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Blood Retinal Barrier

  • Chapter
Retinal Vascular Disease

Abstract

Proper retinal function requires the presence of a well-defined blood-retinal barrier (BRB). In many of the leading causes of medical blindness this BRB is compromised. Indeed, retinopathy of prematurity and age related macular degeneration both include production of aberrant vessels with poor barrier properties. Further, diabetic retinopathy, the leading cause of blindness in working age adults, involves progressive vision loss and is closely associated with macular edema [117]. Increased fluid accumulation, as well as lipid and albumin deposits, is believed to be the result of the breakdown of the BRB that normally controls the neuronal environment. Barrier dysfunction results in increased permeability which diagnostically indicates progressive retinopathy [32]. This chapter will review the normal physiology of the BRB, the changes that occur through the course of diabetic retinopathy, and the known underlying molecular mechanisms that may lead to barrier dysfunction. Elucidating the mechanisms of barrier dysfunction in diabetic retinopathy will further our understanding of its pathogenesis and provide future therapeutic targets.

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References

  1. Agre P, Preston GM, Smith BL, Jung JS, Raina S, Moon C, Guggino WB, Nielsen S (1993) Aquaporin CHIP: the archetypal molecular water channel. Am J Physiol 265:F463–76

    PubMed  CAS  Google Scholar 

  2. Aiello LP (1997) Clinical implications of vascular growth factors in proliferative retinopathies. Curr Opin Ophthalmol 8:19–31

    Article  PubMed  CAS  Google Scholar 

  3. Aiello LP, Avery RL, Arrigg PG, Keyt BA, Jampel HD, Shah ST, Pasquale LR, Thieme H, Iwamoto MA, Park JE, et al. (1994) Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med 331:1480–7

    Article  PubMed  CAS  Google Scholar 

  4. Amin RH, Frank RN, Kennedy A, Eliott D, Puklin JE, Abrams GW (1997) Vascular endothelial growth factor is present in glial cells of the retina and optic nerve of human subjects with nonproliferative diabetic retinopathy. Invest Ophthalmol Vis Sci 38:36–47

    PubMed  CAS  Google Scholar 

  5. Antonetti DA, Barber AJ, Hollinger LA, Wolpert EB, Gardner TW (1999) Vascular endothelial growth factor induces rapid phosphorylation of tight junction proteins occludin and zonula occluden 1. A potential mechanism for vascular permeability in diabetic retinopathy and tumors. J Biol Chem 274:23463–7

    Article  PubMed  CAS  Google Scholar 

  6. 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. Penn State Retina Research Group. Diabetes 47:1953–9

    Article  PubMed  CAS  Google Scholar 

  7. Antonetti DA, Wolpert EB, DeMaio L, Harhaj NS, Scaduto RC, Jr (2002) Hydrocortisone decreases retinal endothelial cell water and solute flux coincident with increased content and decreased phosphorylation of occludin. J Neurochem 80:667–77

    Article  PubMed  CAS  Google Scholar 

  8. Balda MS, Whitney JA, Flores C, Gonzalez S, Cereijido M, Matter K (1996) Functional dissociation of paracellular permeability and transepithelial electrical resistance and disruption of the apical-basolateral intramembrane diffusion barrier by expression of amutant tight junction membrane protein. J Cell Biol 134:1031–49

    Article  PubMed  CAS  Google Scholar 

  9. Barber AJ, Antonetti DA (2003) Mapping the blood vessels with paracellular permeability in the retinas of diabetic rats. Invest Ophthalmol Vis Sci 44:5410–6

    Article  PubMed  Google Scholar 

  10. Barber AJ, Antonetti DA, Gardner TW (2000) Altered expression of retinal occludin and glial fibrillary acidic protein in experimental diabetes. The Penn State Retina Research Group. Invest Ophthalmol Vis Sci 41:3561–8

    PubMed  CAS  Google Scholar 

  11. Bauer HC, Bauer H, Lametschwandtner A, Amberger A, Ruiz P, Steiner M (1993) Neovascularization and the appearance of morphological characteristics of the blood-brain barrier in the embryonic mouse central nervous system. Brain Res Dev Brain Res 75:269–78

    Article  PubMed  CAS  Google Scholar 

  12. Bazzoni G, Martinez-Estrada OM, Mueller F, Nelboeck P, Schmid G, Bartfai T, Dejana E, Brockhaus M (2000) Homophilic interaction of junctional adhesion molecule. J Biol Chem 275:30970–6

    Article  PubMed  CAS  Google Scholar 

  13. Ben-Yosef T, Belyantseva IA, Saunders TL, Hughes ED, Kawamoto K, Van Itallie CM, Beyer LA, Halsey K, Gardner DJ, Wilcox ER, Rasmussen J, Anderson JM, Dolan DF, Forge A, Raphael Y, Camper SA, Friedman TB (2003) Claudin 14 knockout mice, a model for autosomal recessive deafness DFNB29, are deaf due to cochlear hair cell degeneration. Hum Mol Genet 12:2049–61

    Article  PubMed  CAS  Google Scholar 

  14. Bendayan R, Lee G, Bendayan M (2002) Functional expression and localization of P-glycoprotein at the blood brain barrier. Microsc Res Tech 57:365–80

    Article  PubMed  CAS  Google Scholar 

  15. Bergersen L, Johannsson E, Veruki ML, Nagelhus EA, Halestrap A, Sejersted OM, Ottersen OP (1999) Cellular and subcellular expression of monocarboxylate transporters in the pigment epithelium and retina of the rat. Neuroscience 90:319–31

    Article  PubMed  CAS  Google Scholar 

  16. Bertossi M, Virgintino D, Maiorano E, Occhiogrosso M, Roncali L (1997) Ultrastructural and morphometric investigation of human brain capillaries in normal and peritumoral tissues. Ultrastruct Pathol 21:41–9

    Article  PubMed  CAS  Google Scholar 

  17. Boivin D, Bilodeau D, Beliveau R (1996) Regulation of cytoskeletal functions by Rho small GTP-binding proteins in normal and cancer cells. Can J Physiol Pharmacol 74:801–10

    Article  PubMed  CAS  Google Scholar 

  18. Botchkin LM, Matthews G (1993) Chloride current activated by swelling in retinal pigment epithelium cells. Am J Physiol 265:C1037–45

    PubMed  CAS  Google Scholar 

  19. Brightman MW, Reese TS (1969) Junctions between intimately apposed cell membranes in the vertebrate brain. J Cell Biol 40:648–77

    Article  PubMed  CAS  Google Scholar 

  20. Burdo JR, Antonetti DA, Wolpert EB, Connor JR (2003) Mechanisms and regulation of transferrin and iron transport in a model blood-brain barrier system. Neuroscience 121:883–90

    Article  PubMed  CAS  Google Scholar 

  21. Burgel N, Bojarski C, Mankertz J, Zeitz M, Fromm M, Schulzke JD (2002) Mechanisms of diarrhea in collagenous colitis. Gastroenterology 123:433–43

    Article  PubMed  Google Scholar 

  22. Cau J, Hall A (2005) Cdc42 controls the polarity of the actin and microtubule cytoskeletons through two distinct signal transduction pathways. J Cell Sci 118:2579–87

    Article  PubMed  CAS  Google Scholar 

  23. Chakravarthy U, Hayes RG, Stitt AW, Douglas A (1997) Endothelin expression in ocular tissues of diabetic and insulin-treated rats. Invest Ophthalmol Vis Sci 38:2144–51

    PubMed  CAS  Google Scholar 

  24. Chen Y, Lu Q, Schneeberger EE, Goodenough DA (2000) Restoration of tight junction structure and barrier function by down-regulation of the mitogen-activated protein kinase pathway in ras-transformed Madin-Darby canine kidney cells. Mol Biol Cell 11:849–62

    PubMed  CAS  Google Scholar 

  25. Clermont AC, Cahill M, Salti H, Rook SL, Rask-Madsen C, Goddard L, Wong JS, Bursell D, Bursell SE, Aiello LP (2006) Hepatocyte growth factor induces retinal vascular permeability via MAP-kinase and PI-3 kinase without altering retinal hemodynamics. Invest Ophthalmol Vis Sci 47:2701–8

    Article  PubMed  Google Scholar 

  26. Colegio OR, Van Itallie CM, McCrea HJ, Rahner C, Anderson JM (2002) Claudins create charge-selective channels in the paracellular pathway between epithelial cells. Am J Physiol Cell Physiol 283:C142–7

    PubMed  CAS  Google Scholar 

  27. Coomber BL, Stewart PA (1986) Three-dimensional reconstruction of vesicles in endothelium of blood-brain barrier versus highly permeable microvessels. Anat Rec 215:256–61

    Article  PubMed  CAS  Google Scholar 

  28. Cordenonsi M, D’Atri F, Hammar E, Parry DA, Kendrick-Jones J, Shore D, Citi S (1999) Cingulin contains globular and coiled-coil domains and interacts with ZO-1, ZO-2, ZO-3, and myosin. J Cell Biol 147:1569–82

    Article  PubMed  CAS  Google Scholar 

  29. Crocker DJ, Murad TM, Geer JC (1970) Role of the pericyte in wound healing. An ultrastructural study. Exp Mol Pathol 13:51–65

    Article  PubMed  CAS  Google Scholar 

  30. Crook M (2004) Type 2 diabetes mellitus: a disease of the innate immune system? An update. Diabet Med 21:203–7

    Article  PubMed  CAS  Google Scholar 

  31. Cunha-Vaz J, Bernardes R (2005) Nonproliferative retinopathy in diabetes type 2. Initial stages and characterization of phenotypes. Prog Retin Eye Res 24:355–77

    Article  PubMed  Google Scholar 

  32. Cunha-Vaz J, Lobo C, Sousa JC, Oliveiros B, Leite E, de Abreu JR (1998) Progression of retinopathy and alteration of the blood-retinal barrier in patients with type 2 diabetes: a 7-year prospective follow-up study. Graefes Arch Clin Exp Ophthalmol 236:264–8

    Article  PubMed  CAS  Google Scholar 

  33. Cunningham SA, Rodriguez JM, Arrate MP, Tran TM, Brock TA (2002) JAM2 interacts with alpha4beta1. Facilitation by JAM3. J Biol Chem 277:27589–92

    Article  PubMed  CAS  Google Scholar 

  34. D’Atri F, Citi S (2001) Cingulin interacts with F-actin in vitro. FEBS Lett 507:21–4

    Article  PubMed  CAS  Google Scholar 

  35. Damas J (1998) [Starling’s law in 1998]. Rev Med Liege 53:425–30

    PubMed  CAS  Google Scholar 

  36. 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 87:1161–9

    Article  PubMed  CAS  Google Scholar 

  37. Deen WM, Lazzara MJ, Myers BD (2001) Structural determinants of glomerular permeability. Am J Physiol Renal Physiol 281:F579–96

    PubMed  CAS  Google Scholar 

  38. DeMaio L, Antonetti DA, Scaduto RC, Jr, Gardner TW, Tarbell JM (2004) VEGF increases paracellular transport without altering the solvent-drag reflection coefficient. Microvasc Res 68:295–302

    Article  PubMed  CAS  Google Scholar 

  39. DeMaio L, Chang YS, Gardner TW, Tarbell JM, Antonetti DA (2001) Shear stress regulates occludin content and phosphorylation. Am J Physiol Heart Circ Physiol 281:H105–13

    PubMed  CAS  Google Scholar 

  40. Dermietzel R, Krause D (1991) Molecular anatomy of the blood-brain barrier as defined by immunocytochemistry. Int Rev Cytol 127:57–109

    Article  PubMed  CAS  Google Scholar 

  41. Duncan BB, Schmidt MI (2006) The epidemiology of low-grade chronic systemic inflammation and type 2 diabetes. Diabetes Technol Ther 8:7–17

    Article  PubMed  Google Scholar 

  42. Ebnet K, Suzuki A, Ohno S, Vestweber D (2004) Junctional adhesion molecules (JAMs): more molecules with dual functions? J Cell Sci 117:19–29

    Article  PubMed  CAS  Google Scholar 

  43. Enea NA, Hollis TM, Kern JA, Gardner TW (1989) Histamine H1 receptors mediate increased blood-retinal barrier permeability in experimental diabetes. Arch Ophthalmol 107:270–4

    PubMed  CAS  Google Scholar 

  44. Engler C, Krogsaa B, Lund-Andersen H (1991) Blood-retina barrier permeability and its relation to the progression of diabetic retinopathy in type 1 diabetics. An 8-year follow-up study. Graefes Arch Clin Exp Ophthalmol 229:442–6

    Article  PubMed  CAS  Google Scholar 

  45. Etienne-Manneville S, Hall A (2003) Cdc42 regulates GSK-3beta and adenomatous polyposis coli to control cell polarity. Nature 421:753–6

    Article  PubMed  CAS  Google Scholar 

  46. Fanning AS, Anderson JM (1999) Protein modules as organizers of membrane structure. Curr Opin Cell Biol 11:432–9

    Article  PubMed  CAS  Google Scholar 

  47. Fanning AS, Ma TY, Anderson JM (2002) Isolation and functional characterization of the actin binding region in the tight junction protein ZO-1. FASEB J 16:1835–7

    PubMed  CAS  Google Scholar 

  48. Farquhar MG, Palade GE (1963) Junctional complexes in various epithelia. J Cell Biol 17:375–412

    Article  PubMed  CAS  Google Scholar 

  49. Fenstermacher J, Gross P, Sposito N, Acuff V, Pettersen S, Gruber K (1988) Structural and functional variations in capillary systems within the brain. Ann N Y Acad Sci 529:21–30

    Article  PubMed  CAS  Google Scholar 

  50. Festa A, D’Agostino R, Jr, Howard G, Mykkanen L, Tracy RP, Haffner SM (2000) Chronic subclinical inflammation as part of the insulin resistance syndrome: the Insulin Resistance Atherosclerosis Study (IRAS). Circulation 102: 42–7

    PubMed  CAS  Google Scholar 

  51. Frank RN (1991) On the pathogenesis of diabetic retinopathy. A 1990 update. Ophthalmology 98:586–93

    PubMed  CAS  Google Scholar 

  52. Frohlich M, Imhof A, Berg G, Hutchinson WL, Pepys MB, Boeing H, Muche R, Brenner H, Koenig W (2000) Association between C-reactive protein and features of the metabolic syndrome: a population-based study. Diabetes Care 23:1835–9

    Article  PubMed  CAS  Google Scholar 

  53. Fujimoto K (1995) Pericyte-endothelial gap junctions in developing rat cerebral capillaries: a fine structural study. Anat Rec 242:562–5

    Article  PubMed  CAS  Google Scholar 

  54. Fukuhara A, Irie K, Nakanishi H, Takekuni K, Kawakatsu T, Ikeda W, Yamada A, Katata T, Honda T, Sato T, Shimizu K, Ozaki H, Horiuchi H, Kita T, Takai Y (2002) Involvement of nectin in the localization of junctional adhesion molecule at tight junctions. Oncogene 21:7642–55

    Article  PubMed  CAS  Google Scholar 

  55. Fukuhara A, Irie K, Yamada A, Katata T, Honda T, Shimizu K, Nakanishi H, Takai Y (2002) Role of nectin in organization of tight junctions in epithelial cells. Genes Cells 7:1059–72

    Article  PubMed  CAS  Google Scholar 

  56. Furuse M, Hata M, Furuse K, Yoshida Y, Haratake A, Sugitani Y, Noda T, Kubo A, Tsukita S (2002) Claudin-based tight junctions are crucial for the mammalian epidermal barrier: a lesson from claudin-1-deficient mice. J Cell Biol 156:1099–111

    Article  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 123:1777–88

    Article  PubMed  CAS  Google Scholar 

  58. Garcia PJ, Spellman CW (2006) Should all diabetic patients receive statins? Curr Atheroscler Rep 8:13–8

    Article  PubMed  Google Scholar 

  59. Gardiner TA, Anderson HR, Stitt AW (2003) Inhibition of advanced glycation end-products protects against retinal capillary basement membrane expansion during long-term diabetes. J Pathol 201:328–33

    Article  PubMed  CAS  Google Scholar 

  60. Gardner TW, Antonetti DA, Barber AJ, LaNoue KF, Nakamura M (2000) New insights into the pathophysiology of diabetic retinopathy: potential cell-specific therapeutic targets. Diabetes Technol Ther 2:601–8

    Article  PubMed  CAS  Google Scholar 

  61. Goldstein B (2000) Embryonic polarity: a role for microtubules. Curr Biol 10:R820–2

    Article  PubMed  CAS  Google Scholar 

  62. Gonzalez-Mariscal L, Betanzos A, Nava P, Jaramillo BE (2003) Tight junction proteins. Prog Biophys Mol Biol 81:1–44

    Article  PubMed  CAS  Google Scholar 

  63. Guillemot L, Hammar E, Kaister C, Ritz J, Caille D, Jond L, Bauer C, Meda P, Citi S (2004) Disruption of the cingulin gene does not prevent tight junction formation but alters gene expression. J Cell Sci 117:5245–56

    Article  PubMed  CAS  Google Scholar 

  64. 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 U S A 88:3460–4

    Article  PubMed  CAS  Google Scholar 

  65. Guo P, Weinstein AM, Weinbaum S (2003) A dual-pathway ultrastructural model for the tight junction of rat proximal tubule epithelium. AmJ Physiol Renal Physiol 285:F241–57

    CAS  Google Scholar 

  66. Guo S, Kemphues KJ (1996) Molecular genetics of asymmetric cleavage in the early Caenorhabditis elegans embryo. Curr Opin Genet Dev 6:408–15

    Article  PubMed  CAS  Google Scholar 

  67. Haffner SM (2006) The metabolic syndrome: inflammation, diabetes mellitus, and cardiovascular disease. Am J Cardiol 97:3A–11A

    Article  PubMed  CAS  Google Scholar 

  68. Hammes HP (2005) Pericytes and the pathogenesis of diabetic retinopathy. Horm Metab Res 37Suppl 1:39–43

    Article  PubMed  CAS  Google Scholar 

  69. Hammes HP, Lin J, Wagner P, Feng Y, Vom Hagen F, Krzizok T, Renner O, Breier G, Brownlee M, Deutsch U (2004) Angiopoietin-2 causes pericyte dropout in the normal retina: evidence for involvement in diabetic retinopathy. Diabetes 53:1104–10

    Article  PubMed  CAS  Google Scholar 

  70. Harhaj NS, Felinski EA, Wolpert EB, Sundstrom JM, Gardner TW, Antonetti DA (2006) VEGF activation of protein kinase C stimulates occludin phosphorylation and contributes to endothelial permeability. IOVS (in press)

    Google Scholar 

  71. 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

    Article  PubMed  CAS  Google Scholar 

  72. Hirase T, Kawashima S, Wong EY, Ueyama T, Rikitake Y, Tsukita S, Yokoyama M, Staddon JM (2001) Regulation of tight junction permeability and occludin phosphorylation by Rhoa-p160ROCK-dependent and-independent mechanisms. J Biol Chem 276:10423–31

    Article  PubMed  CAS  Google Scholar 

  73. 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(14):1603–13

    PubMed  CAS  Google Scholar 

  74. Hirschi KK, D’Amore PA (1997) Control of angiogenesis by the pericyte: molecular mechanisms and significance. EXS 79:419–28

    PubMed  CAS  Google Scholar 

  75. Hofman P, van Blijswijk BC, Gaillard PJ, Vrensen GF, Schlingemann RO (2001) Endothelial cell hypertrophy induced by vascular endothelial growth factor in the retina: new insights into the pathogenesis of capillary nonperfusion. Arch Ophthalmol 119:861–6

    PubMed  CAS  Google Scholar 

  76. Hurd TW, Gao L, Roh MH, Macara IG, Margolis B (2003) Direct interaction of two polarity complexes implicated in epithelial tight junction assembly. Nat Cell Biol 5:137–42

    Article  PubMed  CAS  Google Scholar 

  77. Jiang WG, Martin TA, Matsumoto K, Nakamura T, Mansel RE (1999) Hepatocyte growth factor/scatter factor decreases the expression of occludin and transendothelial resistance (TER) and increases paracellular permeability in human vascular endothelial cells. J Cell Physiol 181: 319–29

    Article  PubMed  CAS  Google Scholar 

  78. Jin M, Barron E, He S, Ryan SJ, Hinton DR (2002) Regulation of RPE intercellular junction integrity and function by hepatocyte growth factor. Invest Ophthalmol Vis Sci 43:2782–90

    PubMed  Google Scholar 

  79. Joussen AM, Murata T, Tsujikawa A, Kirchhof B, Bursell SE, Adamis AP (2001) Leukocyte-mediated endothelial cell injury and death in the diabetic retina. Am J Pathol 158:147–52

    PubMed  CAS  Google Scholar 

  80. Katsura Y, Okano T, Noritake M, Kosano H, Nishigori H, Kado S, Matsuoka T (1998) Hepatocyte growth factor in vitreous fluid of patients with proliferative diabetic retinopathy and other retinal disorders. Diabetes Care 21: 1759–63

    Article  PubMed  CAS  Google Scholar 

  81. Kausalya PJ, Amasheh S, Gunzel D, Wurps H, Muller D, Fromm M, Hunziker W (2006) Disease-associated mutations affect intracellular traffic and paracellular Mg2+ transport function of Claudin-16. J Clin Invest 116:878–91

    Article  PubMed  CAS  Google Scholar 

  82. Kinukawa Y, Shimura M, Tamai M (1999) Quantifying leukocyte dynamics and plugging in retinal microcirculation of streptozotosin-induced diabetic rats. Curr Eye Res 18:49–55

    Article  PubMed  CAS  Google Scholar 

  83. Kliche S, Waltenberger J (2001) VEGF receptor signaling and endothelial function. IUBMB Life 52:61–6

    Article  PubMed  CAS  Google Scholar 

  84. Knoblich JA (2001) Asymmetric cell division during animal development. Nat Rev Mol Cell Biol 2:11–20

    Article  PubMed  CAS  Google Scholar 

  85. Koblizek TI, Weiss C, Yancopoulos GD, Deutsch U, Risau W (1998) Angiopoietin-1 induces sprouting angiogenesis in vitro. Curr Biol 8:529–32

    Article  PubMed  CAS  Google Scholar 

  86. Korte GE, Burns MS, Bellhorn RW (1989) Epithelium-capillary interactions in the eye: the retinal pigment epithelium and the choriocapillaris. Int Rev Cytol 114:221–48

    Article  PubMed  CAS  Google Scholar 

  87. Kowluru RA (2005) Diabetic retinopathy: mitochondrial dysfunction and retinal capillary cell death. Antioxid Redox Signal 7:1581–87

    Article  PubMed  CAS  Google Scholar 

  88. Kowluru RA (2005) Effect of advanced glycation end products on accelerated apoptosis of retinal capillary cells under in vitro conditions. Life Sci 76:1051–60

    Article  PubMed  CAS  Google Scholar 

  89. Kowluru RA, Atasi L, Ho YS (2006) Role of mitochondrial superoxide dismutase in the development of diabetic retinopathy. Invest Ophthalmol Vis Sci 47:1594–9

    Article  PubMed  Google Scholar 

  90. Kowluru RA, Kennedy A (2001) Therapeutic potential of anti-oxidants and diabetic retinopathy. Expert Opin Investig Drugs 10:1665–76

    Article  PubMed  CAS  Google Scholar 

  91. Kuriyama M, Harada N, Kuroda S, Yamamoto T, Nakafuku M, Iwamatsu A, Yamamoto D, Prasad R, Croce C, Canaani E, Kaibuchi K (1996) Identification of AF-6 and canoe as putative targets for Ras. J Biol Chem 271:607–10

    Article  PubMed  CAS  Google Scholar 

  92. Lacaz-Vieira F, Jaeger MM, Farshori P, Kachar B (1999) Small synthetic peptides homologous to segments of the first external loop of occludin impair tight junction resealing. J Membr Biol 168:289–97

    Article  PubMed  CAS  Google Scholar 

  93. Lecaire T, Palta M, Zhang H, Allen C, Klein R, D’Alessio D (2006) Lower-than-expected prevalence and severity of retinopathy in an incident cohort followed during the first 4–14 years of type 1 diabetes: The Wisconsin Diabetes Registry Study. Am J Epidemiol 164:143–50

    Article  PubMed  Google Scholar 

  94. Lin J, Bierhaus A, Bugert P, Dietrich N, Feng Y, Vom Hagen F, Nawroth P, Brownlee M, Hammes HP (2006) Effect of R-(+)-alpha-lipoic acid on experimental diabetic retinopathy. Diabetologia 49:1089–96

    Article  PubMed  CAS  Google Scholar 

  95. Lindblom P, Gerhardt H, Liebner S, Abramsson A, Enge M, Hellstrom M, Backstrom G, Fredriksson S, Landegren U, Nystrom HC, Bergstrom G, Dejana E, Ostman A, Lindahl P, Betsholtz C (2003) Endothelial PDGF-B retention is required for proper investment of pericytes in the microvessel wall. Genes Dev 17:1835–40

    Article  PubMed  CAS  Google Scholar 

  96. Ling V (1997) Multidrug resistance: molecular mechanisms and clinical relevance. Cancer Chemother Pharmacol 40 Suppl:S3–8

    Article  PubMed  CAS  Google Scholar 

  97. Lu M, Kuroki M, Amano S, Tolentino M, Keough K, Kim I, Bucala R, Adamis AP (1998) Advanced glycation end products increase retinal vascular endothelial growth factor expression. J Clin Invest 101:1219–24

    Article  PubMed  CAS  Google Scholar 

  98. Lu M, Perez VL, Ma N, Miyamoto K, Peng HB, Liao JK, Adamis AP (1999) VEGF increases retinal vascular ICAM-1 expression in vivo. Invest Ophthalmol Vis Sci 40:1808–12

    PubMed  CAS  Google Scholar 

  99. Lutty GA, McLeod DS, Merges C, Diggs A, Plouet J (1996) Localization of vascular endothelial growth factor in human retina and choroid. Arch Ophthalmol 114:971–7

    PubMed  CAS  Google Scholar 

  100. Maines LW, Antonetti DA, Wolpert EB, Smith CD (2005) Evaluation of the role of P-glycoprotein in the uptake of paroxetine, clozapine, phenytoin and carbamazapine by bovine retinal endothelial cells. Neuropharmacology 49:610–7

    PubMed  CAS  Google Scholar 

  101. Mandell KJ, Parkos CA (2005) The JAM family of proteins. Adv Drug Deliv Rev 57:857–67

    Article  PubMed  CAS  Google Scholar 

  102. Marmor MF, Wolfensberger TJ (1998) The retinal pigment epithelium: function and disease. Oxford University Press, New York

    Google Scholar 

  103. Masuzawa K, Goto K, Jesmin S, Maeda S, Miyauchi T, Kaji Y, Oshika T, Hori S (2006) An endothelin type A receptor antagonist reverses upregulated VEGF and ICAM-1 levels in streptozotocin-induced diabetic rat retina. Curr Eye Res 31:79–89

    Article  PubMed  CAS  Google Scholar 

  104. Mazzon E, Puzzolo D, Caputi AP, Cuzzocrea S (2002) Role of IL-10 in hepatocyte tight junction alteration in mouse model of experimental colitis. Mol Med 8:353–66

    PubMed  CAS  Google Scholar 

  105. McCarthy KM, Skare IB, Stankewich MC, Furuse M, Tsukita S, Rogers RA, Lynch RD, Schneeberger EE (1996) Occludin is a functional component of the tight junction. J Cell Sci 109(9):2287–98

    PubMed  CAS  Google Scholar 

  106. McNeil E, Capaldo CT, Macara IG (2006) Zonula occludens-1 function in the assembly of tight junctions in Madin-Darby canine kidney epithelial cells. Mol Biol Cell 17:1922–32

    Article  PubMed  CAS  Google Scholar 

  107. Miller SS, Edelman JL (1990) Active ion transport pathways in the bovine retinal pigment epithelium. J Physiol 424: 283–300

    PubMed  CAS  Google Scholar 

  108. Miller SS, Hughes BA, Machen TE (1982) Fluid transport across retinal pigment epithelium is inhibited by cyclic AMP. Proc Natl Acad Sci U S A 79:2111–5

    Article  PubMed  CAS  Google Scholar 

  109. Miller SS, Steinberg RH (1977) Active transport of ions across frog retinal pigment epithelium. Exp Eye Res 25:235–48

    Article  PubMed  CAS  Google Scholar 

  110. Mitamura Y, Takeuchi S, Matsuda A, Tagawa Y, Mizue Y, Nishihira J (2000) Hepatocyte growth factor levels in the vitreous of patients with proliferative vitreoretinopathy. Am J Ophthalmol 129:678–80

    Article  PubMed  CAS  Google Scholar 

  111. Mitic LL, Anderson JM (1998) Molecular architecture of tight junctions. Annu Rev Physiol 60:121–42

    Article  PubMed  CAS  Google Scholar 

  112. Miyamoto K, Hiroshiba N, Tsujikawa A, Ogura Y (1998) In vivo demonstration of increased leukocyte entrapment in retinal microcirculation of diabetic rats. Invest Ophthalmol Vis Sci 39:2190–4

    PubMed  CAS  Google Scholar 

  113. Miyamoto K, Khosrof S, Bursell SE, Moromizato Y, Aiello LP, Ogura Y, Adamis AP (2000) Vascular endothelial growth factor (VEGF)-induced retinal vascular permeability is mediated by intercellular adhesion molecule-1 (ICAM-1). Am J Pathol 156:1733–9

    PubMed  CAS  Google Scholar 

  114. Miyoshi J, Takai Y (2005) Molecular perspective on tight-junction assembly and epithelial polarity. Adv Drug Deliv Rev 57:815–55

    Article  PubMed  CAS  Google Scholar 

  115. Moore TC, Moore JE, Kaji Y, Frizzell N, Usui T, Poulaki V, Campbell IL, Stitt AW, Gardiner TA, Archer DB, Adamis AP (2003) The role of advanced glycation end products in retinal microvascular leukostasis. Invest Ophthalmol Vis Sci 44:4457–64

    Article  PubMed  Google Scholar 

  116. Morcos Y, Hosie MJ, Bauer HC, Chan-Ling T (2001) Immunolocalization of occludin and claudin-1 to tight junctions in intact CNS vessels of mammalian retina. J Neurocytol 30:107–23

    Article  PubMed  CAS  Google Scholar 

  117. Moss SE, Klein R, Klein BE (1998) The 14-year incidence of visual loss in a diabetic population. Ophthalmology 105: 998–1003

    Article  PubMed  CAS  Google Scholar 

  118. Murata T, Ishibashi T, Inomata H (1993) Immunohistochemical detection of blood-retinal barrier breakdown in streptozotocin-diabetic rats. Graefes Arch Clin Exp Ophthalmol 231:175–7

    Article  PubMed  CAS  Google Scholar 

  119. Murata T, Nakagawa K, Khalil A, Ishibashi T, Inomata H, Sueishi K (1996) The relation between expression of vascular endothelial growth factor and breakdown of the blood-retinal barrier in diabetic rat retinas. Lab Invest 74:819–25

    PubMed  CAS  Google Scholar 

  120. Nagy Z, Peters H, Huttner I (1984) Fracture faces of cell junctions in cerebral endothelium during normal and hyperosmotic conditions. Lab Invest 50:313–22

    PubMed  CAS  Google Scholar 

  121. Nehls V, Denzer K, Drenckhahn D (1992) Pericyte involvement in capillary sprouting during angiogenesis in situ. Cell Tissue Res 270:469–74

    Article  PubMed  CAS  Google Scholar 

  122. Nelson WJ (2003) Adaptation of core mechanisms to generate cell polarity. Nature 422:766–74

    Article  PubMed  CAS  Google Scholar 

  123. 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 U S A 90:7275–9

    Article  PubMed  CAS  Google Scholar 

  124. 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 161:653–60

    Article  PubMed  CAS  Google Scholar 

  125. Nusrat A, Brown GT, Tom J, Drake A, Bui TT, Quan C, Mrsny RJ (2005) Multiple protein interactions involving proposed extracellular loop domains of the tight junction protein occludin. Mol Biol Cell 16:1725–34

    Article  PubMed  CAS  Google Scholar 

  126. 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 1:409–17

    Article  PubMed  CAS  Google Scholar 

  127. 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 3:151–8

    Article  PubMed  CAS  Google Scholar 

  128. Pardridge WM, Boado RJ, Farrell CR (1990) Brain-type glucose transporter (GLUT-1) is selectively localized to the blood-brain barrier. Studies with quantitative western blotting and in situ hybridization. J Biol Chem 265:18035–40

    PubMed  CAS  Google Scholar 

  129. Petronczki M, Knoblich JA (2001) DmPAR-6 directs epithelial polarity and asymmetric cell division of neuroblasts in Drosophila. Nat Cell Biol 3:43–9

    Article  PubMed  CAS  Google Scholar 

  130. Philp NJ, Yoon H, Grollman EF (1998) Monocarboxylate transporter MCT1 is located in the apical membrane and MCT3 in the basal membrane of rat RPE. Am J Physiol 274:R1824–8

    PubMed  CAS  Google Scholar 

  131. Pickup JC, Crook MA (1998) Is type II diabetes mellitus a disease of the innate immune system? Diabetologia 41:1241–8

    Article  PubMed  CAS  Google Scholar 

  132. Qaum T, Xu Q, Joussen AM, Clemens MW, Qin W, Miyamoto K, Hassessian H, Wiegand SJ, Rudge J, Yancopoulos GD, Adamis AP (2001) VEGF-initiated blood-retinal barrier breakdown in early diabetes. Invest Ophthalmol Vis Sci 42:2408–13

    PubMed  CAS  Google Scholar 

  133. Rao VV, Dahlheimer JL, Bardgett ME, Snyder AZ, Finch RA, Sartorelli AC, Piwnica-Worms D (1999) Choroid plexus epithelial expression of MDR1 P glycoprotein and multidrug resistance-associated protein contribute to the blood-cerebrospinal-fluid drug-permeability barrier. Proc Natl Acad Sci U S A 96:3900–5

    Article  PubMed  CAS  Google Scholar 

  134. Rizzolo LJ (1997) Polarity and the development of the outer blood-retinal barrier. Histol Histopathol 12:1057–67

    PubMed  CAS  Google Scholar 

  135. Roh MH, Fan S, Liu CJ, Margolis B (2003) The Crumbs3-Pals1 complex participates in the establishment of polarity in mammalian epithelial cells. J Cell Sci 116:2895–906

    Article  PubMed  CAS  Google Scholar 

  136. Roh MH, Liu CJ, Laurinec S, Margolis B (2002) The carboxyl terminus of zona occludens-3 binds and recruits a mammalian homologue of discs lost to tight junctions. J Biol Chem 277:27501–9

    Article  PubMed  CAS  Google Scholar 

  137. Romero IA, Radewicz K, Jubin E, Michel CC, Greenwood J, Couraud PO, Adamson P (2003) Changes in cytoskeletal and tight junctional proteins correlate with decreased permeability induced by dexamethasone in cultured rat brain endothelial cells. Neurosci Lett 344:112–6

    Article  PubMed  CAS  Google Scholar 

  138. Rothenberg M, Ling V (1989) Multidrug resistance: molecular biology and clinical relevance. J Natl Cancer Inst 81:907–10

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  140. Rymer J, Miller SS, Edelman JL (2001) Epinephrine-induced increases in [Ca2+](in) and KCl-coupled fluid absorption in bovine RPE. Invest Ophthalmol Vis Sci 42:1921–9

    PubMed  CAS  Google Scholar 

  141. 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 11:4131–42

    PubMed  CAS  Google Scholar 

  142. Salathe EP, Venkataraman R (1982) Interaction of fluid movement and particle diffusion across capillary walls. J Biomech Eng 104:57–62

    PubMed  CAS  Google Scholar 

  143. Sasaki H, Matsui C, Furuse K, Mimori-Kiyosue Y, Furuse M, Tsukita S (2003) Dynamic behavior of paired claudin strands within apposing plasma membranes. Proc Natl Acad Sci U S A 100:3971–6

    Article  PubMed  CAS  Google Scholar 

  144. Sato TN, Tozawa Y, Deutsch U, Wolburg-Buchholz K, Fujiwara Y, Gendron-Maguire M, Gridley T, Wolburg H, Risau W, Qin Y (1995) Distinct roles of the receptor tyrosine kinases Tie-1 and Tie-2 in blood vessel formation. Nature 376:70–4

    Article  PubMed  CAS  Google Scholar 

  145. Schinkel AH, Smit JJ, van Tellingen O, Beijnen JH, Wagenaar E, van Deemter L, Mol CA, van der Valk MA, Robanus-Maandag EC, te Riele HP, et al. (1994) Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs. Cell 77:491–502

    Article  PubMed  CAS  Google Scholar 

  146. Schinkel AH, Wagenaar E, Mol CA, van Deemter L (1996) P-glycoprotein in the blood-brain barrier of mice influences the brain penetration and pharmacological activity of many drugs. J Clin Invest 97:2517–24

    Article  PubMed  CAS  Google Scholar 

  147. Schlingemann RO, van Hinsbergh VW (1997) Role of vascular permeability factor/vascular endothelial growth factor in eye disease. Br J Ophthalmol 81:501–12

    Article  PubMed  CAS  Google Scholar 

  148. Schulzke JD, Gitter AH, Mankertz J, Spiegel S, Seidler U, Amasheh S, Saitou M, Tsukita S, Fromm M (2005) Epithelial transport and barrier function in occludin-deficient mice. Biochim Biophys Acta 1669:34–42

    Article  PubMed  CAS  Google Scholar 

  149. Sedlakova R, Shivers RR, Del Maestro RF (1999) Ultrastructure of the blood-brain barrier in the rabbit. J Submicrosc Cytol Pathol 31:149–61

    PubMed  CAS  Google Scholar 

  150. Senger DR, Perruzzi CA, Feder J, Dvorak HF (1986) A highly conserved vascular permeability factor secreted by a variety of human and rodent tumor cell lines. Cancer Res 46:5629–32

    PubMed  CAS  Google Scholar 

  151. Shin K, Straight S, Margolis B (2005) PATJ regulates tight junction formation and polarity in mammalian epithelial cells. J Cell Biol 168:705–11

    Article  PubMed  CAS  Google Scholar 

  152. Shinoda K, Ishida S, Kawashima S, Wakabayashi T, Matsuzaki T, Takayama M, Shinmura K, Yamada M(1999) Comparison of the levels of hepatocyte growth factor and vascular endothelial growth factor in aqueous fluid and serum with grades of retinopathy in patients with diabetes mellitus. Br J Ophthalmol 83:834–7

    PubMed  CAS  Google Scholar 

  153. Stamer WD, Bok D, Hu J, Jaffe GJ, McKay BS (2003) Aquaporin-1 channels in human retinal pigment epithelium: role in transepithelial water movement. Invest Ophthalmol Vis Sci 44:2803–8

    Article  PubMed  Google Scholar 

  154. 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 103:755–66

    Article  PubMed  CAS  Google Scholar 

  155. Stewart PA, Hayakawa K (1994) Early ultrastructural changes in blood-brain barrier vessels of the rat embryo. Brain Res Dev Brain Res 78:25–34

    Article  PubMed  CAS  Google Scholar 

  156. Stitt A, Gardiner TA, Alderson NL, Canning P, Frizzell N, Duffy N, Boyle C, Januszewski AS, Chachich M, Baynes JW, Thorpe SR (2002) The AGE inhibitor pyridoxamine inhibits development of retinopathy in experimental diabetes. Diabetes 51:2826–32

    Article  PubMed  CAS  Google Scholar 

  157. Stitt AW (2003) The role of advanced glycation in the pathogenesis of diabetic retinopathy. Exp Mol Pathol 75:95–108

    Article  PubMed  CAS  Google Scholar 

  158. Strauss O (2005) The retinal pigment epithelium in visual function. Physiol Rev 85:845–81

    Article  PubMed  CAS  Google Scholar 

  159. Suri C, Jones PF, Patan S, Bartunkova S, Maisonpierre PC, Davis S, Sato TN, Yancopoulos GD (1996) Requisite role of angiopoietin-1, a ligand for the TIE2 receptor, during embryonic angiogenesis. Cell 87:1171–80

    Article  PubMed  CAS  Google Scholar 

  160. Suzuki A, Ishiyama C, Hashiba K, Shimizu M, Ebnet K, Ohno S (2002) aPKC kinase activity is required for the asymmetric differentiation of the premature junctional complex during epithelial cell polarization. J Cell Sci 115:3565–73

    Article  PubMed  CAS  Google Scholar 

  161. Suzuki A, Yamanaka T, Hirose T, Manabe N, Mizuno K, Shimizu M, Akimoto K, Izumi Y, Ohnishi T, Ohno S (2001) Atypical protein kinase C is involved in the evolutionarily conserved par protein complex and plays a critical role in establishing epithelia-specific junctional structures. J Cell Biol 152:1183–96

    Article  PubMed  CAS  Google Scholar 

  162. Szkudelski T (2001) The mechanism of alloxan and streptozotocin action in B cells of the rat pancreas. Physiol Res 50:537–46

    PubMed  CAS  Google Scholar 

  163. Takagi C, Bursell SE, Lin YW, Takagi H, Duh E, Jiang Z, Clermont AC, King GL (1996) Regulation of retinal hemodynamics in diabetic rats by increased expression and action of endothelin-1. Invest Ophthalmol Vis Sci 37:2504–18

    PubMed  CAS  Google Scholar 

  164. Tavelin S, Hashimoto K, Malkinson J, Lazorova L, Toth I, Artursson P (2003) A new principle for tight junction modulation based on occludin peptides. Mol Pharmacol 64:1530–40

    Article  PubMed  CAS  Google Scholar 

  165. The Diabetes Control and Complications Trial Research Group (1993) The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 329:977–86

    Article  Google Scholar 

  166. The Diabetes Control and Complications Trial Research Group (1998) Early worsening of diabetic retinopathy in the Diabetes Control and Complications Trial. Arch Ophthalmol 116:874–86.

    Google Scholar 

  167. Turksen K, Troy TC (2004) Barriers built on claudins. J Cell Sci 117:2435–47

    Article  PubMed  CAS  Google Scholar 

  168. Uemura A, Ogawa M, Hirashima M, Fujiwara T, Koyama S, Takagi H, Honda Y, Wiegand SJ, Yancopoulos GD, Nishikawa S (2002) Recombinant angiopoietin-1 restores highe-order architecture of growing blood vessels in mice in the absence of mural cells. J Clin Invest 110:1619–28

    PubMed  CAS  Google Scholar 

  169. Umeda K, Matsui T, Nakayama M, Furuse K, Sasaki H, Furuse M, Tsukita S (2004) Establishment and characterization of cultured epithelial cells lacking expression of ZO-1. J Biol Chem 279:44785–94

    Article  PubMed  CAS  Google Scholar 

  170. Van Itallie CM, Anderson JM (1997) Occludin confers adhesiveness when expressed in fibroblasts. J Cell Sci 110(9):1113–21

    PubMed  Google Scholar 

  171. Van Itallie CM, Fanning AS, Anderson JM (2003) Reversal of charge selectivity in cation or anion-selective epithelial lines by expression of different claudins. Am J Physiol Renal Physiol 285:F1078–84

    PubMed  Google Scholar 

  172. Vialettes B, Silvestre-Aillaud P, Atlan-Gepner C (1994) [Outlook for the future in the treatment of diabetic retinopathy]. Diabetes Metab 20:229–34

    CAS  Google Scholar 

  173. Vietor I, Bader T, Paiha K, Huber LA (2001) Perturbation of the tight junction permeability barrier by occludin loop peptides activates beta-catenin/TCF/LEF-mediated transcription. EMBO Rep 2:306–12

    Article  PubMed  CAS  Google Scholar 

  174. Vincent AM, Brownlee M, Russell JW (2002) Oxidative stress and programmed cell death in diabetic neuropathy. Ann N Y Acad Sci 959:368–83

    Article  PubMed  CAS  Google Scholar 

  175. Vinores SA, McGehee R, Lee A, Gadegbeku C, Campochiaro PA (1990) Ultrastructural localization of blood-retinal barrier breakdown in diabetic and galactosemic rats. J Histochem Cytochem 38:1341–52

    PubMed  CAS  Google Scholar 

  176. Vitale S, Maguire MG, Murphy RP, Hiner CJ, Rourke L, Sackett C, Patz A (1995) Clinically significant macular edema in type I diabetes. Incidence and risk factors. Ophthalmology 102:1170–6

    PubMed  CAS  Google Scholar 

  177. 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 42:221–42

    Article  PubMed  CAS  Google Scholar 

  178. Walsh SV, Hopkins AM, Nusrat A (2000) Modulation of tight junction structure and function by cytokines. Adv Drug Deliv Rev 41:303–13

    Article  PubMed  CAS  Google Scholar 

  179. 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:H434–40

    PubMed  CAS  Google Scholar 

  180. 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 24:4412–20

    Article  PubMed  CAS  Google Scholar 

  181. Wen H, Watry DD, Marcondes MC, Fox HS (2004) Selective decrease in paracellular conductance of tight junctions: role of the first extracellular domain of claudin-5. Mol Cell Biol 24:8408–17

    Article  PubMed  CAS  Google Scholar 

  182. Wilcox ER, Burton QL, Naz S, Riazuddin S, Smith TN, Ploplis B, Belyantseva I, Ben-Yosef T, Liburd NA, Morell RJ, Kachar B, Wu DK, Griffith AJ, Riazuddin S, Friedman TB (2001) Mutations in the gene encoding tight junction claudin-14 cause autosomal recessive deafness DFNB29. Cell 104:165–72

    Article  PubMed  CAS  Google Scholar 

  183. Williams CD, Rizzolo LJ (1997) Remodeling of junctional complexes during the development of the outer blood-retinal barrier. Anat Rec 249:380–8

    Article  PubMed  CAS  Google Scholar 

  184. Wittchen ES, Haskins J, Stevenson BR (1999) Protein interactions at the tight junction. Actin has multiple binding partners, and ZO-1 forms independent complexes with ZO-2 and ZO-3. J Biol Chem 274:35179–85

    Article  PubMed  CAS  Google Scholar 

  185. Wolburg H, Lippoldt A (2002) Tight junctions of the blood-brain barrier: development, composition and regulation. Vascul Pharmacol 38:323–37

    Article  PubMed  CAS  Google Scholar 

  186. 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) 105:586–92

    CAS  Google Scholar 

  187. Wolburg H, Wolburg-Buchholz K, Liebner S, Engelhardt B (2001) Claudin-1, claudin-2 and claudin-11 are present in tight junctions of choroid plexus epithelium of the mouse. Neurosci Lett 307:77–80

    Article  PubMed  CAS  Google Scholar 

  188. Wong V, Gumbiner BM (1997) A synthetic peptide corresponding to the extracellular domain of occludin perturbs the tight junction permeability barrier. J Cell Biol 136:399–409

    Article  PubMed  CAS  Google Scholar 

  189. Wu X, Zhao X, Baylor L, Kaushal S, Eisenberg E, Greene LE (2001) Clathrin exchange during clathrin-mediated endocytosis. J Cell Biol 155:291–300

    Article  PubMed  CAS  Google Scholar 

  190. Xu Q, Qaum T, Adamis AP (2001) Sensitive blood-retinal barrier breakdown quantitation using Evans blue. Invest Ophthalmol Vis Sci 42:789–94

    PubMed  CAS  Google Scholar 

  191. 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 139:785–95

    Article  PubMed  CAS  Google Scholar 

  192. Yamanaka T, Horikoshi Y, Suzuki A, Sugiyama Y, Kitamura K, Maniwa R, Nagai Y, Yamashita A, Hirose T, Ishikawa H, Ohno S (2001) PAR-6 regulates aPKC activity in a novel way and mediates cell-cell contact-induced formation of the epithelial junctional complex. Genes Cells 6:721–31

    Article  PubMed  CAS  Google Scholar 

  193. Yokota T, Ma RC, Park JY, Isshiki K, Sotiropoulos KB, Rauniyar RK, Bornfeldt KE, King GL (2003) Role of protein kinase C on the expression of platelet-derived growth factor and endothelin-1 in the retina of diabetic rats and cultured retinal capillary pericytes. Diabetes 52:838–45

    Article  PubMed  CAS  Google Scholar 

  194. Yoon H, Fanelli A, Grollman EF, Philp NJ (1997) Identification of a unique monocarboxylate transporter (MCT3) in retinal pigment epithelium. Biochem Biophys Res Commun 234:90–4

    Article  PubMed  CAS  Google Scholar 

  195. Yu AS, McCarthy KM, Francis SA, McCormack JM, Lai J, Rogers RA, Lynch RD, Schneeberger EE (2005) Knock-down of occludin expression leads to diverse phenotypic alterations in epithelial cells. Am J Physiol Cell Physiol 288:C1231–41

    Article  PubMed  CAS  Google Scholar 

  196. Zettl KS, Sjaastad MD, Riskin PM, Parry G, Machen TE, Firestone GL (1992) Glucocorticoid-induced formation of tight junctions in mouse mammary epithelial cells in vitro. Proc Natl Acad Sci U S A 89:9069–73

    Article  PubMed  CAS  Google Scholar 

References

  1. Aiello LP (2002) The potential role of PKC beta in diabetic retinopathy and macular edema. Surv Ophthalmol 47Suppl 2:S263–S269

    Article  PubMed  Google Scholar 

  2. Aiello LP, Bursell SE, Clermont A, Duh E, Ishii H, Takagi C, et al. (1997) Vascular endothelial growth factor-induced retinal permeability ismediated by protein kinase C in vivo and suppressed by an orally effective beta-isoform-selective inhibitor. Diabetes 46(9):1473–1480

    Article  PubMed  CAS  Google Scholar 

  3. Alikacem N, Yoshizawa T, Nelson KD, Wilson CA (2000) Quantitative MR imaging study of intravitreal sustained release of VEGF in rabbits. Invest Ophthalmol Vis Sci 41(6):1561–1569

    PubMed  CAS  Google Scholar 

  4. Ando N, Sen HA, Berkowitz BA, Wilson CA, de Juan E, Jr (1994) Localization and quantitation of blood-retinal barrier breakdown in experimental proliferative vitreoretinopathy. Arch Ophthalmol 112(1):117–122

    PubMed  CAS  Google Scholar 

  5. 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. Penn State Retina Research Group. Diabetes 47(12):1953–1959

    Article  PubMed  CAS  Google Scholar 

  6. Barber AJ, Lieth E, Khin SA, Antonetti DA, Buchanan AG, Gardner TW (1998) Neural apoptosis in the retina during experimental and human diabetes. Early onset and effect of insulin. J Clin Invest 102(4):783–791

    Article  PubMed  CAS  Google Scholar 

  7. Berkowitz BA, Roberts R, Luan H, Peysakhov J, Mao X, Thomas KA (2004) Dynamic contrast-enhanced MRI measurements of passive permeability through blood retinal barrier in diabetic rats. Invest Ophthalmol Vis Sci 45(7):2391–2398

    Article  PubMed  Google Scholar 

  8. Berkowitz BA, Sato Y, Wilson CA, de Juan E (1991) Blood-retinal barrier breakdown investigated by real-time magnetic resonance imaging after gadolinium-diethylenetria-minepentaacetic acid injection. Invest Ophthalmol Vis Sci 32(11):2854–2860

    PubMed  CAS  Google Scholar 

  9. Berkowitz BA, Tofts PS, Sen HA, Ando N, de Juan E, Jr (1992) Accurate and precise measurement of blood-retinal barrier breakdown using dynamic Gd-DTPA MRI. Invest Ophthalmol Vis Sci 33(13):3500–3506

    PubMed  CAS  Google Scholar 

  10. Berkowitz BA, Wilson CA, Tofts PS, Peshock RM (1994) Effect of vitreous fluidity on the measurement of blood-retinal barrier permeability using contrast-enhanced MRI. Magn Reson Med 31(1):61–66

    Article  PubMed  CAS  Google Scholar 

  11. Caspers-Velu LE, Wadhwani KC, Rapoport SI, Kador PF (1995) Permeability of the blood-retinal and blood-aqueous barriers in galactose-fed rats. J Ocul Pharmacol Ther 11(3):469–487

    PubMed  CAS  Google Scholar 

  12. Cunha-Vaz JG (2004) The blood-retinal barriers system. Basic concepts and clinical evaluation. Exp Eye Res 78(3):715–721

    Article  PubMed  CAS  Google Scholar 

  13. Cunningham SA, Stephan CC, Arrate MP, Ayer KG, Brock TA (1997) Identification of the extracellular domains of Flt-1 that mediate ligand interactions. Biochem Biophys Res Commun 231(3):596–599

    Article  PubMed  CAS  Google Scholar 

  14. Cunningham SA, Tran TM, Arrate MP, Brock TA (1999) Characterization of vascular endothelial cell growth factor interactions with the kinase insert domain-containing receptor tyrosine kinase. A real time kinetic study. J Biol Chem 274(26):18421–18427

    Article  PubMed  CAS  Google Scholar 

  15. Dallal MM, Chang SW (1994) Evans blue dye in the assessment of permeability-surface area product in perfused rat lungs. J Appl Physiol 77(2):1030–1035

    PubMed  CAS  Google Scholar 

  16. Derevjanik NL, Vinores SA, Xiao WH, Mori K, Turon T, Hudish T, et al. (2002) Quantitative assessment of the integrity of the blood-retinal barrier in mice. Invest Ophthalmol Vis Sci 43(7):2462–2467

    PubMed  Google Scholar 

  17. DiMattio J (1991) In vivo use of neutral radiolabelled molecular probes to evaluate blood-ocular barrier integrity in normal and streptozotocin-diabetic rats. Diabetologia 34(12):862–867

    Article  PubMed  CAS  Google Scholar 

  18. Enea NA, Hollis TM, Kern JA, Gardner TW (1989) Histamine H1 receptors mediate increased blood-retinal barrier permeability in experimental diabetes. Arch Ophthalmol 107(2):270–274

    PubMed  CAS  Google Scholar 

  19. Ennis SR (1990) Permeability of the blood-ocular barrier to mannitol and PAH during experimental diabetes. Curr Eye Res 9(9):827–838

    Article  PubMed  CAS  Google Scholar 

  20. Ennis SR, Betz AL (1986) Sucrose permeability of the blood-retinal and blood-brain barriers. Effects of diabetes, hypertonicity, and iodate. Invest Ophthalmol Vis Sci 27(7):1095–1102

    PubMed  CAS  Google Scholar 

  21. Ferris FL, III, Patz A (1984) Macular edema. A complication of diabetic retinopathy. Surv Ophthalmol 28 Suppl:452–461

    Article  PubMed  Google Scholar 

  22. Frank JA, Dwyer AJ, Girton M, Knop RH, Sank VJ, Gansow OA, et al. (1986) Opening of blood-ocular barrier demonstrated by contrast-enhanced MR imaging. J Comput Assist Tomogr 10(6):912–916

    Article  PubMed  CAS  Google Scholar 

  23. Funatsu H, Wilson CA, Berkowitz BA, Sonkin PL (1997) A comparative study of the effects of argon and diode laser photocoagulation on retinal oxygenation. Graefes Arch Clin Exp Ophthalmol 235(3):168–175

    Article  PubMed  CAS  Google Scholar 

  24. Garner WH, Scheib S, Berkowitz BA, Suzuki M, Wilson CA, Graff G (2001) The effect of partial vitrectomy on blood-ocular barrier function in the rabbit. Curr Eye Res 23(5):372–381

    Article  PubMed  CAS  Google Scholar 

  25. Grimes PA (1985) Fluorescein distribution in retinas of normal and diabetic rats. Exp Eye Res 41(2):227–238

    Article  PubMed  CAS  Google Scholar 

  26. Grimes PA (1988) Carboxyfluorescein distribution in ocular tissues of normal and diabetic rats. Curr Eye Res 7(10):981–988

    Article  PubMed  CAS  Google Scholar 

  27. Jones CW, Cunha-Vaz JG, Rusin MM (1982) Vitreous fluorophotometry in the alloxan-and streptozocin-treated rat. Arch Ophthalmol 100(7):1141–1145

    PubMed  CAS  Google Scholar 

  28. Kent D, Vinores SA, Campochiaro PA (2000) Macular oedema: the role of soluble mediators. Br J Ophthalmol 84(5):542–545

    Article  PubMed  CAS  Google Scholar 

  29. Kirber WM, Nichols CW, Grimes PA, Winegrad AI, Laties AM (1980) A permeability defect of the retinal pigment epithelium. Occurrence in early streptozocin diabetes. Arch Ophthalmol 98(4):725–728

    PubMed  CAS  Google Scholar 

  30. Lightman S, Pinter G, Yuen L, Bradbury M (1990) Permeability changes at blood-retinal barrier in diabetes and effect of aldose reductase inhibition. Am J Physiol 259:R601–R605

    PubMed  CAS  Google Scholar 

  31. Lightman S, Rechthand E, Terubayashi H, Palestine A, Rapaport S, Kador P (1987) Permeability changes in blood-retinal barrier of galactosemic rats are prevented by aldose reductase inhibitors. Diabetes 36:1271–1275

    Article  PubMed  CAS  Google Scholar 

  32. Lobo C, Bernardes R, Faria dA, Jr, Cunha-Vaz JG (1999) Novel imaging techniques for diabetic macular edema. Doc Ophthalmol 97(3–4):341–347

    Article  PubMed  CAS  Google Scholar 

  33. Luan H, Roberts R, Sniegowski M, Goebel DJ, Berkowitz BA (2006) Retinal thickness and subnormal retinal oxygenation response in experimental diabetic retinopathy. Invest Ophthalmol Vis Sci 47(1):320–8

    Article  PubMed  Google Scholar 

  34. Lukaszew RA, Mullins CM, Penn JS, Berkowitz BA (1997) Noninvasive and quantitative staging of hyaloidopathy in experimental retinopathy of prematurity. Invest Ophthalmol Vis Sci 38(4):S747

    Google Scholar 

  35. Lund-Andersen H (2002) Mechanisms for monitoring changes in retinal status following therapeutic intervention in diabetic retinopathy. Surv Ophthalmol 47Suppl 2:S270–S277

    Article  PubMed  Google Scholar 

  36. Maepea O, Karlsson C, Alm A (1984) Blood-ocular and blood-brain barrier function in streptozocin-induced diabetes in rats. Arch Ophthalmol 102(9):1366–1369

    PubMed  CAS  Google Scholar 

  37. Marmor MF (1999) Mechanisms of fluid accumulation in retinal edema. Doc Ophthalmol 97(3–4):239–249

    Article  PubMed  CAS  Google Scholar 

  38. Martin PM, Roon P, Van Ells TK, Ganapathy V, Smith SB (2004) Death of retinal neurons in streptozotocin-induced diabetic mice. Invest Ophthalmol Vis Sci 45(9):3330–3336

    Article  PubMed  Google Scholar 

  39. Mathews MK, Merges C, McLeod DS, Lutty GA (1997) Vascular endothelial growth factor and vascular permeability changes in human diabetic retinopathy. Invest Ophthalmol Vis Sci 38(13):2729–2741

    PubMed  CAS  Google Scholar 

  40. Mayhan WG (2001) Regulation of blood-brain barrier permeability. Microcirculation 8(2):89–104

    Article  PubMed  CAS  Google Scholar 

  41. Menzies SA, Hoff JT, Betz AL (1990) Extravasation of albumin in ischaemic brain oedema. Acta Neurochir Suppl (Wien) 51:220–222

    CAS  Google Scholar 

  42. Metrikin DC, Wilson CA, Berkowitz BA, Lam MK, Wood GK, Peshock RM (1995) Measurement of blood-retinal barrier breakdown in endotoxin-induced endophthalmitis. Invest Ophthalmol Vis Sci 36(7):1361–1370

    PubMed  CAS  Google Scholar 

  43. Murata T, Ishibashi T, Khalil A, Hata Y, Yoshikawa H, Inomata H (1995) Vascular endothelial growth factor plays a role in hyperpermeability of diabetic retinal vessels. Ophthalmic Res 27(1):48–52

    Article  PubMed  CAS  Google Scholar 

  44. Murata T, Nakagawa K, Khalil A, Ishibashi T, Inomata H, Sueishi K (1996) The relation between expression of vascular endothelial growth factor and breakdown of the blood-retinal barrier in diabetic rat retinas. Lab Invest 74(4):819–825

    PubMed  CAS  Google Scholar 

  45. Nagy Z, Szabo M, Huttner I (1985) Blood-brain barrier impairment by low pH buffer perfusion via the internal carotid artery in rat. Acta Neuropathol (Berl) 68(2):160–163

    Article  CAS  Google Scholar 

  46. Park SH, Park JW, Park SJ, Kim KY, Chung JW, Chun MH, et al. (2003) Apoptotic death of photoreceptors in the streptozotocin-induced diabetic rat retina. Diabetologia 46(9):1260–1268

    Article  PubMed  Google Scholar 

  47. Pelc NJ (1993) Optimization of flip angle for T1 dependent contrast in MRI. Magn Reson Med 29(5):695–699

    Article  PubMed  CAS  Google Scholar 

  48. Plehwe WE, McRobbie DW, Lerski RA, Kohner EM (1988) Quantitative magnetic resonance imaging in assessment of the blood-retinal barrier. Invest Ophthalmol Vis Sci 29(5):663–670

    PubMed  CAS  Google Scholar 

  49. Prager TC, Chu HH, Garcia CA, Anderson RE (1982) The influence of vitreous change on vitreous fluorophotometry. Arch Ophthalmol 100(4):594–596

    PubMed  CAS  Google Scholar 

  50. Prager TC, Chu HH, Garcia CA, Anderson RE, Field JB, Orzeck EA, et al. (1983) The use of vitreous fluorophotometry to distinguish between diabetics with and without observable retinopathy: effect of vitreous abnormalities on the measurement. Invest Ophthalmol Vis Sci 24(1):57–65

    PubMed  CAS  Google Scholar 

  51. Prager TC, Wilson DJ, Avery GD, Merritt JH, Garcia CA, Hopen G, et al. (1981) Vitreous fluorophotometry: identification of sources of variability. Invest Ophthalmol Vis Sci 21(6):854–864

    PubMed  CAS  Google Scholar 

  52. Qaum T, Xu Q, Joussen AM, Clemens MW, Qin W, Miyamoto K, et al. (2001) VEGF-initiated blood retinal barrier breakdown in early diabetes. Invest Ophthalmol Vis Sci 42(10):2408–2413

    PubMed  CAS  Google Scholar 

  53. Runge VM, Clanton JA, Lukehart CM, Partain CL, James AE, Jr (1983) Paramagnetic agents for contrast-enhanced NMR imaging: a review. AJR Am J Roentgenol 141(6):1209–1215

    PubMed  CAS  Google Scholar 

  54. Runge VM, Clanton JA, Price AC, Wehr CJ, Herzer WA, Partain CL, et al. (1985) The use of Gd DTPA as a perfusion agent and marker of blood-brain barrier disruption. Magn Reson Imaging 3(1):43–55

    Article  PubMed  CAS  Google Scholar 

  55. Sander B, Larsen M, Engler C, Moldow B, Lund-Andersen H (2002) Diabetic macular oedema: the effect of photocoagulation on fluorescein transport across the blood-retinal barrier. Br J Ophthalmol 86(10):1139–1142

    Article  PubMed  CAS  Google Scholar 

  56. Sander B, Larsen M, Engler C, Strom C, Moldow B, Larsen N, et al. (2002) Diabetic macular oedema: a comparison of vitreous fluorometry, angiography, and retinopathy. Br J Ophthalmol 86(3):316–320

    Article  PubMed  CAS  Google Scholar 

  57. Sander B, Larsen M, Moldow B, Lund-Andersen H (2001) Diabetic macular edema: passive and active transport of fluorescein through the blood-retina barrier. Invest Ophthalmol Vis Sci 42(2):433–438

    PubMed  CAS  Google Scholar 

  58. Sato Y, Berkowitz BA, Wilson CA, de Juan E, Jr (1992) Blood-retinal barrier breakdown caused by diode vs argon laser endophotocoagulation. Arch Ophthalmol 110(2):277–281

    PubMed  CAS  Google Scholar 

  59. Schmiedl U, Ogan MD, Moseley ME, Brasch RC (1986) Comparison of the contrast-enhancing properties of albumin-(Gd-DTPA) and Gd-DTPA at 2.0 T: and experimental study in rats. AJR Am J Roentgenol 147(6):1263–1270

    PubMed  CAS  Google Scholar 

  60. Sen HA, Berkowitz BA, Ando N, de Juan E, Jr (1992) In vivo imaging of breakdown of the inner and outer blood-retinal barriers. Invest Ophthalmol Vis Sci 33(13):3507–3512

    PubMed  CAS  Google Scholar 

  61. Tofts PS, Berkowitz BA (1993) Rapid measurement of capillary permeability using the early part of the dynamic Gd-DTPA MRI enhancement curve. J Magn Reson Series B 102:129–136

    Article  CAS  Google Scholar 

  62. Tofts PS, Berkowitz BA (1994) Measurement of capillary permeability from the Gd enhancement curve: a comparison of bolus and constant infusion injection methods. Magn Reson Imaging 12(1):81–91

    Article  PubMed  CAS  Google Scholar 

  63. Tornquist P, Alm A, Bill A (1990) Permeability of ocular vessels and transport across the blood-retinal-barrier. Eye 4(2):303–309

    PubMed  Google Scholar 

  64. Trick GL, Liggett J, Levy J, Adamsons I, Edwards P, Desai U, et al. (2005) Dynamic contrast enhanced MRI in patients with diabetic macular edema: initial results. Exp Eye Res 81(1):97–102

    Article  PubMed  CAS  Google Scholar 

  65. Vinores SA, Derevjanik NL, Mahlow J, Berkowitz BA, Wilson CA (1998) Electron microscopic evidence for the mechanism of blood-retinal barrier breakdown in diabetic rabbits: comparison with magnetic resonance imaging. Pathol Res Pract 194(7):497–505

    PubMed  CAS  Google Scholar 

  66. Vinores SA, McGehee R, Lee A, Gadegbeku C, Campochiaro PA (1990) Ultrastructural localization of blood-retinal barrier breakdown in diabetic and galactosemic rats. J Histochem Cytochem 38(9):1341–1352

    PubMed  CAS  Google Scholar 

  67. Vinores SA, Van Niel E, Swerdloff JL, Campochiaro PA (1993) Electron microscopic immunocytochemical evidence for the mechanism of blood-retinal barrier breakdown in galactosemic rats and its association with aldose reductase expression and inhibition. Exp Eye Res 57(6):723–735

    Article  PubMed  CAS  Google Scholar 

  68. Wallow IH (1983) Posterior and anterior permeability defects? Morphologic observations on streptozotocintreated rats. Invest Ophthalmol Vis Sci 24(9):1259–1268

    PubMed  CAS  Google Scholar 

  69. Wilson CA, Berkowitz BA, Funatsu H, Metrikin DC, Harrison DW, Lam MK, et al. (1995) Blood-retinal barrier breakdown following experimental retinal ischemia and reperfusion. Exp Eye Res 61(5):547–557

    Article  PubMed  CAS  Google Scholar 

  70. Wilson CA, Berkowitz BA, Sato Y, Ando N, Handa JT, de Juan E, Jr (1992) Treatment with intravitreal steroid reduces blood-retinal barrier breakdown due to retinal photocoagulation. Arch Ophthalmol 110(8):1155–1159

    PubMed  CAS  Google Scholar 

  71. Wilson CA, Fleckenstein JL, Berkowitz BA, Green ME (1992) Preretinal neovascularization in diabetic retinopathy: a preliminary investigation using contrast-enhanced magnetic resonance imaging. J Diabetes Complications 6(4):223–229

    Article  PubMed  CAS  Google Scholar 

  72. Xu Q, Qaum T, Adamis AP (2001) Sensitive blood-retinal barrier breakdown quantitation using Evans blue. Invest Ophthalmol Vis Sci 42(3):789–794

    PubMed  CAS  Google Scholar 

  73. Yi-Ming W, Shu H, Miao CY, Shen FM, Jiang YY, Su DF (2004) Asynchronism of the recovery of baroreflex sensitivity, blood pressure, and consciousness from anesthesia in rats. J Cardiovasc Pharmacol 43(1):1–7

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Cellular & Molecular Physiology, Penn State College of Medicine, 500 University Drive, Hershey, PA, 17033, USA

    Brett E. Phillips PhD & David A. Antonetti PhD

  2. Department of Anatomy and Cell Biology/Department of Ophthalmology, Wayne State University School of Medicine, 540 E. Canfield, Detroit, MI, 48201, USA

    Bruce A. Berkowitz PhD

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  2. David A. Antonetti PhD
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Editors and Affiliations

  1. Department of Ophthalmology, University of Düsseldorf, Moorenstraße 5, 40225, Düsseldorf, Germany

    Antonia M. Joussen MD, PhD (Professor of Ophthalmology) (Professor of Ophthalmology)

  2. Department of Ophthalmology, Penn State College of Medicine, 500 University, Drive Box 850, Hershey, PA, 17033, USA

    Thomas W. Gardner MD, MS (Professor of Ophthalmology) (Professor of Ophthalmology)

  3. Department of Vitreoretinal Surgery, Center for Ophthalmology, University of Cologne, Joseph-Stelzmann-Straße 9, 50931, Cologne, Germany

    Bernd Kirchhof MD (Professor of Ophthalmology) (Professor of Ophthalmology)

  4. Doheny Eye Institute, University of Southern California, 1450 San Pablo Street, Los Angeles, CA, 90033, USA

    Stephen J. Ryan MD (Professor of Ophthalmology) (Professor of Ophthalmology)

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Phillips, B.E., Antonetti, D.A., Berkowitz, B.A. (2007). Blood Retinal Barrier. In: Joussen, A.M., Gardner, T.W., Kirchhof, B., Ryan, S.J. (eds) Retinal Vascular Disease. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-29542-6_8

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