Karen Wolburg-Buchholz
    • 1
  • Petra Fallier-Becker
    • 1
  1. 1.Institute of PathologyUniversity of TübingenTübingenGermany

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