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Pathology and new players in the pathogenesis of brain edema

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Brain edema continues to be a major cause of mortality after diverse types of brain pathologies such as major cerebral infarcts, hemorrhages, trauma, infections and tumors. The classification of edema into vasogenic, cytotoxic, hydrocephalic and osmotic has stood the test of time although it is recognized that in most clinical situations there is a combination of different types of edema during the course of the disease. Basic information about the types of edema is provided for better understanding of the expression pattern of some of the newer molecules implicated in the pathogenesis of brain edema. These molecules include the aquaporins, matrix metalloproteinases and growth factors such as vascular endothelial growth factors A and B and the angiopoietins. The potential of these agents in the treatment of edema is discussed. Since many molecules are involved in the pathogenesis of brain edema, effective treatment cannot be achieved by a single agent but will require the administration of a “magic bullet” containing a variety of agents released at different times during the course of edema in order to be successful.

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References

  1. Aase K, Lymboussaki A, Kaipainen A, Olofsson B, Alitalo K, Eriksson U (1999) Localization of VEGF-B in the mouse embryo suggests a paracrine role of the growth factor in the developing vasculature. Dev Dyn 215:12–25. doi:10.1002/(SICI)1097-0177(199905)215:1<12::AID-DVDY3>3.0.CO;2-N

    PubMed  CAS  Google Scholar 

  2. Abbott NJ (2000) Inflammatory mediators and modulation of blood-brain barrier permeability. Cell Mol Neurobiol 20:131–147. doi:10.1023/A:1007074420772

    PubMed  CAS  Google Scholar 

  3. Adams RH, Alitalo K (2007) Molecular regulation of angiogenesis and lymphangiogenesis. Nat Rev Mol Cell Biol 8:464–478. doi:10.1038/nrm2183

    PubMed  CAS  Google Scholar 

  4. Agre P, King LS, Yasui M, Guggino WB, Ottersen OP, Fujiyoshi Y, Engel A, Nielsen S (2002) Aquaporin water channels—from atomic structure to clinical medicine. J Physiol 542:3–16. doi:10.1113/jphysiol.2002.020818

    PubMed  CAS  Google Scholar 

  5. Amiry-Moghaddam M, Frydenlund DS, Ottersen OP (2004) Anchoring of aquaporin-4 in brain: molecular mechanisms and implications for the physiology and pathophysiology of water transport. Neuroscience 129:999–1010

    PubMed  CAS  Google Scholar 

  6. Amiry-Moghaddam M, Otsuka T, Hurn PD, Traystman RJ, Haug FM, Froehner SC, Adams ME, Neely JD, Agre P, Ottersen OP, Bhardwaj A (2003) An alpha-syntrophin-dependent pool of AQP4 in astroglial end-feet confers bidirectional water flow between blood and brain. Proc Natl Acad Sci USA 100:2106–2111. doi:10.1073/pnas.0437946100

    PubMed  CAS  Google Scholar 

  7. Antonetti DA, Barber AJ, Khin S, Lieth E, Tarbell JM, Gardner TW (1998) Vascular permeability in experimental diabetes is associated with reduced endothelial occludin content: vascular endothelial growth factor decreases occludin in retinal endothelial cells. Diabetes 47:1953–1959. doi:10.2337/diabetes.47.12.1953

    PubMed  CAS  Google Scholar 

  8. Arundine M, Tymianski M (2004) Molecular mechanisms of glutamate-dependent neurodegeneration in ischemia and traumatic brain injury. Cell Mol Life Sci 61:657–668. doi:10.1007/s00018-003-3319-x

    PubMed  CAS  Google Scholar 

  9. 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 20:1681–1689. doi:10.1097/00004647-200012000-00007

    PubMed  CAS  Google Scholar 

  10. 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 21:7724–7732

    PubMed  CAS  Google Scholar 

  11. Audero E, Cascone I, Zanon I, Previtali SC, Piva R, Schiffer D, Bussolino F (2001) Expression of angiopoietin-1 in human glioblastomas regulates tumor-induced angiogenesis: in vivo and in vitro studies. Arterioscler Thromb Vasc Biol 21:536–541

    PubMed  CAS  Google Scholar 

  12. Ayata C, Ropper AH (2002) Ischaemic brain oedema. J Clin Neurosci 9:113–124. doi:10.1054/jocn.2001.1031

    PubMed  Google Scholar 

  13. Badaut J, Hirt L, Granziera C, Bogousslavsky J, Magistretti PJ, Regli L (2001) Astrocyte-specific expression of aquaporin-9 in mouse brain is increased after transient focal cerebral ischemia. J Cereb Blood Flow Metab 21:477–482. doi:10.1097/00004647-200105000-00001

    PubMed  CAS  Google Scholar 

  14. Baffert F, Le T, Thurston G, McDonald DM (2006) Angiopoietin-1 decreases plasma leakage by reducing number and size of endothelial gaps in venules. Am J Physiol Heart Circ Physiol 290:H107–H118. doi:10.1152/ajpheart.00542.2005

    PubMed  CAS  Google Scholar 

  15. Barron KD, Dentinger MP, Kimelberg HK, Nelson LR, Bourke RS, Keegan S, Mankes R, Cragoe EJ Jr (1988) Ultrastructural features of a brain injury model in cat. I. Vascular and neuroglial changes and the prevention of astroglial swelling by a fluorenyl (aryloxy) alkanoic acid derivative (L-644, 711). Acta Neuropathol 75:295–307. doi:10.1007/BF00690538

    PubMed  CAS  Google Scholar 

  16. Black KL, Hoff JT (1985) Leukotrienes increase blood–brain barrier permeability following intraparenchymal injections in rats. Ann Neurol 18:349–351. doi:10.1002/ana.410180313

    PubMed  CAS  Google Scholar 

  17. Bloch O, Auguste KI, Manley GT, Verkman AS (2006) Accelerated progression of kaolin-induced hydrocephalus in aquaporin-4-deficient mice. J Cereb Blood Flow Metab 26:1527–1537. doi:10.1038/sj.jcbfm.9600306

    PubMed  CAS  Google Scholar 

  18. Bloch O, Manley GT (2007) The role of aquaporin-4 in cerebral water transport and edema. Neurosurg Focus 22:E3. doi:10.3171/foc.2007.22.5.4

    PubMed  Google Scholar 

  19. Boyd NL, Park H, Yi H, Boo YC, Sorescu GP, Sykes M, Jo H (2003) Chronic shear induces caveolae formation and alters ERK and Akt responses in endothelial cells. Am J Physiol Heart Circ Physiol 285:H1113–H1122

    PubMed  CAS  Google Scholar 

  20. Breier G, Albrecht U, Sterrer S, Risau W (1992) Expression of vascular endothelial growth factor during embryonic angiogenesis and endothelial cell differentiation. Development 114:521–532

    PubMed  CAS  Google Scholar 

  21. Brightman MW, Zis K, Anders J (1983) Morphology of cerebral endothelium and astrocytes as determinants of the neuronal microenvironment. Acta Neuropathol Suppl 8:21–33

    PubMed  CAS  Google Scholar 

  22. Cancilla PA, Bready J, Berliner J, Sharifi-Nia H, Toga AW, Santori EM, Scully S, deVellis J (1992) Expression of mRNA for glial fibrillary acidic protein after experimental cerebral injury. J Neuropathol Exp Neurol 51:560–565. doi:10.1097/00005072-199209000-00011

    PubMed  CAS  Google Scholar 

  23. Candelario-Jalil E, Yang Y, Rosenberg GA (2008) Diverse roles of matrix metalloproteinases and tissue inhibitors of metalloproteinases in neuroinflammation and cerebral ischemia. Neuroscience 158:983–994. doi:10.1016/j.neuroscience.2008.06.025

    PubMed  Google Scholar 

  24. Chan PH, Fishman RA (1984) The role of arachidonic acid in vasogenic brain edema. Fed Proc 43:210–213

    PubMed  CAS  Google Scholar 

  25. Chan PH, Fishman RA, Caronna J, Schmidley JW, Prioleau G, Lee J (1983) Induction of brain edema following intracerebral injection of arachidonic acid. Ann Neurol 13:625–632. doi:10.1002/ana.410130608

    PubMed  CAS  Google Scholar 

  26. Chang DI, Hosomi N, Lucero J, Heo JH, Abumiya T, Mazar AP, del Zoppo GJ (2003) Activation systems for latent matrix metalloproteinase-2 are upregulated immediately after focal cerebral ischemia. J Cereb Blood Flow Metab 23:1408–1419. doi:10.1097/01.WCB.0000091765.61714.30

    PubMed  CAS  Google Scholar 

  27. Chen CH, Xue R, Zhang J, Li X, Mori S, Bhardwaj A (2007) Effect of osmotherapy with hypertonic saline on regional cerebral edema following experimental stroke: a study utilizing magnetic resonance imaging. Neurocrit Care 7:92–100. doi:10.1007/s12028-007-0033-9

    PubMed  CAS  Google Scholar 

  28. Chiba H, Osanai M, Murata M, Kojima T, Sawada N (2008) Transmembrane proteins of tight junctions. Biochim Biophys Acta 1778:588–600. doi:10.1016/j.bbamem.2007.08.017

    PubMed  CAS  Google Scholar 

  29. Citi S, Sabanay H, Jakes R, Geiger B, Kendrick-Jones J (1988) Cingulin, a new peripheral component of tight junctions. Nature 333:272–276. doi:10.1038/333272a0

    PubMed  CAS  Google Scholar 

  30. Clark AW, Krekoski CA, Bou SS, Chapman KR, Edwards DR (1997) Increased gelatinase A (MMP-2) and gelatinase B (MMP-9) activities in human brain after focal ischemia. Neurosci Lett 238:53–56. doi:10.1016/S0304-3940(97)00859-8

    PubMed  CAS  Google Scholar 

  31. Cohen AW, Hnasko R, Schubert W, Lisanti MP (2004) Role of caveolae and caveolins in health and disease. Physiol Rev 84:1341–1379. doi:10.1152/physrev.00046.2003

    PubMed  CAS  Google Scholar 

  32. Cohen B, Barkan D, Levy Y, Goldberg I, Fridman E, Kopolovic J, Rubinstein M (2001) Leptin induces angiopoietin-2 expression in adipose tissues. J Biol Chem 276:7697–7700. doi:10.1074/jbc.C000634200

    PubMed  CAS  Google Scholar 

  33. Connolly DT, Olander JV, Heuvelman D, Nelson R, Monsell R, Siegel N, Haymore BL, Leimgruber R, Feder J (1989) Human vascular permeability factor. Isolation from U937 cells. J Biol Chem 264:20017–20024

    PubMed  CAS  Google Scholar 

  34. Croll SD, Wiegand SJ (2001) Vascular growth factors in cerebral ischemia. Mol Neurobiol 23:121–135. doi:10.1385/MN:23:2-3:121

    PubMed  CAS  Google Scholar 

  35. Cunningham LA, Wetzel M, Rosenberg GA (2005) Multiple roles for MMPs and TIMPs in cerebral ischemia. Glia 50:329–339. doi:10.1002/glia.20169

    PubMed  Google Scholar 

  36. Dallasta LM, Pisarov LA, Esplen JE, Werley JV, Moses AV, Nelson JA, Achim CL (1999) Blood–brain barrier tight junction disruption in human immunodeficiency virus-1 encephalitis. Am J Pathol 155:1915–1927

    PubMed  CAS  Google Scholar 

  37. Davis S, Aldrich TH, Jones PF, Acheson A, Compton DL, Jain V, Ryan TE, Bruno J, Radziejewski C, Maisonpierre PC, Yancopoulos GD (1996) Isolation of angiopoietin-1, a ligand for the TIE2 receptor, by secretion-trap expression cloning. Cell 87:1161–1169. doi:10.1016/S0092-8674(00)81812-7

    PubMed  CAS  Google Scholar 

  38. de Vries HE, Blom-Roosemalen MC, van OM, De Boer AG, van Berkel TJ, Breimer DD, Kuiper J (1996) The influence of cytokines on the integrity of the blood–brain barrier in vitro. J Neuroimmunol 64:37–43. doi:10.1016/0165-5728(95)00148-4

    PubMed  Google Scholar 

  39. Del Bigio MR (1993) Neuropathological changes caused by hydrocephalus. Acta Neuropathol 85:573–585. doi:10.1007/BF00334666

    PubMed  CAS  Google Scholar 

  40. DiMattio J, Hochwald GM, Malhan C, Wald A (1975) Effects of changes in serum osmolarity on bulk flow of fluid into cerebral ventricles and on brain water content. Pflugers Arch 359:253–264. doi:10.1007/BF00587383

    PubMed  CAS  Google Scholar 

  41. Ding H, Roncari L, Wu X, Lau N, Shannon P, Nagy A, Guha A (2001) Expression and hypoxic regulation of angiopoietins in human astrocytomas. Neuro Oncol 3:1–10. doi:10.1215/15228517-3-1-1

    PubMed  CAS  Google Scholar 

  42. Dirnagl U, Iadecola C, Moskowitz MA (1999) Pathobiology of ischaemic stroke: an integrated view. Trends Neurosci 22:391–397. doi:10.1016/S0166-2236(99)01401-0

    PubMed  CAS  Google Scholar 

  43. Dobrogowska DH, Lossinsky AS, Tarnawski M, Vorbrodt AW (1998) Increased blood–brain barrier permeability and endothelial abnormalities induced by vascular endothelial growth factor. J Neurocytol 27:163–173. doi:10.1023/A:1006907608230

    PubMed  CAS  Google Scholar 

  44. Doczi T, Szerdahelyi P, Gulya K, Kiss J (1982) Brain water accumulation after the central administration of vasopressin. Neurosurgery 11:402–407

    PubMed  CAS  Google Scholar 

  45. Dolman D, Drndarski S, Abbott NJ, Rattray M (2005) Induction of aquaporin 1 but not aquaporin 4 messenger RNA in rat primary brain microvessel endothelial cells in culture. J Neurochem 93:825–833. doi:10.1111/j.1471-4159.2005.03111.x

    PubMed  CAS  Google Scholar 

  46. Dumont DJ, Gradwohl GJ, Fong GH, Auerbach R, Breitman ML (1993) The endothelial-specific receptor tyrosine kinase, tek, is a member of a new subfamily of receptors. Oncogene 8:1293–1301

    PubMed  CAS  Google Scholar 

  47. Easton AS, Fraser PA (1998) Arachidonic acid increases cerebral microvascular permeability by free radicals in single pial microvessels of the anaesthetized rat. J Physiol 507(Pt 2):541–547. doi:10.1111/j.1469-7793.1998.541bt.x

    PubMed  CAS  Google Scholar 

  48. Eliceiri BP, Paul R, Schwartzberg PL, Hood JD, Leng J, Cheresh DA (1999) Selective requirement for Src kinases during VEGF-induced angiogenesis and vascular permeability. Mol Cell 4:915–924. doi:10.1016/S1097-2765(00)80221-X

    PubMed  CAS  Google Scholar 

  49. Elkjaer M, Vajda Z, Nejsum LN, Kwon T, Jensen UB, miry-Moghaddam M, Frokiaer J, Nielsen S (2000) Immunolocalization of AQP9 in liver, epididymis, testis, spleen, and brain. Biochem Biophys Res Commun 276:1118–1128. doi:10.1006/bbrc.2000.3505

    PubMed  CAS  Google Scholar 

  50. Feng D, Nagy JA, Dvorak AM, Dvorak HF (2000) Different pathways of macromolecule extravasation from hyperpermeable tumor vessels. Microvasc Res 59:24–37. doi:10.1006/mvre.1999.2207

    PubMed  CAS  Google Scholar 

  51. Ferrara N, Gerber HP, LeCouter J (2003) The biology of VEGF and its receptors. Nat Med 9:669–676. doi:10.1038/nm0603-669

    PubMed  CAS  Google Scholar 

  52. Fishman RA (1975) Brain edema. N Engl J Med 293:706–711

    PubMed  CAS  Google Scholar 

  53. Forster C (2008) Tight junctions and the modulation of barrier function in disease. Histochem Cell Biol 130:55–70. doi:10.1007/s00418-008-0424-9

    PubMed  Google Scholar 

  54. Fujikawa K, Scherpenseel ID, Jain SK, Presman E, Varticovski L (1999) Role of PI 3-kinase in angiopoietin-1-mediated migration and attachment-dependent survival of endothelial cells. Exp Cell Res 253:663–672. doi:10.1006/excr.1999.4693

    PubMed  CAS  Google Scholar 

  55. Furman CS, Gorelick-Feldman DA, Davidson KG, Yasumura T, Neely JD, Agre P, Rash JE (2003) Aquaporin-4 square array assembly: opposing actions of M1 and M23 isoforms. Proc Natl Acad Sci USA 100:13609–13614. doi:10.1073/pnas.2235843100

    PubMed  CAS  Google Scholar 

  56. Furuse M, Fujita K, Hiiragi T, Fujimoto K, Tsukita S (1998) Claudin-1 and -2: novel integral membrane proteins localizing at tight junctions with no sequence similarity to occludin. J Cell Biol 141:1539–1550. doi:10.1083/jcb.141.7.1539

    PubMed  CAS  Google Scholar 

  57. 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 123:1777–1788. doi:10.1083/jcb.123.6.1777

    PubMed  CAS  Google Scholar 

  58. Furuse M, Tsukita S (2006) Claudins in occluding junctions of humans and flies. Trends Cell Biol 16:181–188. doi:10.1016/j.tcb.2006.02.006

    PubMed  CAS  Google Scholar 

  59. Gamble JR, Drew J, Trezise L, Underwood A, Parsons M, Kasminkas L, Rudge J, Yancopoulos G, Vadas MA (2000) Angiopoietin-1 is an antipermeability and anti-inflammatory agent in vitro and targets cell junctions. Circ Res 87:603–607

    PubMed  CAS  Google Scholar 

  60. Goldman CK, Bharara S, Palmer CA, Vitek J, Tsai JC, Weiss HL, Gillespie GY (1997) Brain edema in meningiomas is associated with increased vascular endothelial growth factor expression. Neurosurgery 40:1269–1277. doi:10.1097/00006123-199706000-00029

    PubMed  CAS  Google Scholar 

  61. Gow A, Southwood CM, Li JS, Pariali M, Riordan GP, Brodie SE, Danias J, Bronstein JM, Kachar B, Lazzarini RA (1999) CNS myelin and sertoli cell tight junction strands are absent in Osp/claudin-11 null mice. Cell 99:649–659. doi:10.1016/S0092-8674(00)81553-6

    PubMed  CAS  Google Scholar 

  62. Gumbiner B, Lowenkopf T, Apatira D (1991) Identification of a 160-kDa polypeptide that binds to the tight junction protein ZO-1. Proc Natl Acad Sci USA 88:3460–3464. doi:10.1073/pnas.88.8.3460

    PubMed  CAS  Google Scholar 

  63. Hansen TM, Moss AJ, Brindle NP (2008) Vascular endothelial growth factor and angiopoietins in neurovascular regeneration and protection following stroke. Curr Neurovasc Res 5:236–245. doi:10.2174/156720208786413433

    PubMed  CAS  Google Scholar 

  64. Hasegawa H, Ma T, Skach W, Matthay MA, Verkman AS (1994) Molecular cloning of a mercurial-insensitive water channel expressed in selected water-transporting tissues. J Biol Chem 269:5497–5500

    PubMed  CAS  Google Scholar 

  65. Haskins J, Gu L, Wittchen ES, Hibbard J, Stevenson BR (1998) ZO-3, a novel member of the MAGUK protein family found at the tight junction, interacts with ZO-1 and occludin. J Cell Biol 141:199–208. doi:10.1083/jcb.141.1.199

    PubMed  CAS  Google Scholar 

  66. Hawkins BT, Egleton RD (2008) Pathophysiology of the blood–brain barrier: animal models and methods. Curr Top Dev Biol 80:277–309. doi:10.1016/S0070-2153(07)80007-X

    PubMed  CAS  Google Scholar 

  67. Hayashi T, Abe K, Suzuki H, Itoyama Y (1997) Rapid induction of vascular endothelial growth factor gene expression after transient middle cerebral artery occlusion in rats. Stroke 28:2039–2044

    PubMed  CAS  Google Scholar 

  68. Hirase T, Staddon JM, Saitou M, Ando-Akatsuka Y, Itoh M, Furuse M, Fujimoto K, Tsukita S, Rubin LL (1997) Occludin as a possible determinant of tight junction permeability in endothelial cells. J Cell Sci 110(Pt 14):1603–1613

    PubMed  CAS  Google Scholar 

  69. Hofman P, Blaauwgeers HGT, Tolentino MJ, Adamis AP, Cardozo BJN, Vrensen GFJM, Schlingemann RO (2000) VEGF-A induced hyperpermeability of blood–retinal barrier endothelium in vivo is predominantly associated with pinocytotic vesicular transport and not with formation of fenestrations. Curr Eye Res 21:637–645. doi:10.1076/0271-3683(200008)21:2;1-V;FT637

    PubMed  CAS  Google Scholar 

  70. Holash J, Maisonpierre PC, Compton D, Boland P, Alexander CR, Zagzag D, Yancopoulos GD, Wiegand SJ (1999) Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF. Science 284:1994–1998. doi:10.1126/science.284.5422.1994

    PubMed  CAS  Google Scholar 

  71. Holash J, Wiegand SJ, Yancopoulos GD (1999) New model of tumor angiogenesis: dynamic balance between vessel regression and growth mediated by angiopoietins and VEGF. Oncogene 18:5356–5362. doi:10.1038/sj.onc.1203035

    PubMed  CAS  Google Scholar 

  72. Houck KA, Ferrara N, Winer J, Cachianes G, Li B, Leung DW (1991) The vascular endothelial growth factor family: identification of a fourth molecular species and characterization of alternative splicing of RNA. Mol Endocrinol 5:1806–1814. doi:10.1210/mend-5-12-1806

    PubMed  CAS  Google Scholar 

  73. Ikezu T, Ueda H, Trapp BD, Nishiyama K, Sha JF, Volonte D, Galbiati F, Byrd AL, Bassell G, Serizawa H, Lane WS, Lisanti MP, Okamoto T (1998) Affinity-purification and characterization of caveolins from the brain: differential expression of caveolin-1, -2, and -3 in brain endothelial and astroglial cell types. Brain Res 804:177–192. doi:10.1016/S0006-8993(98)00498-3

    PubMed  CAS  Google Scholar 

  74. Jho D, Mehta D, Ahmmed G, Gao XP, Tiruppathi C, Broman M, Malik AB (2005) Angiopoietin-1 opposes VEGF-induced increase in endothelial permeability by inhibiting TRPC1-dependent Ca2 influx. Circ Res 96:1282–1290. doi:10.1161/01.RES.0000171894.03801.03

    PubMed  CAS  Google Scholar 

  75. Jones N, Iljin K, Dumont DJ, Alitalo K (2001) Tie receptors: new modulators of angiogenic and lymphangiogenic responses. Nat Rev Mol Cell Biol 2:257–267. doi:10.1038/35067005

    PubMed  CAS  Google Scholar 

  76. Joo F (1994) Insight into the regulation by second messenger molecules of the permeability of the blood–brain barrier. Microsc Res Tech 27:507–515. doi:10.1002/jemt.1070270605

    PubMed  CAS  Google Scholar 

  77. Kalkanis SN, Carroll RS, Zhang J, Zamani AA, Black PM (1996) Correlation of vascular endothelial growth factor messenger RNA expression with peritumoral vasogenic cerebral edema in meningiomas. J Neurosurg 85:1095–1101

    PubMed  CAS  Google Scholar 

  78. Katayama Y, Kawamata T (2003) Edema fluid accumulation within necrotic brain tissue as a cause of the mass effect of cerebral contusion in head trauma patients. Acta Neurochir Suppl (Wien) 86:323–327

    CAS  Google Scholar 

  79. Kempski O, von AU, Schurer L, Baethmann A (1990) Intravenous glutamate enhances edema formation after a freezing lesion. Adv Neurol 52:219–223

    PubMed  CAS  Google Scholar 

  80. Kimelberg HK (1995) Current concepts of brain edema. Review of laboratory investigations. J Neurosurg 83:1051–1059

    PubMed  CAS  Google Scholar 

  81. Klatzo I (1967) Presidental address. Neuropathological aspects of brain edema. J Neuropathol Exp Neurol 26:1–14. doi:10.1097/00005072-196701000-00001

    PubMed  CAS  Google Scholar 

  82. Klatzo I (1987) Pathophysiological aspects of brain edema. Acta Neuropathol 72:236–239. doi:10.1007/BF00691095

    PubMed  CAS  Google Scholar 

  83. Klatzo I (1994) Evolution of brain edema concepts. Acta Neurochir Suppl (Wien) 60:3–6

    CAS  Google Scholar 

  84. Klatzo I, Chui E, Fujiwara K, Spatz M (1980) Resolution of vasogenic brain edema. Adv Neurol 28:359–373

    PubMed  CAS  Google Scholar 

  85. Klatzo I, Piraux A, Laskowski EJ (1958) The relationship between edema, blood–brain barrier and tissue elements in a local brain injury. J Neuropathol Exp Neurol 17:548–564. doi:10.1097/00005072-195810000-00002

    PubMed  CAS  Google Scholar 

  86. Kniesel U, Wolburg H (2000) Tight junctions of the blood–brain barrier. Cell Mol Neurobiol 20:57–76. doi:10.1023/A:1006995910836

    PubMed  CAS  Google Scholar 

  87. Kovacs Z, Ikezaki K, Samoto K, Inamura T, Fukui M (1996) VEGF and flt. Expression time kinetics in rat brain infarct. Stroke 27:1865–1872

    PubMed  CAS  Google Scholar 

  88. Kuroiwa T, Cahn R, Juhler M, Goping G, Campbell G, Klatzo I (1985) Role of extracellular proteins in the dynamics of vasogenic brain edema. Acta Neuropathol 66:3–11. doi:10.1007/BF00698288

    PubMed  CAS  Google Scholar 

  89. Kuroiwa T, Miyasaka N, Fengyo Z, Yamada I, Nakane M, Nagaoka T, Tamura A, Ohno K (2007) Experimental ischemic brain edema: morphological and magnetic resonance imaging findings. Neurosurg Focus 22:E11. doi:10.3171/foc.2007.22.5.12

    PubMed  Google Scholar 

  90. Kuroiwa T, Ting P, Martinez H, Klatzo I (1985) The biphasic opening of the blood–brain barrier to proteins following temporary middle cerebral artery occlusion. Acta Neuropathol 68:122–129. doi:10.1007/BF00688633

    PubMed  CAS  Google Scholar 

  91. Lagercrantz J, Farnebo F, Larsson C, Tvrdik T, Weber G, Piehl F (1998) A comparative study of the expression patterns for vegf, vegf-b/vrf and vegf-c in the developing and adult mouse. Bba Gene Struct Express 1398:157–163

    CAS  Google Scholar 

  92. Lee KR, Betz AL, Keep RF, Chenevert TL, Kim S, Hoff JT (1995) Intracerebral infusion of thrombin as a cause of brain edema. J Neurosurg 83:1045–1050

    PubMed  CAS  Google Scholar 

  93. Lee SW, Kim WJ, Jun HO, Choi YK, Kim KW (2009) Angiopoietin-1 reduces vascular endothelial growth factor-induced brain endothelial permeability via upregulation of ZO-2. Int J Mol Med 23:279–284

    PubMed  CAS  Google Scholar 

  94. Leppert D, Lindberg RL, Kappos L, Leib SL (2001) Matrix metalloproteinases: multifunctional effectors of inflammation in multiple sclerosis and bacterial meningitis. Brain Res Brain Res Rev 36:249–257. doi:10.1016/S0165-0173(01)00101-1

    PubMed  CAS  Google Scholar 

  95. Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N (1989) Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 246:1306–1309. doi:10.1126/science.2479986

    PubMed  CAS  Google Scholar 

  96. Li X, Hahn CN, Parsons M, Drew J, Vadas MA, Gamble JR (2004) Role of protein kinase Czeta in thrombin-induced endothelial permeability changes: inhibition by angiopoietin-1. Blood 104:1716–1724. doi:10.1182/blood-2003-11-3744

    PubMed  CAS  Google Scholar 

  97. Liang D, Bhatta S, Gerzanich V, Simard JM (2007) Cytotoxic edema: mechanisms of pathological cell swelling. Neurosurg Focus 22:E2. doi:10.3171/foc.2007.22.5.3

    PubMed  Google Scholar 

  98. Lo EH, Dalkara T, Moskowitz MA (2003) Mechanisms, challenges and opportunities in stroke. Nat Rev Neurosci 4:399–415. doi:10.1038/nrn1106

    PubMed  CAS  Google Scholar 

  99. Longatti P, Basaldella L, Orvieto E, Dei TA, Martinuzzi A (2006) Aquaporin(s) expression in choroid plexus tumours. Pediatr Neurosurg 42:228–233. doi:10.1159/000092359

    PubMed  Google Scholar 

  100. Lossinsky AS, Shivers RR (2004) Structural pathways for macromolecular and cellular transport across the blood–brain barrier during inflammatory conditions. Histol Histopathol 19:535–564 (Review)

    PubMed  CAS  Google Scholar 

  101. Machein MR, Kullmer J, Fiebich BL, Plate KH, Warnke PC (1999) Vascular endothelial growth factor expression, vascular volume, and capillary permeability in human brain tumors. Neurosurgery 44:732–740. doi:10.1097/00006123-199904000-00022

    PubMed  CAS  Google Scholar 

  102. Machein MR, Plate KH (2000) VEGF in brain tumors. J Neurooncol 50:109–120. doi:10.1023/A:1006416003964

    PubMed  CAS  Google Scholar 

  103. Maisonpierre PC, Suri C, Jones PF, Bartunkova S, Wiegand SJ, Radziejewski C, Compton D, McClain J, Aldrich TH, Papadopoulos N, Daly TJ, Davis S, Sato TN, Yancopoulos GD (1997) Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science 277:55–60. doi:10.1126/science.277.5322.55

    PubMed  CAS  Google Scholar 

  104. Makinen T, Olofsson B, Karpanen T, Hellman U, Soker S, Klagsbrun M, Eriksson U, Alitalo K (1999) Differential binding of vascular endothelial growth factor B splice and proteolytic isoforms to neuropilin-1. J Biol Chem 274:21217–21222. doi:10.1074/jbc.274.30.21217

    PubMed  CAS  Google Scholar 

  105. Manley GT, Fujimura M, Ma T, Noshita N, Filiz F, Bollen AW, Chan P, Verkman AS (2000) Aquaporin-4 deletion in mice reduces brain edema after acute water intoxication and ischemic stroke. Nat Med 6:159–163. doi:10.1038/72256

    PubMed  CAS  Google Scholar 

  106. Marmarou A (2007) A review of progress in understanding the pathophysiology and treatment of brain edema. Neurosurg Focus 22:E1

    Google Scholar 

  107. Marmarou A, Nakamura T, Tanaka K, Hochwald GM (1984) The distribution of water in edema. In: Go KG, Baethmann A (eds) Recent progress in the study and therapy of brain edema. Plenum Press, New York, pp 37–44

    Google Scholar 

  108. 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 156:965–976

    PubMed  CAS  Google Scholar 

  109. Martin-Padura I, Lostaglio S, Schneemann M, Williams L, Romano M, Fruscella P, Panzeri C, Stoppacciaro A, Ruco L, Villa A, Simmons D, Dejana E (1998) Junctional adhesion molecule, a novel member of the immunoglobulin superfamily that distributes at intercellular junctions and modulates monocyte transmigration. J Cell Biol 142:117–127. doi:10.1083/jcb.142.1.117

    PubMed  CAS  Google Scholar 

  110. Mayhan WG (2000) Nitric oxide donor-induced increase in permeability of the blood–brain barrier. Brain Res 866:101–108. doi:10.1016/S0006-8993(00)02254-X

    PubMed  CAS  Google Scholar 

  111. Meng S, Qiao M, Lin L, Del Bigio MR, Tomanek B, Tuor UI (2004) Correspondence of AQP4 expression and hypoxic-ischaemic brain oedema monitored by magnetic resonance imaging in the immature and juvenile rat. Eur J Neurosci 19:2261–2269. doi:10.1111/j.0953-816X.2004.03315.x

    PubMed  Google Scholar 

  112. Milhorat TH (1992) Classification of the cerebral edemas with reference to hydrocephalus and pseudotumor cerebri. Childs Nerv Syst 8:301–306. doi:10.1007/BF00296558

    PubMed  CAS  Google Scholar 

  113. Milhorat TH, Clark RG, Hammock MK (1970) Experimental hydrocephalus. 2. Gross pathological findings in acute and subacute obstructive hydrocephalus in the dog and monkey. J Neurosurg 32:390–399

    PubMed  CAS  Google Scholar 

  114. Milhorat TH, Clark RG, Hammock MK, McGrath PP (1970) Structural, ultrastructural, and permeability changes in the ependyma and surrounding brain favoring equilibration in progressive hydrocephalus. Arch Neurol 22:397–407

    PubMed  CAS  Google Scholar 

  115. Minshall RD, Malik AB (2006) Transport across the endothelium: regulation of endothelial permeability. Handb Exp Pharmacol 107–144

  116. Minshall RD, Sessa WC, Stan RV, Anderson RG, Malik AB (2003) Caveolin regulation of endothelial function. Am J Physiol Lung Cell Mol Physiol 285:L1179–L1183

    PubMed  CAS  Google Scholar 

  117. Monier S, Parton RG, Vogel F, Behlke J, Henske A, Kurzchalia TV (1995) VIP21-caveolin, a membrane protein constituent of the caveolar coat, oligomerizes in vivo and in vitro. Mol Biol Cell 6:911–927

    PubMed  CAS  Google Scholar 

  118. Morita K, Furuse M, Fujimoto K, Tsukita S (1999) Claudin multigene family encoding four-transmembrane domain protein components of tight junction strands. Proc Natl Acad Sci USA 96:511–516. doi:10.1073/pnas.96.2.511

    PubMed  CAS  Google Scholar 

  119. Mun-Bryce S, Rosenberg GA (1998) Matrix metalloproteinases in cerebrovascular disease. J Cereb Blood Flow Metab 18:1163–1172. doi:10.1097/00004647-199811000-00001

    PubMed  CAS  Google Scholar 

  120. Nag S (2007) Structure and pathology of the blood–brain barrier. In: Lathja A (ed) Handbook of neurochemistry and molecular neurobiology. Springer, New York, pp 58–78

    Google Scholar 

  121. Nag S, Manias JL, Stewart DJ (2009) Blood–brain barrier breakdown is associated with increased expression of phosphorylated caveolin-1 in endothelium. J Neuropathol Appl Neurobiology. doi: 10.1111/j.1365-2990.2008.01009.x

  122. Nag S (1996) Cold-injury of the cerebral cortex: immunolocalization of cellular proteins and blood-brain barrier permeability studies. J Neuropathol Exp Neurol 55:880–888

    PubMed  CAS  Google Scholar 

  123. Nag S (2002) The blood–brain barrier and cerebral angiogenesis: lessons from the cold-injury model. Trends Mol Med 8:38–44. doi:10.1016/S1471-4914(01)02221-3

    PubMed  CAS  Google Scholar 

  124. Nag S (2003) Blood–brain barrier permeability using tracers and immunohistochemistry. Methods Mol Med 89:133–144

    PubMed  CAS  Google Scholar 

  125. Nag S (2003) Morphology and molecular properties of cellular components of normal cerebral vessels. Methods Mol Med 89:3–36

    PubMed  CAS  Google Scholar 

  126. Nag S (2003) Pathophysiology of blood–brain barrier breakdown. Methods Mol Med 89:97–119

    PubMed  CAS  Google Scholar 

  127. Nag S, Eskandarian MR, Davis J, Eubanks JH (2002) Differential expression of vascular endothelial growth factor-A (VEGF-A) and VEGF-B after brain injury. J Neuropathol Exp Neurol 61:778–788

    PubMed  CAS  Google Scholar 

  128. Nag S, Papneja T, Venugopalan R, Stewart DJ (2005) Increased angiopoietin2 expression is associated with endothelial apoptosis and blood–brain barrier breakdown. Lab Invest 85:1189–1198. doi:10.1038/labinvest.3700325

    PubMed  CAS  Google Scholar 

  129. 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 81:41–49

    PubMed  CAS  Google Scholar 

  130. Nag S, Robertson DM, Dinsdale HB (1980) Morphological changes in spontaneously hypertensive rats. Acta Neuropathol 52:27–34. doi:10.1007/BF00687225

    PubMed  CAS  Google Scholar 

  131. Nag S, Takahashi JL, Kilty DW (1997) Role of vascular endothelial growth factor in blood–brain barrier breakdown and angiogenesis in brain trauma. J Neuropathol Exp Neurol 56:912–921. doi:10.1097/00005072-199708000-00009

    PubMed  CAS  Google Scholar 

  132. 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 114:459–469. doi:10.1007/s00401-007-0274-x

    PubMed  CAS  Google Scholar 

  133. Nagy Z, Peters H, Huttner I (1984) Fracture faces of cell junctions in cerebral endothelium during normal and hyperosmotic conditions. Lab Invest 50:313–322

    PubMed  CAS  Google Scholar 

  134. 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 17:171–180

    PubMed  CAS  Google Scholar 

  135. Nielsen S, Smith BL, Christensen EI, Agre P (1993) Distribution of the aquaporin CHIP in secretory and resorptive epithelia and capillary endothelia. Proc Natl Acad Sci USA 90:7275–7279. doi:10.1073/pnas.90.15.7275

    PubMed  CAS  Google Scholar 

  136. 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 161:653–660. doi:10.1083/jcb.200302070

    PubMed  CAS  Google Scholar 

  137. Nourhaghighi N, Teichert-Kuliszewska K, Davis J, Stewart DJ, Nag S (2003) Altered expression of angiopoietins during blood–brain barrier breakdown and angiogenesis. Lab Invest 83:1211–1222. doi:10.1097/01.LAB.0000082383.40635.FE

    PubMed  CAS  Google Scholar 

  138. Nusrat A, Parkos CA, Verkade P, Foley CS, Liang TW, Innis-Whitehouse W, Eastburn KK, Madara JL (2000) Tight junctions are membrane microdomains. J Cell Sci 113(Pt 10):1771–1781

    PubMed  CAS  Google Scholar 

  139. Olesen SP, Crone C (1986) Substances that rapidly augment ionic conductance of endothelium in cerebral venules. Acta Physiol Scand 127:233–241. doi:10.1111/j.1748-1716.1986.tb07898.x

    PubMed  CAS  Google Scholar 

  140. Olofsson B, Korpelainen E, Pepper MS, Mandriota SJ, Aase K, Kumar V, Gunji Y, Jeltsch MM, Shibuya M, Alitaloi K, Eriksson U (1998) Vascular endothelial growth factor B (VEGF-B) binds to VEGF receptor-1 and regulates plasminogen activator activity in endothelial cells. Proc Natl Acad Sci USA 95:11709–11714. doi:10.1073/pnas.95.20.11709

    PubMed  CAS  Google Scholar 

  141. Olofsson B, Pajusola K, Kaipainen A, von Euler G, Joukov V, Saksela O, Orpana A, Pettersson RF, Alitalo K, Eriksson U (1996) Vascular endothelial growth factor B, a novel growth factor for endothelial cells. Proc Natl Acad Sci USA 93:2576–2581. doi:10.1073/pnas.93.6.2576

    PubMed  CAS  Google Scholar 

  142. Olofsson B, Pajusola K, von Euler G, Chilov D, Alitalo K, Eriksson U (1996) Genomic organization of the mouse and human genes for vascular endothelial growth factor B (VEGF-B) and characterization of a second splice isoform. J Biol Chem 271:19310–19317. doi:10.1074/jbc.271.32.19310

    PubMed  CAS  Google Scholar 

  143. Oshio K, Watanabe H, Song Y, Verkman AS, Manley GT (2005) Reduced cerebrospinal fluid production and intracranial pressure in mice lacking choroid plexus water channel aquaporin-1. FASEB J 19:76–78

    PubMed  CAS  Google Scholar 

  144. Ostermann G, Weber KS, Zernecke A, Schroder A, Weber C (2002) JAM-1 is a ligand of the beta(2) integrin LFA-1 involved in transendothelial migration of leukocytes. Nat Immunol 3:151–158. doi:10.1038/ni755

    PubMed  CAS  Google Scholar 

  145. Otrock ZK, Makarem JA, Shamseddine AI (2007) Vascular endothelial growth factor family of ligands and receptors. Blood Cells Mol Dis 38:258–268. doi:10.1016/j.bcmd.2006.12.003 (Review)

    PubMed  CAS  Google Scholar 

  146. Oury TD, Piantadosi CA, Crapo JD (1993) Cold-induced brain edema in mice. Involvement of extracellular superoxide dismutase and nitric oxide. J Biol Chem 268:15394–15398

    PubMed  CAS  Google Scholar 

  147. Papadopoulos MC, Manley GT, Krishna S, Verkman AS (2004) Aquaporin-4 facilitates reabsorption of excess fluid in vasogenic brain edema. FASEB J 18:1291–1293

    PubMed  CAS  Google Scholar 

  148. Papadopoulos MC, Saadoun S, Binder DK, Manley GT, Krishna S, Verkman AS (2004) Molecular mechanisms of brain tumor edema. Neuroscience 129:1011–1020. doi:10.1016/j.neuroscience.2004.05.044

    PubMed  CAS  Google Scholar 

  149. Papadopoulos MC, Verkman AS (2005) Aquaporin-4 gene disruption in mice reduces brain swelling and mortality in pneumococcal meningitis. J Biol Chem 280:13906–13912. doi:10.1074/jbc.M413627200

    PubMed  CAS  Google Scholar 

  150. Papadopoulos MC, Verkman AS (2007) Aquaporin-4 and brain edema. Pediatr Nephrol 22:778–784. doi:10.1007/s00467-006-0411-0

    PubMed  Google Scholar 

  151. Papadopoulos MC, Verkman AS (2008) Potential utility of aquaporin modulators for therapy of brain disorders. Prog Brain Res 170:589–601. doi:10.1016/S0079-6123(08)00446-9

    PubMed  CAS  Google Scholar 

  152. Papadopoulos SM, Black KL, Hoff JT (1989) Cerebral edema induced by arachidonic acid: role of leukocytes and 5-lipoxygenase products. Neurosurgery 25:369–372. doi:10.1097/00006123-198909000-00008

    PubMed  CAS  Google Scholar 

  153. Papapetropoulos A, Fulton D, Mahboubi K, Kalb RG, OConnor DS, Li FZ, Altieri DC, Sessa WC (2000) Angiopoietin-1 inhibits endothelial cell apoptosis via the Akt/survivin pathway. J Biol Chem 275:9102–9105. doi:10.1074/jbc.275.13.9102

    PubMed  CAS  Google Scholar 

  154. Pappius HM, Oh JH, Dossetor JB (1967) The effects of rapid hemodialysis on brain tissues and cerebrospinal fluid of dogs. Can J Physiol Pharmacol 45:129–147

    PubMed  CAS  Google Scholar 

  155. Pardridge WM (1998) Blood–brain barrier methodology and biology. In: Pardridge WM (ed) Introduction to the blood–brain barrier. Methodology, biology and pathology. Cambridge University Press, Cambridge, pp 1–8

    Google Scholar 

  156. Parton RG, Simons K (2007) The multiple faces of caveolae. Nat Rev Mol Cell Biol 8:185–194. doi:10.1038/nrm2122

    PubMed  CAS  Google Scholar 

  157. Paul R, Zhang ZG, Eliceiri BP, Jiang Q, Boccia AD, Zhang RL, Chopp M, Cheresh DA (2001) Src deficiency or blockade of Src activity in mice provides cerebral protection following stroke. Nat Med 7:222–227. doi:10.1038/84675

    PubMed  CAS  Google Scholar 

  158. Pichiule P, Chavez JC, Xu K, LaManna JC (1999) Vascular endothelial growth factor upregulation in transient global ischemia induced by cardiac arrest and resuscitation in rat brain. Brain Res Mol Brain Res 74:83–90. doi:10.1016/S0169-328X(99)00261-2

    PubMed  CAS  Google Scholar 

  159. Pizurki L, Zhou Z, Glynos K, Roussos C, Papapetropoulos A (2003) Angiopoietin-1 inhibits endothelial permeability, neutrophil adherence and IL-8 production. Br J Pharmacol 139:329–336. doi:10.1038/sj.bjp.0705259

    PubMed  CAS  Google Scholar 

  160. Plate KH (1999) Mechanisms of angiogenesis in the brain. J Neuropathol Exp Neurol 58:313–320. doi:10.1097/00005072-199904000-00001

    PubMed  CAS  Google Scholar 

  161. Plate KH, Breier G, Weich HA, Risau W (1992) Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo. Nature 359:845–848. doi:10.1038/359845a0

    PubMed  CAS  Google Scholar 

  162. Plumb J, McQuaid S, Mirakhur M, Kirk J (2002) Abnormal endothelial tight junctions in active lesions and normal-appearing white matter in multiple sclerosis. Brain Pathol 12:154–169

    PubMed  Google Scholar 

  163. Proescholdt MA, Heiss JD, Walbridge S, Muhlhauser J, Capogrossi MC, Oldfield EH, Merrill MJ (1999) Vascular endothelial growth factor (VEGF) modulates vascular permeability and inflammation in rat brain. J Neuropathol Exp Neurol 58:613–627. doi:10.1097/00005072-199906000-00006

    PubMed  CAS  Google Scholar 

  164. Provias J, Claffey K, del Aguila L, Lau N, Feldkamp M, Guha A (1997) Meningiomas: role of vascular endothelial growth factor/vascular permeability factor in angiogenesis and peritumoral edema. Neurosurgery 40:1016–1026. doi:10.1097/00006123-199705000-00027

    PubMed  CAS  Google Scholar 

  165. Puri MC, Rossant J, Alitalo K, Bernstein A, Partanen J (1995) The receptor tyrosine kinase TIE is required for integrity and survival of vascular endothelial cells. EMBO J 14:5884–5891

    PubMed  CAS  Google Scholar 

  166. Raab S, Plate KH (2007) Different networks, common growth factors: shared growth factors and receptors of the vascular and the nervous system. Acta Neuropathol 113:607–626. doi:10.1007/s00401-007-0228-3

    PubMed  CAS  Google Scholar 

  167. Rash JE, Davidson KG, Yasumura T, Furman CS (2004) Freeze-fracture and immunogold analysis of aquaporin-4 (AQP4) square arrays, with models of AQP4 lattice assembly. Neuroscience 129:915–934. doi:10.1016/j.neuroscience.2004.06.076

    PubMed  CAS  Google Scholar 

  168. 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 95:11981–11986. doi:10.1073/pnas.95.20.11981

    PubMed  CAS  Google Scholar 

  169. Raymond JJ, Robertson DM, Dinsdale HB (1986) Pharmacological modification of bradykinin induced breakdown of the blood–brain barrier. Can J Neurol Sci 13:214–220

    PubMed  CAS  Google Scholar 

  170. Reese TS, Karnovsky MJ (1967) Fine structural localization of a blood–brain barrier to exogenous peroxidase. J Cell Biol 34:207–217. doi:10.1083/jcb.34.1.207

    PubMed  CAS  Google Scholar 

  171. Reiss Y, Machein MR, Plate KH (2005) The role of angiopoietins during angiogenesis in gliomas. Brain Pathol 15:311–317

    Article  PubMed  CAS  Google Scholar 

  172. Reulen HJ (1976) Vasogenic brain oedema. New aspects in its formation, resolution and therapy. Br J Anaesth 48:741–752. doi:10.1093/bja/48.8.741

    PubMed  CAS  Google Scholar 

  173. Reulen HJ, Graham R, Spatz M, Klatzo I (1977) Role of pressure gradients and bulk flow in dynamics of vasogenic brain edema. J Neurosurg 46:24–35

    PubMed  CAS  Google Scholar 

  174. Reulen HJ, Tsuyumu M, Tack A, Fenske AR, Prioleau GR (1978) Clearance of edema fluid into cerebrospinal fluid. A mechanism for resolution of vasogenic brain edema. J Neurosurg 48:754–764

    PubMed  CAS  Google Scholar 

  175. Rizzo V, Morton C, DePaola N, Schnitzer JE, Davies PF (2003) Recruitment of endothelial caveolae into mechanotransduction pathways by flow conditioning in vitro. Am J Physiol Heart Circ Physiol 285:H1720–H1729

    PubMed  CAS  Google Scholar 

  176. Roberts WG, Palade GE (1995) Increased microvascular permeability and endothelial fenestration induced by vascular endothelial growth factor. J Cell Sci 108(Pt 6):2369–2379

    PubMed  CAS  Google Scholar 

  177. Roberts WG, Palade GE (1997) Neovasculature induced by vascular endothelial growth factor is fenestrated. Cancer Res 57:765–772

    PubMed  CAS  Google Scholar 

  178. Rosenberg GA (2002) Matrix metalloproteinases in neuroinflammation. Glia 39:279–291. doi:10.1002/glia.10108

    PubMed  Google Scholar 

  179. Rosenberg GA, Estrada EY, Dencoff JE (1998) Matrix metalloproteinases and TIMPs are associated with blood–brain barrier opening after reperfusion in rat brain. Stroke 29:2189–2195

    PubMed  CAS  Google Scholar 

  180. Rosenberg GA, Navratil M, Barone F, Feuerstein G (1996) Proteolytic cascade enzymes increase in focal cerebral ischemia in rat. J Cereb Blood Flow Metab 16:360–366. doi:10.1097/00004647-199605000-00002

    PubMed  CAS  Google Scholar 

  181. Rosenberg GA, Yang Y (2007) Vasogenic edema due to tight junction disruption by matrix metalloproteinases in cerebral ischemia. Neurosurg Focus 22:E4. doi:10.3171/foc.2007.22.5.5

    PubMed  Google Scholar 

  182. Rosenblum WI (2007) Cytotoxic edema: monitoring its magnitude and contribution to brain swelling. J Neuropathol Exp Neurol 66:771–778. doi:10.1097/nen.0b013e3181461965

    PubMed  Google Scholar 

  183. Rothberg KG, Heuser JE, Donzell WC, Ying YS, Glenney JR, Anderson RG (1992) Caveolin, a protein component of caveolae membrane coats. Cell 68:673–682. doi:10.1016/0092-8674(92)90143-Z

    PubMed  CAS  Google Scholar 

  184. Roviezzo F, Tsigkos S, Kotanidou A, Bucci M, Brancaleone V, Cirino G, Papapetropoulos A (2005) Angiopoietin-2 causes inflammation in vivo by promoting vascular leakage. J Pharmacol Exp Ther 314:738–744. doi:10.1124/jpet.105.086553

    PubMed  CAS  Google Scholar 

  185. Roy H, Bhardwaj S, Yla-Herttuala S (2006) Biology of vascular endothelial growth factors. FEBS Lett 580:2879–2887. doi:10.1016/j.febslet.2006.03.087

    PubMed  CAS  Google Scholar 

  186. Runting AS, Stacker SA, Wilks AF (1993) Tie2, a putative protein tyrosine kinase from a new class of cell surface receptor. Growth Factors 9:99–105

    PubMed  CAS  Google Scholar 

  187. Saadoun S, Papadopoulos MC, Davies DC, Bell BA, Krishna S (2002) Increased aquaporin 1 water channel expression in human brain tumours. Br J Cancer 87:621–623. doi:10.1038/sj.bjc.6600512

    PubMed  CAS  Google Scholar 

  188. 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 72:262–265. doi:10.1136/jnnp.72.2.262

    PubMed  CAS  Google Scholar 

  189. Saitou M, Furuse M, Sasaki H, Schulzke JD, Fromm M, Takano H, Noda T, Tsukita S (2000) Complex phenotype of mice lacking occludin, a component of tight junction strands. Mol Biol Cell 11:4131–4142

    PubMed  CAS  Google Scholar 

  190. Scherer PE, Okamoto T, Chun M, Nishimoto I, Lodish HF, Lisanti MP (1996) Identification, sequence, and expression of caveolin-2 defines a caveolin gene family. Proc Natl Acad Sci USA 93:131–135. doi:10.1073/pnas.93.1.131

    PubMed  CAS  Google Scholar 

  191. Schilling L, Wahl M (1997) Brain edema: pathogenesis and therapy. Kidney Int Suppl 59:S69–S75

    PubMed  CAS  Google Scholar 

  192. Schilling L, Wahl M (1999) Mediators of cerebral edema. In: Roach RC (ed) Hypoxia: into the next millennium. Kluwer Academic/Plenum Publishing, New York, pp 123–141

    Google Scholar 

  193. Schuier FJ, Hossmann KA (1980) Experimental brain infarcts in cats. II. Ischemic brain edema. Stroke 11:593–601

    PubMed  CAS  Google Scholar 

  194. 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 219:983–985. doi:10.1126/science.6823562

    PubMed  CAS  Google Scholar 

  195. Sharma HS, Dey PK (1986) Influence of long-term immobilization stress on regional blood–brain barrier permeability, cerebral blood flow and 5-HT level in conscious normotensive young rats. J Neurol Sci 72:61–76. doi:10.1016/0022-510X(86)90036-5

    PubMed  CAS  Google Scholar 

  196. Silberstein C, Bouley R, Huang Y, Fang P, Pastor-Soler N, Brown D, Van Hoek AN (2004) Membrane organization and function of M1 and M23 isoforms of aquaporin-4 in epithelial cells. Am J Physiol Renal Physiol 287:F501–F511. doi:10.1152/ajprenal.00439.2003

    PubMed  CAS  Google Scholar 

  197. Smith QR, Rapoport SI (1986) Cerebrovascular permeability coefficients to sodium, potassium, and chloride. J Neurochem 46:1732–1742

    PubMed  CAS  Google Scholar 

  198. Song L, Ge S, Pachter JS (2007) Caveolin-1 regulates expression of junction-associated proteins in brain microvascular endothelial cells. Blood 109:1515–1523. doi:10.1182/blood-2006-07-034009

    PubMed  CAS  Google Scholar 

  199. Song L, Pachter JS (2004) Monocyte chemoattractant protein-1 alters expression of tight junction-associated proteins in brain microvascular endothelial cells. Microvasc Res 67:78–89. doi:10.1016/j.mvr.2003.07.001

    PubMed  CAS  Google Scholar 

  200. Sternlicht MD, Werb Z (2001) How matrix metalloproteinases regulate cell behavior. Annu Rev Cell Dev Biol 17:463–516. doi:10.1146/annurev.cellbio.17.1.463

    PubMed  CAS  Google Scholar 

  201. 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 103:755–766. doi:10.1083/jcb.103.3.755

    PubMed  CAS  Google Scholar 

  202. Stratmann A, Risau W, Plate KH (1998) Cell type-specific expression of angiopoietin-1 and angiopoietin-2 suggests a role in glioblastoma angiogenesis. Am J Pathol 153:1459–1466

    PubMed  CAS  Google Scholar 

  203. Stummer W (2007) Mechanisms of tumor-related brain edema. Neurosurg Focus 22:E8. doi:10.3171/foc.2007.22.5.9

    PubMed  Google Scholar 

  204. Sun MC, Honey CR, Berk C, Wong NL, Tsui JK (2003) Regulation of aquaporin-4 in a traumatic brain injury model in rats. J Neurosurg 98:565–569

    Article  PubMed  CAS  Google Scholar 

  205. Tait MJ, Saadoun S, Bell BA, Papadopoulos MC (2008) Water movements in the brain: role of aquaporins. Trends Neurosci 31:37–43. doi:10.1016/j.tins.2007.11.003

    PubMed  CAS  Google Scholar 

  206. Thiex R, Tsirka SE (2007) Brain edema after intracerebral hemorrhage: mechanisms, treatment options, management strategies, and operative indications. Neurosurg Focus 22:E6. doi:10.3171/foc.2007.22.5.7

    PubMed  Google Scholar 

  207. Thurston G, Rudge JS, Ioffe E, Zhou H, Ross L, Croll SD, Glazer N, Holash J, McDonald DM, Yancopoulos GD (2000) Angiopoietin-1 protects the adult vasculature against plasma leakage. Nat Med 6:460–463. doi:10.1038/74725

    PubMed  CAS  Google Scholar 

  208. Thurston G, Suri C, Smith K, McClain J, Sato TN, Yancopoulos GD, McDonald DM (1999) Leakage-resistant blood vessels in mice transgenically overexpressing angiopoietin-1. Science 286:2511–2514. doi:10.1126/science.286.5449.2511

    PubMed  CAS  Google Scholar 

  209. Tischer E, Mitchell R, Hartman T, Silva M, Gospodarowicz D, Fiddes JC, Abraham JA (1991) The human gene for vascular endothelial growth factor. Multiple protein forms are encoded through alternative exon splicing. J Biol Chem 266:11947–11954

    PubMed  CAS  Google Scholar 

  210. Tsukita S, Furuse M, Itoh M (2001) Multifunctional strands in tight junctions. Nat Rev Mol Cell Biol 2:285–293. doi:10.1038/35067088

    PubMed  CAS  Google Scholar 

  211. Tsuyumu M, Reulen HJ, Prioleau G (1981) Dynamics of formation and resolution of vasogenic brain oedema. I. Measurement of oedema clearance into ventricular CSF. Acta Neurochir (Wien) 57:1–13. doi:10.1007/BF01665107

    CAS  Google Scholar 

  212. Turksen K, Troy TC (2004) Barriers built on claudins. J Cell Sci 117:2435–2447. doi:10.1242/jcs.01235

    PubMed  CAS  Google Scholar 

  213. Unterberg A, Wahl M, Baethmann A (1984) Effects of bradykinin on permeability and diameter of pial vessels in vivo. J Cereb Blood Flow Metab 4:574–585

    PubMed  CAS  Google Scholar 

  214. Unterberg A, Wahl M, Baethmann A (1988) Effects of free radicals on permeability and vasomotor response of cerebral vessels. Acta Neuropathol 76:238–244. doi:10.1007/BF00687770

    PubMed  CAS  Google Scholar 

  215. Unterberg AW, Stover J, Kress B, Kiening KL (2004) Edema and brain trauma. Neuroscience 129:1021–1029. doi:10.1016/j.neuroscience.2004.06.046

    PubMed  CAS  Google Scholar 

  216. Valenzuela DM, Griffiths JA, Rojas J, Aldrich TH, Jones PF, Zhou H, McClain J, Copeland NG, Gilbert DJ, Jenkins NA, Huang T, Papadopoulos N, Maisonpierre PC, Davis S, Yancopoulos GD (1999) Angiopoietins 3 and 4: diverging gene counterparts in mice and humans. Proc Natl Acad Sci USA 96:1904–1909. doi:10.1073/pnas.96.5.1904

    PubMed  CAS  Google Scholar 

  217. Van Itallie CM, Anderson JM (2006) Claudins and epithelial paracellular transport. Annu Rev Physiol 68:403–429. doi:10.1146/annurev.physiol.68.040104.131404

    PubMed  Google Scholar 

  218. van Bruggen N, Thibodeaux H, Palmer JT, Lee WP, Fu L, Cairns B, Tumas D, Gerlai R, Williams SP, Campagne MV, Ferrara N (1999) VEGF antagonism reduces edema formation and tissue damage after ischemia/reperfusion injury in the mouse brain. J Clin Invest 104:1613–1620. doi:10.1172/JCI8218

    PubMed  Google Scholar 

  219. Vaquero J, Butterworth RF (2007) Mechanisms of brain edema in acute liver failure and impact of novel therapeutic interventions. Neurol Res 29:683–690. doi:10.1179/016164107X240099

    PubMed  CAS  Google Scholar 

  220. Verkman AS (2005) More than just water channels: unexpected cellular roles of aquaporins. J Cell Sci 118:3225–3232. doi:10.1242/jcs.02519

    PubMed  CAS  Google Scholar 

  221. Virgintino D, Robertson D, Errede M, Benagiano V, Tauer U, Roncali L, Bertossi M (2002) Expression of caveolin-1 in human brain microvessels. Neuroscience 115:145–152. doi:10.1016/S0306-4522(02)00374-3

    PubMed  CAS  Google Scholar 

  222. Volonte D, Galbiati F, Pestell RG, Lisanti MP (2001) Cellular stress induces the tyrosine phosphorylation of caveolin-1 (Tyr14) via activation of p38 mitogen-activated protein kinase and c-Src kinase. J Biol Chem 276:8094–8103. doi:10.1074/jbc.M009245200

    PubMed  CAS  Google Scholar 

  223. Vorbrodt AW, Dobrogowska DH (2003) Molecular anatomy of intercellular junctions in brain endothelial and epithelial barriers: electron microscopist’s view. Brain Res Brain Res Rev 42:221–242. doi:10.1016/S0165-0173(03)00177-2

    PubMed  CAS  Google Scholar 

  224. Vorbrodt AW, Lossinsky AS, Wisniewski HM, Suzuki R, Yamaguchi T, Masaoka H, Klatzo I (1985) Ultrastructural observations on the transvascular route of protein removal in vasogenic brain edema. Acta Neuropathol 66:265–273. doi:10.1007/BF00690958

    PubMed  CAS  Google Scholar 

  225. Wahl M, Unterberg A, Baethmann A, Schilling L (1988) Mediators of blood–brain barrier dysfunction and formation of vasogenic brain edema. J Cereb Blood Flow Metab 8:621–634

    PubMed  CAS  Google Scholar 

  226. Wald A, Hochwald GM, Gandhi M (1978) Evidence for the movement of fluid, macromolecules and ions from the brain extracellular space to the CSF. Brain Res 151:283–290. doi:10.1016/0006-8993(78)90885-5

    PubMed  CAS  Google Scholar 

  227. Wang W, Dentler WL, Borchardt RT (2001) VEGF increases BMEC monolayer permeability by affecting occludin expression and tight junction assembly. Am J Physiol Heart Circ Physiol 280:H434–H440

    PubMed  CAS  Google Scholar 

  228. Warth A, Simon P, Capper D, Goeppert B, Tabatabai G, Herzog H, Dietz K, Stubenvoll F, Ajaaj R, Becker R, Weller M, Meyermann R, Wolburg H, Mittelbronn M (2007) Expression pattern of the water channel aquaporin-4 in human gliomas is associated with blood–brain barrier disturbance but not with patient survival. J Neurosci Res 85:1336–1346. doi:10.1002/jnr.21224

    PubMed  CAS  Google Scholar 

  229. Wasterlain CG, Posner JB (1968) Cerebral edema in water intoxication. I. Clinical and chemical observations. Arch Neurol 19:71–78

    PubMed  CAS  Google Scholar 

  230. Wasterlain CG, Torack RM (1968) Cerebral edema in water intoxication. II. An ultrastructural study. Arch Neurol 19:79–87

    PubMed  CAS  Google Scholar 

  231. Watts RG, Wright JL, Atkinson LL, Merchant RE (1989) Histopathological and blood–brain barrier changes in rats induced by an intracerebral injection of human recombinant interleukin 2. Neurosurgery 25:202–208. doi:10.1097/00006123-198908000-00008

    PubMed  CAS  Google Scholar 

  232. Wei EP, Ellison MD, Kontos HA, Povlishock JT (1986) O2 radicals in arachidonate-induced increased blood–brain barrier permeability to proteins. Am J Physiol 251:H693–H699

    PubMed  CAS  Google Scholar 

  233. Westergaard E (1977) The blood–brain barrier to horseradish peroxidase under normal and experimental conditions. Acta Neuropathol 39:181–187. doi:10.1007/BF00691695

    PubMed  CAS  Google Scholar 

  234. Williams TM, Lisanti MP (2004) The caveolin genes: from cell biology to medicine. Ann Med 36:584–595. doi:10.1080/07853890410018899

    PubMed  CAS  Google Scholar 

  235. Witzenbichler B, Asahara T, Murohara T, Silver M, Spyridopoulos I, Magner M, Principe N, Kearney M, Hu JS, Isner JM (1998) Vascular endothelial growth factor-c (VEGF-C/VEGF-2) promotes angiogenesis in the setting of tissue ischemia. Am J Pathol 153:381–394

    PubMed  CAS  Google Scholar 

  236. Wolburg H, Noell S, Mack A, Wolburg-Buchholz K, Fallier-Becker P (2008) Brain endothelial cells and the glio-vascular complex. Cell Tissue Res 335:75–96. doi:10.1007/s00441-008-0658-9

    PubMed  Google Scholar 

  237. Wong AL, Haroon ZA, Werner S, Dewhirst MW, Greenberg CS, Peters KG (1997) Tie2 expression and phosphorylation in angiogenic and quiescent adult tissues. Circ Res 81:567–574

    PubMed  CAS  Google Scholar 

  238. Xi G, Keep RF, Hoff JT (2002) Pathophysiology of brain edema formation. Neurosurg Clin N Am 13:371–383. doi:10.1016/S1042-3680(02)00007-4

    PubMed  Google Scholar 

  239. Yamamoto N, Yoneda K, Asai K, Sobue K, Tada T, Fujita Y, Katsuya H, Fujita M, Aihara N, Mase M, Yamada K, Miura Y, Kato T (2001) Alterations in the expression of the AQP family in cultured rat astrocytes during hypoxia and reoxygenation. Brain Res Mol Brain Res 90:26–38. doi:10.1016/S0169-328X(01)00064-X

    PubMed  CAS  Google Scholar 

  240. Yamamoto T, Harada N, Kano K, Taya S, Canaani E, Matsuura Y, Mizoguchi A, Ide C, Kaibuchi K (1997) The Ras target AF-6 interacts with ZO-1 and serves as a peripheral component of tight junctions in epithelial cells. J Cell Biol 139:785–795. doi:10.1083/jcb.139.3.785

    PubMed  CAS  Google Scholar 

  241. 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 27:697–709. doi:10.1038/sj.jcbfm.9600440

    PubMed  CAS  Google Scholar 

  242. Yeung D, Manias JL, Stewart DJ, Nag S (2008) Decreased junctional adhesion molecule-A expression during blood–brain barrier breakdown. Acta Neuropathol 115:635–642. doi:10.1007/s00401-008-0364-4

    PubMed  CAS  Google Scholar 

  243. Yla-Herttuala S, Rissanen TT, Vajanto I, Hartikainen J (2007) Vascular endothelial growth factors: biology and current status of clinical applications in cardiovascular medicine. J Am Coll Cardiol 49:1015–1026. doi:10.1016/j.jacc.2006.09.053

    PubMed  Google Scholar 

  244. Zadeh G, Guha A (2003) Neoangiogenesis in human astrocytomas: expression and functional role of angiopoietins and their cognate receptors. Front Biosci 8:e128–e137. doi:10.2741/964

    PubMed  CAS  Google Scholar 

  245. Zador Z, Bloch O, Yao X, Manley GT (2007) Aquaporins: role in cerebral edema and brain water balance. Prog Brain Res 161:185–194. doi:10.1016/S0079-6123(06)61012-1

    PubMed  CAS  Google Scholar 

  246. Zagzag D, Amirnovin R, Greco MA, Yee H, Holash J, Wiegand SJ, Zabski S, Yancopoulos GD, Grumet M (2000) Vascular apoptosis and involution in gliomas precede neovascularization: a novel concept for glioma growth and angiogenesis. Lab Invest 80:837–849

    PubMed  CAS  Google Scholar 

  247. Zagzag D, Hooper A, Friedlander DR, Chan W, Holash J, Wiegand SJ, Yancopoulos GD, Grumet M (1999) In situ expression of angiopoietins in astrocytomas identifies angiopoietin-2 as an early marker of tumor angiogenesis. Exp Neurol 159:391–400. doi:10.1006/exnr.1999.7162

    PubMed  CAS  Google Scholar 

  248. Zhang ZG, Zhang L, Croll SD, Chopp M (2002) Angiopoietin-1 reduces cerebral blood vessel leakage and ischemic lesion volume after focal cerebral embolic ischemia in mice. Neuroscience 113:683–687. doi:10.1016/S0306-4522(02)00175-6

    PubMed  CAS  Google Scholar 

  249. Zhong Y, Saitoh T, Minase T, Sawada N, Enomoto K, Mori M (1993) Monoclonal antibody 7H6 reacts with a novel tight junction-associated protein distinct from ZO-1, cingulin and ZO-2. J Cell Biol 120:477–483. doi:10.1083/jcb.120.2.477

    PubMed  CAS  Google Scholar 

  250. Zlokovic BV (2008) The blood–brain barrier in health and chronic neurodegenerative disorders. Neuron 57:178–201. doi:10.1016/j.neuron.2008.01.003

    PubMed  CAS  Google Scholar 

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Acknowledgments

This review is dedicated to Dr. Igor Klatzo, an experimental neuropathologist par excellence, an innovative thinker and friend who died on 5th May 2007. Work in the author’s laboratory is supported by the Heart and Stroke Foundation of Ontario, Grant 6003.

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  1. Department of Laboratory Medicine and Pathobiology, Banting Institute, University of Toronto, Rm 417, 100 College Street, Toronto, ON, M5G 1L5, Canada

    Sukriti Nag & Janet L. Manias

  2. Ottawa Health Research Institute, University of Ottawa, Ottawa, ON, Canada

    Duncan J. Stewart

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  1. Sukriti Nag
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  2. Janet L. Manias
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Correspondence to Sukriti Nag.

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Nag, S., Manias, J.L. & Stewart, D.J. Pathology and new players in the pathogenesis of brain edema. Acta Neuropathol 118, 197–217 (2009). https://doi.org/10.1007/s00401-009-0541-0

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