Skip to main content
SpringerLink
Log in
Book cover

The Blood-Brain and Other Neural Barriers pp 3–47Cite as

Morphology and Properties of Brain Endothelial Cells

  • Protocol
  • First Online:

Part of the book series: Methods in Molecular Biology ((MIMB,volume 686))

Abstract

The molecular advances in various aspects of brain endothelial cell function in steady states are considerable and difficult to summarize in one chapter. Therefore, this chapter focuses on endothelial permeability mechanisms in steady states and disease namely vasogenic edema. The morphology and properties of caveolae and tight junctions that are involved in endothelial permeability to macromolecules are reviewed. Endothelial transport functions are briefly reviewed. Diseases with alterations of endothelial permeability are mentioned and details are provided of the molecular alterations in caveolae and tight junctions in vasogenic edema. Other factors involved in increased endothelial permeability such as the matrix metalloproteinases are briefly discussed. Of the modulators of endothelial permeability, angioneurins such as the vascular endothelial growth factors and angiopoietins are discussed. The chapter concludes with a brief discussion on delivery of therapeutic substances across endothelium.

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

Protocol
USD   49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   139.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   179.00
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

Springer Nature is developing a new tool to find and evaluate Protocols. Learn more

References

  1. Ehrlich P (1885) Das Sauerstoff-Bedürfnis des Organismus:Eine farbenanalytische studie

    Google Scholar 

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

    PubMed  CAS  Google Scholar 

  3. Lok J, Gupta P, Guo S, Kim WJ, Whalen MJ, Van LK, Lo EH (2007) Cell-cell signaling in the neurovascular unit. Neurochem Res 32:2032–2045

    PubMed  CAS  Google Scholar 

  4. Nag S (2003) Ultracytochemical studies of the compromised blood-brain barrier. Methods Mol Med 89:145–160

    PubMed  CAS  Google Scholar 

  5. Vorbrodt AW, Dobrogowska DH, Lossinsky AS, Wisniewski HM (1986) Ultrastructural localization of lectin receptors on the luminal and abluminal aspects of brain micro-blood vessels. J Histochem Cytochem 34:251–261

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  7. Wolburg H, Noell S, Mack A, Wolburg-Buchholz K, Fallier-Becker P (2009) Brain endothelial cells and the glio-vascular complex. Cell Tissue Res 335:75–96

    PubMed  Google Scholar 

  8. Palade G (1953) Fine structure of blood capillaries. J Appl Physiol 24:1424–1436

    Google Scholar 

  9. Yamada E (1955) The fine structure of the gall bladder epithelium of the mouse. J Biophys Biochem Cytol 1:445–458

    PubMed  CAS  Google Scholar 

  10. 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

    PubMed  CAS  Google Scholar 

  11. Stan RV (2005) Structure of caveolae. Biochim Biophys Acta 1746:334–348

    PubMed  CAS  Google Scholar 

  12. Stan RV (2007) Endothelial stomatal and fenestral diaphragms in normal vessels and angiogenesis. J Cell Mol Med 11:621–643

    PubMed  CAS  Google Scholar 

  13. Richter T, Floetenmeyer M, Ferguson C, Galea J, Goh J, Lindsay MR, Morgan GP, Marsh BJ, Parton RG (2008) High-resolution 3D quantitative analysis of caveolar ultrastructure and caveola-cytoskeleton interactions. Traffic 9:893–909

    PubMed  CAS  Google Scholar 

  14. Stan RV, Ghitescu L, Jacobson BS, Palade GE (1999) Isolation, cloning, and localization of rat PV-1, a novel endothelial caveolar protein. J Cell Biol 145:1189–1198

    PubMed  CAS  Google Scholar 

  15. Stan RV, Kubitza M, Palade GE (1999) PV-1 is a component of the fenestral and stomatal diaphragms in fenestrated endothelia. Proc Natl Acad Sci USA 96:13203–13207

    PubMed  CAS  Google Scholar 

  16. Nag S, Robertson DM, Dinsdale HB (1979) Quantitative estimate of pinocytosis in experimental acute hypertension. Acta Neuropathol (Berl) 46:107–116

    CAS  Google Scholar 

  17. Connell CJ, Mercer KL (1974) Freeze-fracture appearance of the capillary endothelium in the cerebral cortex of mouse brain. Am J Anat 140:595–599

    PubMed  CAS  Google Scholar 

  18. Stewart PA, Magliocco M, Hayakawa K, Farrell CL, Del Maestro RF, Girvin J, Kaufmann JC, Vinters HV, Gilbert J (1987) A quantitative analysis of blood-brain barrier ultrastructure in the aging human. Microvasc Res 33:270–282

    PubMed  CAS  Google Scholar 

  19. Simionescu M, Simionescu N, Palade GE (1974) Morphometric data on the endothelium of blood capillaries. J Cell Biol 60:128–152

    PubMed  CAS  Google Scholar 

  20. Coomber BL, Stewart PA (1985) Morphometric analysis of CNS microvascular endothelium. Microvasc Res 30:99–115

    PubMed  CAS  Google Scholar 

  21. Gross PM, Sposito NM, Pettersen SE, Fenstermacher JD (1986) Differences in function and structure of the capillary endothelium in gray matter, white matter and a circumventricular organ of rat brain. Blood Vessels 23:261–270

    PubMed  CAS  Google Scholar 

  22. Thomas CM, Smart EJ (2008) Caveolae structure and function. J Cell Mol Med 12:796–809

    PubMed  CAS  Google Scholar 

  23. Gafencu A, Stanescu M, Toderici AM, Heltianu C, Simionescu M (1998) Protein and fatty acid composition of caveolae from apical plasmalemma of aortic endothelial cells. Cell Tissue Res 293:101–110

    PubMed  CAS  Google Scholar 

  24. Liu P, Anderson RG (1995) Compartmental-ized production of ceramide at the cell surface. J Biol Chem 270:27179–27185

    PubMed  CAS  Google Scholar 

  25. 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

    PubMed  CAS  Google Scholar 

  26. 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

    PubMed  CAS  Google Scholar 

  27. 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 (Berl) 114:459–469

    CAS  Google Scholar 

  28. Shin T, Kim H, Jin JK, Moon C, Ahn M, Tanuma N, Matsumoto Y (2005) Expression of caveolin-1, -2, and -3 in the spinal cords of Lewis rats with experimental autoimmune encephalomyelitis. J Neuroimmunol 165: 11–20

    PubMed  CAS  Google Scholar 

  29. 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

    PubMed  CAS  Google Scholar 

  30. 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 

  31. 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: 2449–2452

    PubMed  CAS  Google Scholar 

  32. Fra AM, Williamson E, Simons K, Parton RG (1995) De novo formation of caveolae in lymphocytes by expression of VIP21-caveolin. Proc Natl Acad Sci USA 92:8655–8659

    PubMed  CAS  Google Scholar 

  33. Parton RG, Hanzal-Bayer M, Hancock JF (2006) Biogenesis of caveolae: a structural model for caveolin-induced domain formation. J Cell Sci 119:787–796

    PubMed  CAS  Google Scholar 

  34. Parat MO (2009) The biology of caveolae: achievements and perspectives. Int Rev Cell Mol Biol 273:117–162

    PubMed  CAS  Google Scholar 

  35. Vinten J, Johnsen AH, Roepstorff P, Harpoth J, Tranum-Jensen J (2005) Identification of a major protein on the cytosolic face of caveolae. Biochim Biophys Acta 1717:34–40

    PubMed  CAS  Google Scholar 

  36. Hill MM, Bastiani M, Luetterforst R, Kirkham M, Kirkham A, Nixon SJ, Walser P, Abankwa D, Oorschot VM, Martin S, Hancock JF, Parton RG (2008) PTRF-Cavin, a conserved cytoplasmic protein required for caveola formation and function. Cell 132:113–124

    PubMed  CAS  Google Scholar 

  37. Liu L, Pilch PF (2008) A critical role of cavin (polymerase I and transcript release factor) in caveolae formation and organization. J Biol Chem 283:4314–4322

    PubMed  CAS  Google Scholar 

  38. Oh P, Borgstrom P, Witkiewicz H, Li Y, Borgstrom BJ, Chrastina A, Iwata K, Zinn KR, Baldwin R, Testa JE, Schnitzer JE (2007) Live dynamic imaging of caveolae pumping targeted antibody rapidly and specifically across endothelium in the lung. Nat Biotechnol 25:327–337

    PubMed  CAS  Google Scholar 

  39. Schubert W, Frank PG, Razani B, Park DS, Chow CW, Lisanti MP (2001) Caveolae-deficient endothelial cells show defects in the uptake and transport of albumin in vivo. J Biol Chem 276:48619–48622

    PubMed  CAS  Google Scholar 

  40. Li S, Couet J, Lisanti MP (1996) Src tyrosine kinases, Galpha subunits, and H-Ras share a common membrane-anchored scaffolding protein, caveolin. Caveolin binding negatively regulates the auto-activation of Src tyrosine kinases. J Biol Chem 271:29182–29190

    PubMed  CAS  Google Scholar 

  41. Frank PG, Woodman SE, Park DS, Lisanti MP (2003) Caveolin, caveolae, and endothelial cell function. Arterioscler Thromb Vasc Biol 23:1161–1168

    PubMed  CAS  Google Scholar 

  42. 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 

  43. Anderson RG, Kamen BA, Rothberg KG, Lacey SW (1992) Potocytosis: sequestration and transport of small molecules by caveolae. Science 255:410–411

    PubMed  CAS  Google Scholar 

  44. Frank PG, Pavlides S, Lisanti MP (2009) Caveolae and transcytosis in endothelial cells: role in atherosclerosis. Cell Tissue Res 335:41–47

    PubMed  CAS  Google Scholar 

  45. Predescu D, Vogel SM, Malik AB (2004) Functional and morphological studies of protein transcytosis in continuous endothelia. Am J Physiol Lung Cell Mol Physiol 287:L895–L901

    PubMed  CAS  Google Scholar 

  46. Simionescu M, Popov D, Sima A (2009) Endothelial transcytosis in health and disease. Cell Tissue Res 335:27–40

    PubMed  Google Scholar 

  47. Schnitzer JE, Oh P, McIntosh DP (1996) Role of GTP hydrolysis in fission of caveolae directly from plasma membranes. Science 274:239–242

    PubMed  CAS  Google Scholar 

  48. Lisanti MP, Scherer PE, Tang Z, Sargiacomo M (1994) Caveolae, caveolin and caveolin-rich membrane domains: a signalling hypothesis. Trends Cell Biol 4:231–235

    PubMed  CAS  Google Scholar 

  49. Rothberg KG, Ying YS, Kamen BA, Anderson RG (1990) Cholesterol controls the clustering of the glycophospholipid-anchored membrane receptor for 5-methyltetrahydrofolate. J Cell Biol 111:2931–2938

    PubMed  CAS  Google Scholar 

  50. Parton RG (1994) Ultrastructural localization of gangliosides; GM1 is concentrated in caveolae. J Histochem Cytochem 42:155–166

    PubMed  CAS  Google Scholar 

  51. Simionescu M, Simionescu N (1991) Endothelial transport of macromolecules: transcytosis and endocytosis. A look from cell biology. Cell Biol Rev 25:1–78

    PubMed  CAS  Google Scholar 

  52. Schnitzer JE, Allard J, Oh P (1995) NEM inhibits transcytosis, endocytosis, and capillary permeability: implication of caveolae fusion in endothelia. Am J Physiol 268:H48–H55

    PubMed  CAS  Google Scholar 

  53. Palade GE, Simionescu M, Simionescu N (1979) Structural aspects of the permeability of the microvascular endothelium. Acta Physiol Scand Suppl 463:11–32

    PubMed  CAS  Google Scholar 

  54. Schnitzer JE (2001) Caveolae: from basic trafficking mechanisms to targeting transcytosis for tissue-specific drug and gene delivery in vivo. Adv Drug Deliv Rev 49:265–280

    PubMed  CAS  Google Scholar 

  55. McIntosh DP, Schnitzer JE (1999) Caveolae require intact VAMP for targeted transport in vascular endothelium. Am J Physiol 277:H2222–H2232

    PubMed  CAS  Google Scholar 

  56. Schnitzer JE, Liu J, Oh P (1995) Endothelial caveolae have the molecular transport machinery for vesicle budding, docking, and fusion including VAMP, NSF, SNAP, annexins, and GTPases. J Biol Chem 270:14399–14404

    PubMed  CAS  Google Scholar 

  57. Fra AM, Masserini M, Palestini P, Sonnino S, Simons K (1995) A photo-reactive derivative of ganglioside GM1 specifically cross-links VIP21-caveolin on the cell surface. Febs Lett 375:11–14

    PubMed  CAS  Google Scholar 

  58. Sargiacomo M, Scherer PE, Tang Z, Kubler E, Song KS, Sanders MC, Lisanti MP (1995) Oligomeric structure of caveolin: implications for caveolae membrane organization. Proc Natl Acad Sci USA 92:9407–9411

    PubMed  CAS  Google Scholar 

  59. Oh P, McIntosh DP, Schnitzer JE (1998) Dynamin at the neck of caveolae mediates their budding to form transport vesicles by GTP-driven fission from the plasma membrane of endothelium. J Cell Biol 141:101–114

    PubMed  CAS  Google Scholar 

  60. Hussain NK, Jenna S, Glogauer M, Quinn CC, Wasiak S, Guipponi M, Antonarakis SE, Kay BK, Stossel TP, Lamarche-Vane N, McPherson PS (2001) Endocytic protein intersectin-l regulates actin assembly via Cdc42 and N-WASP. Nat Cell Biol 3:927–932

    PubMed  CAS  Google Scholar 

  61. Schilling K, Opitz N, Wiesenthal A, Oess S, Tikkanen R, Muller-Esterl W, Icking A (2006) Translocation of endothelial nitric-oxide synthase involves a ternary complex with caveolin-1 and NOSTRIN. Mol Biol Cell 17:3870–3880

    PubMed  CAS  Google Scholar 

  62. Mehta D, Malik AB (2006) Signaling mechanisms regulating endothelial permeability. Physiol Rev 86:279–367

    PubMed  CAS  Google Scholar 

  63. Lisanti MP, Scherer PE, Vidugiriene J, Tang Z, Hermanowski-Vosatka A, Tu YH, Cook RF, Sargiacomo M (1994) Characterization of caveolin-rich membrane domains isolated from an endothelial-rich source: implications for human disease. J Cell Biol 126:111–126

    PubMed  CAS  Google Scholar 

  64. Hay JC, Scheller RH (1997) SNAREs and NSF in targeted membrane fusion. Curr Opin Cell Biol 9:505–512

    PubMed  CAS  Google Scholar 

  65. Rothman JE (1994) Intracellular membrane fusion. Adv Second Messenger Phosphopro-tein Res 29:81–96

    PubMed  CAS  Google Scholar 

  66. Couet J, Belanger MM, Roussel E, Drolet MC (2001) Cell biology of caveolae and caveolin. Adv Drug Deliv Rev 49:223–235

    PubMed  CAS  Google Scholar 

  67. McIntosh DP, Tan XY, Oh P, Schnitzer JE (2002) Targeting endothelium and its dynamic caveolae for tissue-specific transcytosis in vivo: a pathway to overcome cell barriers to drug and gene delivery. Proc Natl Acad Sci USA 99:1996–2001

    PubMed  CAS  Google Scholar 

  68. Simionescu M, Gafencu A, Antohe F (2002) Transcytosis of plasma macromolecules in endothelial cells: a cell biological survey. Microsc Res Tech 57:269–288

    PubMed  CAS  Google Scholar 

  69. Stan RV (2002) Structure and function of endothelial caveolae. Microsc Res Tech 57:350–364

    PubMed  Google Scholar 

  70. Shea SM, Raskova J (1983) Vesicular diffusion and thermal forces. Fed Proc 42: 2431–2434

    PubMed  CAS  Google Scholar 

  71. Farrell CL, Shivers RR (1984) Capillary junctions of the rat are not affected by osmotic opening of the blood-brain barrier. Acta Neuropathol (Berl) 63:179–189

    CAS  Google Scholar 

  72. Nag S (1998) Blood-brain barrier permeability measured with histochemistry. In Pardridge WM (Ed) Introduction to the Blood-Brain Barrier. Methodology, biology and pathology, Cambridge University Press, Cambridge, pp 113–121

    Google Scholar 

  73. Shivers RR, Harris RJ (1984) Opening of the blood-brain barrier in Anolis carolinensis. A high voltage electron microscope protein tracer study. Neuropathol Appl Neurobiol 10:343–356

    PubMed  CAS  Google Scholar 

  74. Muir AR, Peters A (1962) Quintuple-layered membrane junctions at terminal bars between endothelial cells. J Cell Biol 12:443–448

    PubMed  CAS  Google Scholar 

  75. Reese TS, Karnovsky MJ (1967) Fine structural localization of a blood-brain barrier to exogenous peroxidase. J Cell Biol 34: 207–217

    PubMed  CAS  Google Scholar 

  76. 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 

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

    PubMed  CAS  Google Scholar 

  78. Crone C, Olesen SP (1982) Electrical resistance of brain microvascular endothelium. Brain Res 241:49–55

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  80. Krause D, Mischeck U, Galla HJ, Dermietzel R (1991) Correlation of zonula occludens ZO-1 antigen expression and transendothelial resistance in porcine and rat cultured cerebral endothelial cells. Neurosci Lett 128: 301–304

    PubMed  CAS  Google Scholar 

  81. Tilling T, Korte D, Hoheisel D, Galla HJ (1998) Basement membrane proteins influence brain capillary endothelial barrier function in vitro. J Neurochem 71:1151–1157

    PubMed  CAS  Google Scholar 

  82. 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 

  83. 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

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  85. Turksen K, Troy TC (2004) Barriers built on claudins. J Cell Sci 117:2435–2447

    PubMed  CAS  Google Scholar 

  86. Van Itallie CM, Anderson JM (2006) Claudins and epithelial paracellular transport. Annu Rev Physiol 68:403–429

    PubMed  Google Scholar 

  87. Hamazaki Y, Itoh M, Sasaki H, Furuse M, Tsukita S (2002) Multi-PDZ domain protein 1 (MUPP1) is concentrated at tight junctions through its possible interaction with claudin-1 and junctional adhesion molecule. J Biol Chem 277:455–461

    PubMed  CAS  Google Scholar 

  88. Furuse M, Tsukita S (2006) Claudins in occluding junctions of humans and flies. Trends Cell Biol 16:181–188

    PubMed  CAS  Google Scholar 

  89. Furuse M, Sasaki H, Fujimoto K, Tsukita S (1998) A single gene product, claudin-1 or -2, reconstitutes tight junction strands and recruits occludin in fibroblasts. J Cell Biol 143:391–401

    PubMed  CAS  Google Scholar 

  90. 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 

  91. 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

    PubMed  CAS  Google Scholar 

  92. Tang VW, Goodenough DA (2003) Paracellular ion channel at the tight junction. Biophys J 84:1660–1673

    PubMed  CAS  Google Scholar 

  93. Krause G, Winkler L, Piehl C, Blasig I, Piontek J, Muller SL (2009) Structure and function of extracellular claudin domains. Ann N Y Acad Sci 1165:34–43

    PubMed  CAS  Google Scholar 

  94. 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

    PubMed  CAS  Google Scholar 

  95. 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 

  96. 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

    PubMed  CAS  Google Scholar 

  97. Balda MS, Matter K (2008) Tight junctions at a glance. J Cell Sci 121:3677–3682

    PubMed  CAS  Google Scholar 

  98. Barrios-Rodiles M, Brown KR, Ozdamar B, Bose R, Liu Z, Donovan RS, Shinjo F, Liu Y, Dembowy J, Taylor IW, Luga V, Przulj N, Robinson M, Suzuki H, Hayashizaki Y, Jurisica I, Wrana JL (2005) High-throughput mapping of a dynamic signaling network in mammalian cells. Science 307:1621–1625

    PubMed  CAS  Google Scholar 

  99. Wang Z, Mandell KJ, Parkos CA, Mrsny RJ, Nusrat A (2005) The second loop of occludin is required for suppression of Raf1-induced tumor growth. Oncogene 24:4412–4420

    PubMed  CAS  Google Scholar 

  100. Bazzoni G (2003) The JAM family of junctional adhesion molecules. Curr Opin Cell Biol 15:525–530

    PubMed  CAS  Google Scholar 

  101. Palmeri D, van ZA, Huang CC, Hemmerich S, Rosen SD (2000) Vascular endothelial junction-associated molecule, a novel member of the immunoglobulin superfamily, is localized to intercellular boundaries of endothelial cells. J Biol Chem 275:19139–19145

    PubMed  CAS  Google Scholar 

  102. Arrate MP, Rodriguez JM, Tran TM, Brock TA, Cunningham SA (2001) Cloning of human junctional adhesion molecule 3 (JAM3) and its identification as the JAM2 counter-receptor. J Biol Chem 276:45826–45832

    PubMed  CAS  Google Scholar 

  103. 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

    PubMed  CAS  Google Scholar 

  104. 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

    PubMed  CAS  Google Scholar 

  105. Naik MU, Mousa SA, Parkos CA, Naik UP (2003) Signaling through JAM-1 and alphavbeta3 is required for the angiogenic action of bFGF: dissociation of the JAM-1 and alphavbeta3 complex. Blood 102:2108–2114

    PubMed  CAS  Google Scholar 

  106. Kornecki E, Walkowiak B, Naik UP, Ehrlich YH (1990) Activation of human platelets by a stimulatory monoclonal antibody. J Biol Chem 265:10042–10048

    PubMed  CAS  Google Scholar 

  107. Ozaki H, Ishii K, Arai H, Horiuchi H, Kawamoto T, Suzuki H, Kita T (2000) Junctional adhesion molecule (JAM) is phosphorylated by protein kinase C upon platelet activation. Biochem Biophys Res Commun 276:873–878

    PubMed  CAS  Google Scholar 

  108. Barton ES, Forrest JC, Connolly JL, Chappell JD, Liu Y, Schnell FJ, Nusrat A, Parkos CA, Dermody TS (2001) Junction adhesion molecule is a receptor for reovirus. Cell 104:441–451

    PubMed  CAS  Google Scholar 

  109. Forrest JC, Campbell JA, Schelling P, Stehle T, Dermody TS (2003) Structure-function analysis of reovirus binding to junctional adhesion molecule 1. Implications for the mechanism of reovirus attachment. J Biol Chem 278:48434–48444

    PubMed  CAS  Google Scholar 

  110. Bazzoni G, MartinezEstrada OM, Orsenigo F, Cordenonsi M, Citi S, Dejana E (2000) Interaction of junctional adhesion molecule with the tight junction components ZO-1, cingulin, and occludin. J Biol Chem 275:20520–20526

    PubMed  CAS  Google Scholar 

  111. Ebnet K, Schulz CU, Meyer zu Brickwedde MK, Pendl GG, Vestweber D (2000) Junctional adhesion molecule interacts with the PDZ domain-containing proteins AF-6 and ZO-1. J Biol Chem 275:27979-27988

    Google Scholar 

  112. Ebnet K, Aurrand-Lions M, Kuhn A, Kiefer F, Butz S, Zander K, Meyer zu Brickwedde MK, Suzuki A, Imhof BA, Vestweber D (2003) The junctional adhesion molecule (JAM) family members JAM-2 and JAM-3 associate with the cell polarity protein PAR-3: a possible role for JAMs in endothelial cell polarity. J Cell Sci 116:3879–3891

    PubMed  CAS  Google Scholar 

  113. Bradfield PF, Nourshargh S, Aurrand-Lions M, Imhof BA (2007) JAM family and related proteins in leukocyte migration (Vestweber series). Arterioscler Thromb Vasc Biol 27:2104–2112

    PubMed  CAS  Google Scholar 

  114. Weber C, Fraemohs L, Dejana E (2007) The role of junctional adhesion molecules in vascular inflammation. Nat Rev Immunol 7:467–477

    PubMed  CAS  Google Scholar 

  115. Nag S (1995) Role of the endothelial cytoskeleton in blood-brain-barrier permeability to protein. Acta Neuropathol (Berl) 90:454–460

    CAS  Google Scholar 

  116. Nag S, Robertson DM, Dinsdale HB (1978) Cytoplasmic filaments in intracerebral cortical vessels. Ann Neurol 3:555–559

    PubMed  CAS  Google Scholar 

  117. Pardridge WM, Nowlin DM, Choi TB, Yang J, Calaycay J, Shively JE (1989) Brain capillary 46,000 dalton protein is cytoplasmic actin and is localized to endothelial plasma membrane. J Cereb Blood Flow Metab 9:675–680

    PubMed  CAS  Google Scholar 

  118. Itoh M, Furuse M, Morita K, Kubota K, Saitou M, Tsukita S (1999) Direct binding of three tight junction-associated MAGUKs, ZO-1, ZO-2, and ZO-3, with the COOH termini of claudins. J Cell Biol 147:1351–1363

    PubMed  CAS  Google Scholar 

  119. Guillemot L, Paschoud S, Pulimeno P, Foglia A, Citi S (2008) The cytoplasmic plaque of tight junctions: a scaffolding and signalling center. Biochim Biophys Acta 1778:601–613

    PubMed  CAS  Google Scholar 

  120. Matter K, Balda MS (2007) Epithelial tight junctions, gene expression and nucleo-junctional interplay. J Cell Sci 120:1505–1511

    PubMed  CAS  Google Scholar 

  121. Paris L, Tonutti L, Vannini C, Bazzoni G (2008) Structural organization of the tight junctions. Biochim Biophys Acta 1778:646–659

    PubMed  CAS  Google Scholar 

  122. Hartsock A, Nelson WJ (2008) Adherens and tight junctions: structure, function and connections to the actin cytoskeleton. Biochim Biophys Acta 1778:660–669

    PubMed  CAS  Google Scholar 

  123. Funke L, Dakoji S, Bredt DS (2005) Membrane-associated guanylate kinases regulate adhesion and plasticity at cell junctions. Annu Rev Biochem 74:219–245

    PubMed  CAS  Google Scholar 

  124. Staddon JM, Rubin LL (1996) Cell adhesion, cell junctions and the blood-brain barrier. Curr Opin Neurobiol 6:622–627

    PubMed  CAS  Google Scholar 

  125. Fanning AS, Jameson BJ, Jesaitis LA, Anderson JM (1998) The tight junction protein ZO-1 establishes a link between the transmembrane protein occludin and the actin cytoskeleton. J Biol Chem 273:29745–29753

    PubMed  CAS  Google Scholar 

  126. Furuse M, Itoh M, Hirase T, Nagafuchi A, Yonemura S, Tsukita S, Tsukita S (1994) Direct association of occludin with ZO-1 and its possible involvement in the localization of occludin at tight junctions. J Cell Biol 127:1617–1626

    PubMed  CAS  Google Scholar 

  127. Itoh M, Morita K, Tsukita S (1999) Characterization of ZO-2 as a MAGUK family member associated with tight as well as adherens junctions with a binding affinity to occludin and alpha catenin. J Biol Chem 274:5981–5986

    PubMed  CAS  Google Scholar 

  128. Kale G, Naren AP, Sheth P, Rao RK (2003) Tyrosine phosphorylation of occludin attenuates its interactions with ZO-1, ZO-2, and ZO-3. Biochem Biophys Res Commun 302:324–329

    PubMed  CAS  Google Scholar 

  129. 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 

  130. 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

    PubMed  CAS  Google Scholar 

  131. 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

    PubMed  CAS  Google Scholar 

  132. Anderson JM, Stevenson BR, Jesaitis LA, Goodenough DA, Mooseker MS (1988) Characterization of ZO-1, a protein component of the tight junction from mouse liver and Madin-Darby canine kidney cells. J Cell Biol 106:1141–1149

    PubMed  CAS  Google Scholar 

  133. Stevenson BR, Anderson JM, Goodenough DA, Mooseker MS (1988) Tight junction structure and ZO-1 content are identical in two strains of Madin-Darby canine kidney cells which differ in transepithelial resistance. J Cell Biol 107:2401–2408

    PubMed  CAS  Google Scholar 

  134. Chiba H, Osanai M, Murata M, Kojima T, Sawada N (2008) Transmembrane proteins of tight junctions. Biochim Biophys Acta 1778:588–600

    PubMed  CAS  Google Scholar 

  135. Forster C (2008) Tight junctions and the modulation of barrier function in disease. Histochem Cell Biol 130:55–70

    PubMed  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  137. Navarro P, Ruco L, Dejana E (1998) Differential localization of VE- and N-cadherins in human endothelial cells: VE-cadherin competes with N-cadherin for junctional localization. J Cell Biol 140:1475–1484

    PubMed  CAS  Google Scholar 

  138. Bazzoni G, Dejana E (2004) Endothelial cell-to-cell junctions: molecular organization and role in vascular homeostasis. Physiol Rev 84:869–901

    PubMed  CAS  Google Scholar 

  139. Weis WI, Nelson WJ (2006) Re-solving the cadherin-catenin-actin conundrum. J Biol Chem 281:35593–35597

    PubMed  CAS  Google Scholar 

  140. Staddon JM, Herrenknecht K, Smales C, Rubin LL (1995) Evidence that tyrosine phosphorylation may increase tight junction permeability. J Cell Sci 108 (Pt 2):609–619

    PubMed  CAS  Google Scholar 

  141. Schulze C, Smales C, Rubin LL, Staddon JM (1997) Lysophosphatidic acid increases tight junction permeability in cultured brain endothelial cells. J Neurochem 68:991–1000

    PubMed  CAS  Google Scholar 

  142. Rudini N, Dejana E (2008) Adherens junctions. Curr Biol 18:R1080–R1082

    PubMed  CAS  Google Scholar 

  143. Dejana E, Orsenigo F, Lampugnani MG (2008) The role of adherens junctions and VE-cadherin in the control of vascular ­permeability. J Cell Sci 121:2115–2122

    PubMed  CAS  Google Scholar 

  144. Dejana E, Orsenigo F, Molendini C, Baluk P, McDonald DM (2009) Organization and signaling of endothelial cell-to-cell junctions in various regions of the blood and lymphatic vascular trees. Cell Tissue Res 335:17–25

    PubMed  Google Scholar 

  145. Rubin LL, Staddon JM (1999) The cell biology of the blood-brain barrier. Annu Rev Neurosci 22:11–28

    PubMed  CAS  Google Scholar 

  146. Oldendorf WH, Brown WJ (1975) Greater number of capillary endothelial cell mitochondria in brain than in muscle. Proc Soc Exp Biol Med 149:736–738

    PubMed  CAS  Google Scholar 

  147. Oldendorf WH, Cornford ME, Brown WJ (1977) The large apparent work capability of the blood-brain barrier: a study of the mitochondrial content of capillary endothelial cells in brain and other tissues of the rat. Ann Neurol 1:409–417

    PubMed  CAS  Google Scholar 

  148. Claudio L, Kress Y, Norton WT, Brosnan CF (1989) Increased vesicular transport and decreased mitochondrial content in blood-brain barrier endothelial cells during experimental autoimmune encephalomyelitis. Am J Pathol 135:1157–1168

    PubMed  CAS  Google Scholar 

  149. Li JY, Boado RJ, Pardridge WM (2001) Blood-brain barrier genomics. J Cereb Blood Flow Metabol 21:61–68

    CAS  Google Scholar 

  150. Li JY, Boado RJ, Pardridge WM (2002) Rat blood-brain barrier genomics. II. J Cereb Blood Flow Metab 22:1319-1326

    PubMed  CAS  Google Scholar 

  151. Shusta EV, Boado RJ, Mathern GW, Pardridge WM (2002) Vascular genomics of the human brain. J Cereb Blood Flow Metab 22:245–252

    PubMed  CAS  Google Scholar 

  152. Enerson BE, Drewes LR (2006) The rat blood-brain barrier transcriptome. J Cereb Blood Flow Metab 26:959–973

    PubMed  CAS  Google Scholar 

  153. Liu X, Tu M, Kelly RS, Chen C, Smith BJ (2004) Development of a computational approach to predict blood-brain barrier permeability. Drug Metab Dispos 32:132–139

    PubMed  CAS  Google Scholar 

  154. Pardridge WM (2005) Molecular biology of the blood-brain barrier. Mol Biotechnol 30:57–70

    PubMed  CAS  Google Scholar 

  155. Birnbaum MJ, Haspel HC, Rosen OM (1986) Cloning and characterization of a cDNA encoding the rat brain glucose-transporter protein. Proc Natl Acad Sci USA 83: 5784–5788

    PubMed  CAS  Google Scholar 

  156. Maher F, Vannucci SJ, Simpson IA (1994) Glucose transporter proteins in brain. FASEB J 8:1003–1011

    PubMed  CAS  Google Scholar 

  157. Cornford EM, Hyman S, Swartz BE (1994) The human brain GLUT1 glucose transporter: ultrastructural localization to the blood-brain barrier endothelia. J Cereb Blood Flow Metab 14:106–112

    PubMed  CAS  Google Scholar 

  158. 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: 5779–5783

    PubMed  CAS  Google Scholar 

  159. Hawkins RA, O’Kane RL, Simpson IA, Vina JR (2006) Structure of the blood-brain barrier and its role in the transport of amino acids. J Nutr 136:218S–226S

    PubMed  CAS  Google Scholar 

  160. Lipton SA (2005) The molecular basis of memantine action in Alzheimer’s disease and other neurologic disorders: low-affinity, uncompetitive antagonism. Curr Alzheimer Res 2:155–165

    PubMed  CAS  Google Scholar 

  161. Nag S (1990) Ultracytochemical localisation of Na+, K(+)-ATPase in cerebral endothelium in acute hypertension. Acta Neuropathol (Berl) 80:7–11

    CAS  Google Scholar 

  162. Taylor CJ, Nicola PA, Wang S, Barrand MA, Hladky SB (2006) Transporters involved in regulation of intracellular pH in primary cultured rat brain endothelial cells. J Physiol 576:769–785

    PubMed  CAS  Google Scholar 

  163. Zlokovic BV, Mackic JB, Djuricic B, Davson H (1989) Kinetic analysis of leucine-enkephalin cellular uptake at the luminal side of the blood-brain barrier of an in situ perfused guinea-pig brain. J Neurochem 53:1333–1340

    PubMed  CAS  Google Scholar 

  164. Zlokovic BV, Susic VT, Davson H, Begley DJ, Jankov RM, Mitrovic DM, Lipovac MN (1989) Saturable mechanism for delta sleep-inducing peptide (DSIP) at the blood-brain barrier of the vascularly perfused guinea pig brain. Peptides 10:249–254

    PubMed  CAS  Google Scholar 

  165. Banks WA (2006) The CNS as a target for peptides and peptide-based drugs. Expert Opin Drug Deliv 3:707–712

    PubMed  CAS  Google Scholar 

  166. Zlokovic BV (1995) Cerebrovascular permeability to peptides: manipulations of transport systems at the blood-brain barrier. Pharm Res 12:1395–1406

    PubMed  CAS  Google Scholar 

  167. Zlokovic BV, Hyman S, McComb JG, Lipovac MN, Tang G, Davson H (1990) Kinetics of arginine-vasopressin uptake at the blood-brain barrier. Biochim Biophys Acta 1025:191–198

    PubMed  CAS  Google Scholar 

  168. Borst P, Elferink RO (2002) Mammalian ABC transporters in health and disease. Annu Rev Biochem 71:537–592

    PubMed  CAS  Google Scholar 

  169. Dean M, Allikmets R (2001) Complete characterization of the human ABC gene family. J Bioenerg Biomembr 33:475–479

    PubMed  CAS  Google Scholar 

  170. Ronaldson PT, Persidsky Y, Bendayan R (2008) Regulation of ABC membrane transporters in glial cells: relevance to the pharmacotherapy of brain HIV-1 infection. Glia 56:1711–1735

    PubMed  Google Scholar 

  171. Leggas M, Adachi M, Scheffer GL, Sun D, Wielinga P, Du G, Mercer KE, Zhuang Y, Panetta JC, Johnston B, Scheper RJ, Stewart CF, Schuetz JD (2004) Mrp4 confers resistance to topotecan and protects the brain from chemotherapy. Mol Cell Biol 24: 7612–7621

    PubMed  CAS  Google Scholar 

  172. Miller DS, Nobmann SN, Gutmann H, Toeroek M, Drewe J, Fricker G (2000) Xenobiotic transport across isolated brain microvessels studied by confocal microscopy. Mol Pharmacol 58:1357–1367

    PubMed  CAS  Google Scholar 

  173. Zhang Y, Schuetz JD, Elmquist WF, Miller DW (2004) Plasma membrane localization of multidrug resistance-associated protein homologs in brain capillary endothelial cells. J Pharmacol Exp Ther 311:449–455

    PubMed  CAS  Google Scholar 

  174. Hori S, Ohtsuki S, Tachikawa M, Kimura N, Kondo T, Watanabe M, Nakashima E, Terasaki T (2004) Functional expression of rat ABCG2 on the luminal side of brain capillaries and its enhancement by astrocyte-derived soluble factor(s). J Neurochem 90: 526–536

    PubMed  CAS  Google Scholar 

  175. Lee YJ, Kusuhara H, Jonker JW, Schinkel AH, Sugiyama Y (2005) Investigation of efflux transport of dehydroepiandrosterone sulfate and mitoxantrone at the mouse blood-brain barrier: a minor role of breast cancer resistance protein. J Pharmacol Exp Ther 312:44–52

    PubMed  CAS  Google Scholar 

  176. Lee G, Babakhanian K, Ramaswamy M, Prat A, Wosik K, Bendayan R (2007) Expression of the ATP-binding cassette membrane transporter, ABCG2, in human and rodent brain microvessel endothelial and glial cell culture systems. Pharm Res 24:1262–1274

    PubMed  CAS  Google Scholar 

  177. Zhang W, Mojsilovic-Petrovic J, Andrade MF, Zhang H, Ball M, Stanimirovic DB (2003) The expression and functional characterization of ABCG2 in brain endothelial cells and vessels. FASEB J 17:2085–2087

    PubMed  Google Scholar 

  178. Abbott NJ, Patabendige AA, Dolman DE, Yusof SR, Begley DJ (2009) Structure and function of the blood-brain barrier. Neurobiol Dis 37:13–25

    PubMed  Google Scholar 

  179. Begley DJ (2004) ABC transporters and the blood-brain barrier. Curr Pharm Des 10: 1295–1312

    PubMed  CAS  Google Scholar 

  180. Carvey PM, Hendey B, Monahan AJ (2009) The blood-brain barrier in neurodegenerative disease: a rhetorical perspective. J Neurochem 111:291–314

    PubMed  CAS  Google Scholar 

  181. Nag S and Begley DJ (2005) Blood-brain barrier, exchange of metabolites and gases. In Kalimo H (Ed) Pathology and Genetics. Cerebrovascular Diseases, ISN Neuropath Press, Basel, pp 22–29

    Google Scholar 

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

    PubMed  CAS  Google Scholar 

  183. Nag S, Manias JL, Stewart DJ (2009) Pathology and new players in the pathogenesis of brain edema. Acta Neuropathol 118: 197–217

    PubMed  Google Scholar 

  184. Hawkins BT, Egleton RD (2008) Pathophysiology of the blood-brain barrier: animal models and methods. Curr Top Dev Biol 80:277–309

    PubMed  CAS  Google Scholar 

  185. Starr JM, Wardlaw J, Ferguson K, MacLullich A, Deary IJ, Marshall I (2003) Increased blood-brain barrier permeability in type II diabetes demonstrated by gadolinium magnetic resonance imaging. J Neurol Neurosurg Psychiatry 74:70–76

    PubMed  CAS  Google Scholar 

  186. Bell RD, Zlokovic BV (2009) Neurovascular mechanisms and blood-brain barrier disorder in Alzheimer’s disease. Acta Neuropathol 118:103–113

    PubMed  CAS  Google Scholar 

  187. Vogelgesang S, Cascorbi I, Schroeder E, Pahnke J, Kroemer HK, Siegmund W, Kunert-Keil C, Walker LC, Warzok RW (2002) Deposition of Alzheimer’s beta-amyloid is inversely correlated with P-glycoprotein expression in the brains of elderly non-demented humans. Pharmacogenetics 12:535–541

    PubMed  CAS  Google Scholar 

  188. Kortekaas R, Leenders KL, van Oostrom JC, Vaalburg W, Bart J, Willemsen AT, Hendrikse NH (2005) Blood-brain barrier dysfunction in parkinsonian midbrain in vivo. Ann Neurol 57:176–179

    PubMed  CAS  Google Scholar 

  189. Lee G, Bendayan R (2004) Functional expression and localization of P-glycoprotein in the central nervous system: relevance to the pathogenesis and treatment of neurological disorders. Pharm Res 21:1313–1330

    PubMed  CAS  Google Scholar 

  190. Nag S (2002) The blood-brain barrier and cerebral angiogenesis: lessons from the cold-injury model. Trends Mol Med 8:38–44

    PubMed  CAS  Google Scholar 

  191. Wolburg H, Neuhaus J, Kniesel U, Krauss B, Schmid EM, Ocalan 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 (Pt 5): 1347–1357

    PubMed  CAS  Google Scholar 

  192. Wolburg H, Wolburg-Buchholz K, Kraus J, Rascher-Eggstein G, Liebner S, Hamm S, Duffner F, Grote EH, 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 (Berl) 105: 586–592

    CAS  Google Scholar 

  193. 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 

  194. Schnitzer JE, Carley WW, Palade GE (1988) Specific albumin binding to microvascular endothelium in culture. Am J Physiol 254:H425–H437

    PubMed  CAS  Google Scholar 

  195. 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

    PubMed  CAS  Google Scholar 

  196. 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 

  197. 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 

  198. 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 

  199. Banks WA, Erickson MA (2010) The blood-brain barrier and immune function and dysfunction. Neurobiol Dis 37:26–32

    PubMed  CAS  Google Scholar 

  200. Engelhardt B, Sorokin L (2009) The blood-brain and the blood-cerebrospinal fluid barriers: function and dysfunction. Semin Immunopathol 31:497–511

    PubMed  Google Scholar 

  201. Pachter JS, de Vries HE, Fabry Z (2003) The blood-brain barrier and its role in immune privilege in the central nervous system. J Neuropathol Exp Neurol 62:593–604

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    CAS  Google Scholar 

  204. Habgood MD, Bye N, Dziegielewska KM, Ek CJ, Lane MA, Potter A, Morganti-Kossmann C, Saunders NR (2007) Changes in blood-brain barrier permeability to large and small molecules following traumatic brain injury in mice. Eur J Neurosci 25:231–238

    PubMed  CAS  Google Scholar 

  205. Vorbrodt AW (1993) Morphological evidence of the functional polarization of brain microvascular endothelium. In Pardridge WM (Ed) The Blood-Brain Barrier. Cellular and Molecular Biology, Raven, New York, pp 137–164

    Google Scholar 

  206. Nag S (1986) Cerebral endothelial plasma membrane alterations in acute hypertension. Acta Neuropathol (Berl) 70:38–43

    CAS  Google Scholar 

  207. Hardebo JE, Kahrstrom J (1985) Endothelial negative surface charge areas and blood-brain barrier function. Acta Physiol Scand 125:495–499

    PubMed  CAS  Google Scholar 

  208. Nagy Z, Peters H, Huttner I (1983) Charge-related alterations of the cerebral endothelium. Lab Invest 49: 662–671

    PubMed  CAS  Google Scholar 

  209. Nag S, Manias JL, Stewart DJ (2009) Expression of endothelial phosphorylated caveolin-1 is increased in brain injury. Neuropathol Appl Neurobiol 35:417–426

    PubMed  CAS  Google Scholar 

  210. Mayhan WG (2000) Nitric oxide donor-induced increase in permeability of the blood-brain barrier. Brain Res 866:101–108

    PubMed  CAS  Google Scholar 

  211. 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 

  212. 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 

  213. 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

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  215. 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 

  216. 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

    PubMed  CAS  Google Scholar 

  217. Song L, Ge S, Pachter JS (2007) Caveolin-1 regulates expression of junction-associated proteins in brain microvascular endothelial cells. Blood 109:1515–1523

    PubMed  CAS  Google Scholar 

  218. Bentzel CJ, Hainau B, Edelman A, Anagnostopoulos T, Benedetti EL (1976) Effect of plant cytokinins on microfilaments and tight junction permeability. Nature 264:666–668

    PubMed  CAS  Google Scholar 

  219. Stevenson BR, Begg DA (1994) Concentration-dependent effects of cytochalasin D on tight junctions and actin filaments in MDCK epithelial cells. J Cell Sci 107 (Pt 3):367–375

    PubMed  CAS  Google Scholar 

  220. Nico B, Frigeri A, Nicchia GP, Corsi P, Ribatti D, Quondamatteo F, Herken R, Girolamo F, Marzullo A, Svelto M, Roncali L (2003) Severe alterations of endothelial and glial cells in the blood-brain barrier of dystrophic mdx mice. Glia 42:235–251

    PubMed  Google Scholar 

  221. Allen RD, Weiss DG, Hayden JH, Brown DT, Fujiwake H, Simpson M (1985) Gliding movement of and bidirectional transport along single native microtubules from squid axoplasm: evidence for an active role of microtubules in cytoplasmic transport. J Cell Biol 100:1736–1752

    PubMed  CAS  Google Scholar 

  222. Schnapp BJ, Vale RD, Sheetz MP, Reese TS (1985) Single microtubules from squid axoplasm support bidirectional movement of organelles. Cell 40:455–462

    PubMed  CAS  Google Scholar 

  223. Liu SM, Magnusson KE, Sundqvist T (1993) Microtubules are involved in transport of macromolecules by vesicles in cultured bovine aortic endothelial cells. J Cell Physiol 156:311–316

    PubMed  CAS  Google Scholar 

  224. Sternlicht MD, Werb Z (2001) How matrix metalloproteinases regulate cell behavior. Annu Rev Cell Dev Biol 17:463–516

    PubMed  CAS  Google Scholar 

  225. Rosenberg GA (2002) Matrix metalloproteinases in neuroinflammation. Glia 39:279–291

    PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  227. 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

    PubMed  Google Scholar 

  228. 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

    PubMed  CAS  Google Scholar 

  229. Mun-Bryce S, Rosenberg GA (1998) Matrix metalloproteinases in cerebrovascular disease. J Cereb Blood Flow Metab 18:1163–1172

    PubMed  CAS  Google Scholar 

  230. Rosenberg GA, Yang Y (2007) Vasogenic edema due to tight junction disruption by matrix metalloproteinases in cerebral ischemia. Neurosurg Focus 22:E4

    PubMed  Google Scholar 

  231. 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

    PubMed  CAS  Google Scholar 

  232. 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

    PubMed  CAS  Google Scholar 

  233. 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

    PubMed  CAS  Google Scholar 

  234. 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 

  235. 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 

  236. Abbott NJ (2000) Inflammatory mediators and modulation of blood-brain barrier permeability. Cell Mol Neurobiol 20:131–147

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  238. Segura I, De SF, Hohensinner PJ, Almodovar CR, Carmeliet P (2009) The neurovascular link in health and disease: an update. Trends Mol Med 15:439–451

    PubMed  CAS  Google Scholar 

  239. Zacchigna S, Lambrechts D, Carmeliet P (2008) Neurovascular signalling defects in neurodegeneration. Nat Rev Neurosci 9: 169–181

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  241. Ferrara N, Gerber HP, LeCouter J (2003) The biology of VEGF and its receptors. Nat Med 9:669–676

    PubMed  CAS  Google Scholar 

  242. Otrock ZK, Makarem JA, Shamseddine AI (2007) Vascular endothelial growth factor family of ligands and receptors: review. Blood Cells Mol Dis 38:258–268

    PubMed  CAS  Google Scholar 

  243. 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

    PubMed  CAS  Google Scholar 

  244. Roy H, Bhardwaj S, Yla-Herttuala S (2006) Biology of vascular endothelial growth factors. Febs Lett 580:2879–2887

    PubMed  CAS  Google Scholar 

  245. 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

    PubMed  Google Scholar 

  246. Segura AM, Luna RE, Horiba K, StetlerStevenson WG, McAllister HA, Willerson JT, Ferrans VJ (1998) Immunohistochemistry of matrix metalloproteinases and their inhibitors in thoracic aortic aneurysms and aortic valves of patients with Marfan’s syndrome. Circulation 98:II331-II337

    Google Scholar 

  247. 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 

  248. 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

    PubMed  CAS  Google Scholar 

  249. 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

    PubMed  CAS  Google Scholar 

  250. 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

    PubMed  CAS  Google Scholar 

  251. 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

    PubMed  CAS  Google Scholar 

  252. Hofman P, Blaauwgeers HGT, Tolentino MJ, Adamis AP, Cardozo BJN, Vrensen GFJ M, 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

    PubMed  CAS  Google Scholar 

  253. 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

    PubMed  CAS  Google Scholar 

  254. 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

    PubMed  CAS  Google Scholar 

  255. 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

    PubMed  CAS  Google Scholar 

  256. 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 

  257. 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

    PubMed  CAS  Google Scholar 

  258. 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

    PubMed  CAS  Google Scholar 

  259. 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

    PubMed  CAS  Google Scholar 

  260. Olofsson B, Korpelainen E, Pepper MS, Mandriota SJ, Aase K, Kumar V, Gunji Y, Jeltsch MM, Shibuya M, Alitalo 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

    PubMed  CAS  Google Scholar 

  261. 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. Develop Dynam 215:12–25

    CAS  Google Scholar 

  262. 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 

  263. Sun Y, Jin K, Childs JT, Xie L, Mao XO, Greenberg DA (2006) Vascular endothelial growth factor-B (VEGFB) stimulates neurogenesis: evidence from knockout mice and growth factor administration. Dev Biol 289:329–335

    PubMed  CAS  Google Scholar 

  264. 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

    PubMed  CAS  Google Scholar 

  265. 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

    PubMed  CAS  Google Scholar 

  266. 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

    PubMed  CAS  Google Scholar 

  267. 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 

  268. 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

    PubMed  CAS  Google Scholar 

  269. 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 

  270. 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 

  271. 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

    PubMed  CAS  Google Scholar 

  272. 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 

  273. 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 

  274. 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

    PubMed  CAS  Google Scholar 

  275. 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

    PubMed  CAS  Google Scholar 

  276. 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

    PubMed  CAS  Google Scholar 

  277. 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 

  278. 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

    PubMed  CAS  Google Scholar 

  279. 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 

  280. 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

    PubMed  CAS  Google Scholar 

  281. 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

    PubMed  CAS  Google Scholar 

  282. 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

    PubMed  CAS  Google Scholar 

  283. 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

    PubMed  CAS  Google Scholar 

  284. 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. Nature Med 6:460–463

    PubMed  CAS  Google Scholar 

  285. 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 

  286. 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

    PubMed  CAS  Google Scholar 

  287. Croll SD, Wiegand SJ (2001) Vascular growth factors in cerebral ischemia. Mol Neurobiol 23:121–135

    PubMed  CAS  Google Scholar 

  288. 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

    PubMed  CAS  Google Scholar 

  289. Machein MR, Plate KH (2000) VEGF in brain tumors. J Neurooncol 50:109–120

    PubMed  CAS  Google Scholar 

  290. 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

    PubMed  CAS  Google Scholar 

  291. Plate KH (1999) Mechanisms of angiogenesis in the brain. J Neuropathol Exp Neurol 58:313–320

    PubMed  CAS  Google Scholar 

  292. 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 

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

    PubMed  CAS  Google Scholar 

  294. 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

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  296. 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

    PubMed  CAS  Google Scholar 

  297. 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 

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

    PubMed  CAS  Google Scholar 

  299. Zagzag D, Hooper A, Friedlander DR, Chan W, Holash J, Wiegand SJ, Yancopoulos G D, 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

    PubMed  CAS  Google Scholar 

  300. 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

    PubMed  CAS  Google Scholar 

  301. 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

    PubMed  CAS  Google Scholar 

  302. 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 

  303. Provias J, Claffey K, delAguila 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

    PubMed  CAS  Google Scholar 

  304. vanBruggen N, Thibodeaux H, Palmer JT, Lee WP, Fu L, Cairns B, Tumas D, Gerlai R, Williams S P, Campagne M V, 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

    CAS  Google Scholar 

  305. 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

    PubMed  CAS  Google Scholar 

  306. Pardridge WM (2006) Molecular Trojan horses for blood-brain barrier drug delivery. Curr Opin Pharmacol 6:494–500

    PubMed  CAS  Google Scholar 

  307. Boado RJ (2007) Blood-brain barrier transport of non-viral gene and RNAi therapeutics. Pharm Res 24:1772–1787

    PubMed  CAS  Google Scholar 

  308. Kumar P, Wu H, McBride JL, Jung KE, Kim MH, Davidson BL, Lee SK, Shankar P, Manjunath N (2007) Transvascular delivery of small interfering RNA to the central nervous system. Nature 448:39–43

    PubMed  CAS  Google Scholar 

  309. Pardridge WM, Triguero D, Buciak J (1989) Transport of histone through the blood-brain barrier. J Pharmacol Exp Ther 251:821–826

    PubMed  CAS  Google Scholar 

  310. Demeule M, Poirier J, Jodoin J, Bertrand Y, Desrosiers RR, Dagenais C, Nguyen T, Lanthier J, Gabathuler R, Kennard M, Jefferies WA, Karkan D, Tsai S, Fenart L, Cecchelli R, Beliveau R (2002) High transcytosis of melanotransferrin (P97) across the blood-brain barrier. J Neurochem 83:924–933

    PubMed  CAS  Google Scholar 

  311. Prince WS, McCormick LM, Wendt DJ, Fitzpatrick PA, Schwartz KL, Aguilera AI, Koppaka V, Christianson TM, Vellard MC, Pavloff N, Lemontt JF, Qin M, Starr CM, Bu G, Zankel TC (2004) Lipoprotein receptor binding, cellular uptake, and lysosomal delivery of fusions between the receptor-associated protein (RAP) and alpha-L-iduronidase or acid alpha-glucosidase. J Biol Chem 279:35037–35046

    PubMed  CAS  Google Scholar 

  312. Schwarze SR, Ho A, Vocero-Akbani A, Dowdy SF (1999) In vivo protein transduction: delivery of a biologically active protein into the mouse. Science 285:1569–1572

    PubMed  CAS  Google Scholar 

  313. Broadwell RD, Balin BJ, Salcman M (1988) Transcytotic pathway for blood-borne protein through the blood-brain barrier. Proc Natl Acad Sci USA 85:632–636

    PubMed  CAS  Google Scholar 

  314. Adenot M, Merida P, Lahana R (2007) Applications of a blood-brain barrier technology platform to predict CNS penetration of various chemotherapeutic agents. 2. Cationic peptide vectors for brain delivery. Chemotherapy 53:73–76

    PubMed  CAS  Google Scholar 

  315. Demeule M, Currie JC, Bertrand Y, Che C, Nguyen T, Regina A, Gabathuler R, Castaigne JP, Beliveau R (2008) Involvement of the low-density lipoprotein receptor-related protein in the transcytosis of the brain delivery vector angiopep-2. J Neurochem 106:1534–1544

    PubMed  CAS  Google Scholar 

  316. Kreuter J, Hekmatara T, Dreis S, Vogel T, Gelperina S, Langer K (2007) Covalent attachment of apolipoprotein A-I and apolipoprotein B-100 to albumin nanoparticles enables drug transport into the brain. J Control Release 118:54–58

    PubMed  CAS  Google Scholar 

  317. Serres S, Anthony DC, Jiang Y, Broom KA, Campbell SJ, Tyler DJ, van Kasteren SI, Davis BG, Sibson NR (2009) Systemic inflammatory response reactivates immune-mediated lesions in rat brain. J Neurosci 29:4820–4828

    PubMed  CAS  Google Scholar 

  318. van Kasteren SI, Campbell SJ, Serres S, Anthony DC, Sibson NR, Davis BG (2009) Glyconanoparticles allow pre-symptomatic in vivo imaging of brain disease. Proc Natl Acad Sci USA 106:18–23

    PubMed  Google Scholar 

  319. von Zur MC, Sibson NR, Peter K, Campbell SJ, Wilainam P, Grau GE, Bode C, Choudhury RP, Anthony DC (2008) A contrast agent recognizing activated platelets reveals murine cerebral malaria pathology undetectable by conventional MRI. J Clin Invest 118: 1198–1207

    Google Scholar 

  320. Kroll RA, Pagel MA, Muldoon LL, RomanGoldstein S, Fiamengo, SA, Neuwelt EA (1998) Improving drug delivery to intracerebral tumor and surrounding brain in a rodent model: A comparison of osmotic versus bradykinin modification of the blood-brain and/or blood-tumor barriers. Neurosurgery 43:879–886

    PubMed  CAS  Google Scholar 

  321. Jahnke K, Doolittle ND, Muldoon LL, Neuwelt EA (2006) Implications of the blood-brain barrier in primary central nervous system lymphoma. Neurosurg Focus 21:E11

    PubMed  Google Scholar 

  322. Neuwelt EA (2004) Mechanisms of disease: the blood-brain barrier. Neurosurgery 54: 131–140

    PubMed  Google Scholar 

  323. Muldoon LL, Nilaver G, Kroll RA, Pagel MA, Breakefield XO, Chiocca EA, Davidson BL, Weissleder R, Neuwelt EA (1995) Comparison of intracerebral inoculation and osmotic blood-brain barrier disruption for delivery of adenovirus, herpesvirus, and iron oxide particles to normal rat brain. Am J Pathol 147:1840–1851

    PubMed  CAS  Google Scholar 

  324. Liu J, Oh P, Horner T, Rogers RA, Schnitzer JE (1997) Organized endothelial cell surface signal transduction in caveolae distinct from glycosylphosphatidylinositol-anchored protein microdomains. J Biol Chem 272: 7211–7222

    PubMed  CAS  Google Scholar 

  325. Uittenbogaard A, Shaul PW, Yuhanna IS, Blair A, Smart EJ (2000) High density lipoprotein prevents oxidized low density lipoprotein-induced inhibition of endothelial nitric-oxide synthase localization and activation in caveolae. J Biol Chem 275:11278–11283

    PubMed  CAS  Google Scholar 

  326. Tiruppathi C, Song W, Bergenfeldt M, Sass P, Malik AB (1997) Gp60 activation mediates albumin transcytosis in endothelial cells by tyrosine kinase-dependent pathway. J Biol Chem 272:25968–25975

    PubMed  CAS  Google Scholar 

  327. Yuhanna IS, Zhu Y, Cox BE, Hahner LD, Osborne-Lawrence S, Lu P, Marcel YL, Anderson RG, Mendelsohn ME, Hobbs HH, Shaul PW (2001) High-density lipoprotein binding to scavenger receptor-BI activates endothelial nitric oxide synthase. Nat Med 7:853–857

    PubMed  CAS  Google Scholar 

  328. Feng Y, Venema VJ, Venema RC, Tsai N, Behzadian MA, Caldwell RB (1999) VEGF-induced permeability increase is mediated by caveolae. Invest Ophthalmol Vis Sci 40:157–167

    PubMed  CAS  Google Scholar 

  329. Lupu C, Goodwin CA, Westmuckett AD, Emeis JJ, Scully MF, Kakkar VV, Lupu F (1997) Tissue factor pathway inhibitor in endothelial cells colocalizes with glycolipid microdomains/caveolae. Regulatory mechanism(s) of the anticoagulant properties of the endothelium. Arterioscler Thromb Vasc Biol 17:2964–2974

    PubMed  CAS  Google Scholar 

  330. Demeule M, Jodoin J, Gingras D, Beliveau R (2000) P-glycoprotein is localized in caveolae in resistant cells and in brain capillaries. Febs Lett 466:219–224

    PubMed  CAS  Google Scholar 

  331. Annabi B, Lachambre M, Bousquet-Gagnon N, Page M, Gingras D, Beliveau R (2001) Localization of membrane-type 1 matrix metalloproteinase in caveolae membrane domains. Biochem J 353:547–553

    PubMed  CAS  Google Scholar 

  332. Puyraimond A, Fridman R, Lemesle M, Arbeille B, Menashi S (2001) MMP-2 colocalizes with caveolae on the surface of endothelial cells. Exp Cell Res 262:28–36

    PubMed  CAS  Google Scholar 

  333. Igarashi J, Michel T (2000) Agonist-modulated targeting of the EDG-1 receptor to plasmalemmal caveolae. eNOS activation by sphingosine 1-phosphate and the role of caveolin-1 in sphingolipid signal transduction. J Biol Chem 275:32363–32370

    PubMed  CAS  Google Scholar 

  334. Wei Y, Yang X, Liu Q, Wilkins JA, Chapman HA (1999) A role for caveolin and the urokinase receptor in integrin-mediated adhesion and signaling. J Cell Biol 144:1285–1294

    PubMed  CAS  Google Scholar 

  335. Ju H, Venema VJ, Liang H, Harris MB, Zou R, Venema RC (2000) Bradykinin activates the Janus-activated kinase/signal transducers and activators of transcription (JAK/STAT) pathway in vascular endothelial cells: localization of JAK/STAT signalling proteins in plasmalemmal caveolae. Biochem J 351:257–264

    PubMed  CAS  Google Scholar 

  336. Chun M, Liyanage UK, Lisanti MP, Lodish HF (1994) Signal transduction of a G protein-coupled receptor in caveolae: colocalization of endothelin and its receptor with caveolin. Proc Natl Acad Sci USA 91:11728–11732

    PubMed  CAS  Google Scholar 

  337. Oh P, Schnitzer JE (2001) Segregation of heterotrimeric G proteins in cell surface microdomains. G(q) binds caveolin to concentrate in caveolae, whereas G(i) and G(s) target lipid rafts by default. Mol Biol Cell 12:685–698

    PubMed  CAS  Google Scholar 

  338. Rizzo V, Sung A, Oh P, Schnitzer JE (1998) Rapid mechanotransduction in situ at the luminal cell surface of vascular endothelium and its caveolae. J Biol Chem 273:26323–26329

    PubMed  CAS  Google Scholar 

  339. Shaul PW, Smart EJ, Robinson LJ, German Z, Yuhanna IS, Ying Y, Anderson RG, Michel T (1996) Acylation targets emdothelial nitric-oxide synthase to plasmalemmal caveolae. J Biol Chem 271:6518–6522

    PubMed  CAS  Google Scholar 

  340. Garcia-Cardena G, Oh P, Liu J, Schnitzer JE, Sessa WC (1996) Targeting of nitric oxide synthase to endothelial cell caveolae via palmitoylation: implications for nitric oxide signaling. Proc Natl Acad Sci USA 93: 6448–6453

    PubMed  CAS  Google Scholar 

  341. Spisni E, Griffoni C, Santi S, Riccio M, Marulli R, Bartolini G, Toni M, Ullrich V, Tomasi V (2001) Colocalization prostacyclin (PGI2) synthase–caveolin-1 in endothelial cells and new roles for PGI2 in angiogenesis. Exp Cell Res 266:31–43

    PubMed  CAS  Google Scholar 

  342. Teubl M, Groschner K, Kohlwein SD, Mayer B, Schmidt K (1999) Na(+)/Ca(2+) exchange facilitates Ca(2+)-dependent activation of endothelial nitric-oxide synthase. J Biol Chem 274:29529–29535

    PubMed  CAS  Google Scholar 

  343. Impagnatiello MA, Weitzer S, Gannon G, Compagni A, Cotten M, Christofori G (2001) Mammalian sprouty-1 and -2 are membrane-anchored phosphoprotein inhibitors of growth factor signaling in endothelial cells. J Cell Biol 152:1087–1098

    PubMed  CAS  Google Scholar 

  344. Fujimoto T, Nakade S, Miyawaki A, Mikoshiba K, Ogawa K (1992) Localization of inositol 1,4,5-trisphosphate receptor-like protein in plasmalemmal caveolae. J Cell Biol 119:1507–1513

    PubMed  Google Scholar 

  345. Schnitzer JE, Oh P, Jacobson BS, Dvorak AM (1995) Caveolae from luminal plasmalemma of rat lung endothelium: microdomains enriched in caveolin, Ca(2+)-ATPase, and inositol trisphosphate receptor. Proc Natl Acad Sci USA 92:1759–1763

    PubMed  CAS  Google Scholar 

  346. Chambliss KL, Yuhanna IS, Mineo C, Liu P, German Z, Sherman TS, Mendelsohn ME, Anderson RG, Shaul PW (2000) Estrogen receptor alpha and endothelial nitric oxide synthase are organized into a functional signaling module in caveolae. Circ Res 87:E44–E52

    PubMed  CAS  Google Scholar 

  347. McDonald KK, Zharikov S, Block ER, Kilberg MS (1997) A caveolar complex between the cationic amino acid transporter 1 and endothelial nitric-oxide synthase may explain the “arginine paradox”. J Biol Chem 272:31213–31216

    PubMed  CAS  Google Scholar 

  348. Henley JR, Krueger EW, Oswald BJ, McNiven MA (1998) Dynamin-mediated internalization of caveolae. J Cell Biol 141:85–99

    PubMed  CAS  Google Scholar 

  349. 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

    PubMed  CAS  Google Scholar 

  350. 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

    PubMed  CAS  Google Scholar 

  351. 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

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  353. 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 160:423–432

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work is supported by multiple grants from the Heart and Stroke Foundation of Ontario from 1978-2009.

Author information

Authors and Affiliations

  1. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada

    Sukriti Nag

Authors
  1. Sukriti Nag
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Banting Institute, Dept. Laboratory Med. & Pathobiology, University of Toronto, College St. 100, Toronto, M5G 1L5, Ontario, Canada

    Sukriti Nag

Rights and permissions

Reprints and permissions

Copyright information

© 2011 Springer Science+Business Media, LLC

About this protocol

Cite this protocol

Nag, S. (2011). Morphology and Properties of Brain Endothelial Cells. In: Nag, S. (eds) The Blood-Brain and Other Neural Barriers. Methods in Molecular Biology, vol 686. Humana Press. https://doi.org/10.1007/978-1-60761-938-3_1

Download citation

  • DOI: https://doi.org/10.1007/978-1-60761-938-3_1

  • Published:

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-60761-937-6

  • Online ISBN: 978-1-60761-938-3

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation