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Cellular mechanisms of blood-retinal barrier dysfunction in macular edema

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Abstract

Purpose: To determine the mechanism of blood-retinal barrier (BRB) dysfunction in human and experimental specimens using immunocytochemistry. Methods: Extravascular albumin was localized in clinical specimens and retinas from transgenic mice that overexpress vascular endothelial growth factor (VEGF) in the photoreceptors. Transgenic mouse retinas were also labeled with Griffonia simplicifolia isolectin-B4 (GSA), a lectin that binds to endothelial cells. Results: The BRB is established by the presence of tight junctions between the retinal vascular endothelial (RVE) cells and the RPE cells and by a paucity of intraendothelial cell vesicles. When BRB breakdown occurs in human ocular disorders such as diabetic retinopathy, retinitis pigmentosa, or cystoid macular edema, staining for extravascular albumin reveals leakage through the tight junctions, an upregulation of intraendothelial vesicles, and permeation of RVE or RPE cells that have undergone degenerative changes. VEGF, in addition to inducing neovascularization (NV), promotes vascular leakage. In VEGF transgenic mice, BRB failure is confined to the outer retina, the area where NV occurs. GSA binds to the luminal and abluminal surfaces of RVE cells in new and established vessels and to intraendothelial vesicles and interendothelial cell junctions in areas of vascular leakage. Conclusion: BRB dysfunction may be mediated by leakage through the tight junctions of RVE or RPE cells, by trans-endothelial vesicular transport, or by permeation of RVE or RPE cells that have undergone degenerative changes. GSA may be a useful marker to assist in recognizing open tight junctions and an increase in intraendothelial cell vesicles, which are indicative of BRB failure.

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References

  1. Patz A, Schaltz H, Berkow JW, GittelsohmAM, Ticho U.Macular edema: an overlooked complication of diabetic retinopathy. Am Acad Ophthalmol Otolaryngol 1973; 77: 34-42.

    Google Scholar 

  2. Cunha-Vaz JG. The blood-retinal barriers. Doc Ophthalmol 1976; 41: 287-327.

    Article  PubMed  CAS  Google Scholar 

  3. Eagle RC Jr. Mechanisms of maculopathy. Ophthalmology 1984; 91: 613-25.

    PubMed  Google Scholar 

  4. Vinores SA. Assessment of blood-retinal barrier integrity. Histol Histopath 1995; 10: 141-54.

    CAS  Google Scholar 

  5. Rizzolo LJ. Polarity and the development of the outer blood-retinal barrier. Histol Histopathol 1997; 12: 1057-67.

    PubMed  CAS  Google Scholar 

  6. Vinores SA, Derevjanik NL, Mahlow J, Berkowitz BA, Wilson CA. Electron microscopic evidence for the mechanism of blood-retinal barrier breakdown in diabetic rabbits: Comparison with magnetic resonance imaging. Path Res Pract 1998; 194: 497-505.

    PubMed  CAS  Google Scholar 

  7. Vinores SA, Gadegbeku C, Campochiaro PA, Green WR. Immunohistochemical localization of blood-retinal barrier breakdown in human diabetics. Am J Path 1989; 134: 231-5.

    PubMed  CAS  Google Scholar 

  8. Vinores SA, Campochiaro PA, Lee A, McGehee R, Gadegbeku C, Green WR. Localization of blood-retinal barrier breakdown in human pathologic specimens by immunohistochemical staining for albumin. Lab Invest 1990; 62: 742-50.

    PubMed  CAS  Google Scholar 

  9. Vinores SA, Amin A, Derevjanik NL, Green WR, Campochiaro PA. Immunohistochemical localization of blood-retinal barrier breakdown sites associated with post-surgical macular edema. Histochem J 1994; 26: 655-65.

    Article  PubMed  CAS  Google Scholar 

  10. Vinores SA, Küchle M, Mahlow J, Chiu C, Green WR, Campochiaro PA. Bloodocular barrier breakdown in eyes with ocular melanoma. A potential role for vascular endothelial growth factor/vascular permeability factor. Am J Pathol 1995; 147: 1289-97.

    PubMed  CAS  Google Scholar 

  11. Vinores SA, Küchle M, Derevjanik NL, Henderer JD, Mahlow J, Green WR, Campochiaro PA. Blood-retinal barrier breakdown in retinitis pigmentosa: light and electron microscopic immunolocalization. Histol Histopathol 1995; 10: 913-23.

    PubMed  CAS  Google Scholar 

  12. Vinores SA, Youssri AI, Luna JD, Chen Y-S, Bhargave S, Vinores MA, Schoenfeld C-L, Peng B, Chan C-C, LaRochelle W, Green WR, Campochiaro PA. Upregulation of vascular endothelial growth factor in ischemic and non-ischemic human and experimental retinal disease. Histol Histopathol 1997; 12: 99-109.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  14. Vinores SA, Van Niel E, Swerdloff JL, Campochiaro PA. 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 1993; 57: 723-35.

    Article  PubMed  CAS  Google Scholar 

  15. Luna JD, Chan C-C, Derevjanik NL, Mahlow J, Chiu C, Peng B, Tobe T, Campochiaro PA, Vinores SA. Blood-retinal barrier (BRB) breakdown in experimental autoimmune uveoretinitis: Comparison with vascular endothelial growth factor, tumor necrosis factor α, and interleukin-1ß-mediated breakdown. J Neurosci Res 1997; 49: 268-80.

    Article  PubMed  CAS  Google Scholar 

  16. Vinores SA, Sen H, Campochiaro PA. An adenosine agonist and prostaglandin E1 cause breakdown of the blood-retinal barrier by opening tight junctions between vascular endothelial cells. Invest Ophthalmol Vis Sci 1992; 33: 1870-8.

    PubMed  CAS  Google Scholar 

  17. Vinores SA, Van Niel E, Swerdloff JL, Campochiaro PA. Electron microscopic immunocytochemical demonstration of blood-retinal barrier breakdown in human diabetics and its association with aldose reductase in retinal vascular endothelium and retinal pigment epithelium. Histochem J 1993; 25: 648-63.

    Article  PubMed  CAS  Google Scholar 

  18. Mizutani M, Kern TS, Lorenzi M. Accelerated death of retinal microvascular cells in human and experimental diabetic retinopathy. J Clin Invest 1996; 97: 2883-90.

    Article  PubMed  CAS  Google Scholar 

  19. Ábrahám CS, Deli MA, Joó F, Megyeri P, Torpier G. Intracarotid tumor necrosis factor-α administration increases the blood-brain barrier permeability in cerebral cortex of the newborn pig: quantitative aspects of double-labelling studies and confocal laser scanning analysis. Neurosci Lett 1996; 208: 85-8.

    Article  PubMed  Google Scholar 

  20. Cuff CA, Martiney JA, Berman JW, Brosnan CF. Differential effects of transforming growth factor-ß-1 on interleukin-1-induced cellular inflammation and vascular permeability in the rabbit retina. J Neuroimmunol 1996; 70: 21-8.

    Article  PubMed  CAS  Google Scholar 

  21. Lutty GA, McLeod DS, Merges C, Diggs A, Plouét J. Localization of vascular endothelial growth factor in human retina and choroid. Arch Ophthalmol 1996; 114: 971-7.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  23. Pe'er J, Folberg R, Itin A, Gnessin H, Hemo I, Keshet E. Upregulated expression of vascular endothelial growth factor in proliferative diabetic retinopathy. Br J Ophthalmol 1996; 80: 241-5.

    PubMed  Google Scholar 

  24. Tolentino MJ, Miller JW, Gragoudas ES, Jakobiec FA, Flynn E, Chatzistefanou K, Ferrara N, Adamis AP. Intravitreous injections of vascular endothelial growth factor produce retinal ischemia and microangiopathy in an adult primate. Ophthalmology 1996; 103: 1820-8.

    PubMed  CAS  Google Scholar 

  25. Anthony DL, Bolton SJ, Fearn S, Perry VH. Age-related effects of interleukin-1ß on polymorphonuclear neutrophil-dependent increases in blood-brain barrier permeability in rats. Brain 1997; 120: 435-44.

    Article  PubMed  Google Scholar 

  26. Duchini A, Govindarajan S, Santucci M, Zampi M, Hofman FM. Effects of tumor necrosis factor-alpha and interleukin-6 on fluid-phase permeability and ammonia diffusion in CNS-derived endothelial cells. J Invest Med 1996; 44: 474-82.

    CAS  Google Scholar 

  27. Mathews MK, Merges C, McLeod DS, Lutty GA. Vascular endothelial growth factor and vascular permeability changes in human diabetic retinopathy. Invest Ophthalmol Vis Sci 1997; 38: 2729-41.

    PubMed  CAS  Google Scholar 

  28. Ozaki H, Hayashi H, Vinores SA, Moromizato Y, Campochiaro PA, Oshima K. Intravitreal sustained release of VEGF causes retinal neovascularization in rabbits and breakdown of the blood-retinal barrier in rabbits and primates. Exp Eye Res 1997; 64: 505-17.

    Article  PubMed  CAS  Google Scholar 

  29. Campochiaro PA, Sen HA. Adenosine and its agonists cause retinal vasodilation and hemorrhages: Implications for ischemic retinopathies. Arch Ophthalmol 1989; 107: 412-6.

    PubMed  CAS  Google Scholar 

  30. Jampel LM. Pharmacologic therapy of aphakic cystoid macular edema: A review. Ophthalmology 1982; 80: 891-7.

    Google Scholar 

  31. Sears ML. Aphakic cystoid macular edema: The pharmacology of ocular trauma. Surv Ophthalmol 1984; 28: 525-34.

    Article  PubMed  CAS  Google Scholar 

  32. Hangai M, Yoshimura N, Honda Y. Increased cytokine gene expression in rat retina following transient ischemia. Ophthalmic Res 1996; 28: 248-54.

    Article  PubMed  CAS  Google Scholar 

  33. Saito K, Suyama K, Nishida K, Sei Y, Basile AS. Early increases in TNF-α, IL-6 and IL-1ß levels following transient cerebral ischemia in gerbil brain. Neurosci Lett 1996; 206: 149-52.

    Article  PubMed  CAS  Google Scholar 

  34. Goldberg MA, Schneider TJ. Similarities between the oxygen-sensing mechanisms regulating the expression of vascular endothelial growth factor and erythropoietin. J Biol Chem 1994; 269: 4355-9.

    PubMed  CAS  Google Scholar 

  35. Minchenko A, Bauer T, Salceda S, Caro J. Hypoxic stimulation of vascular endothelial growth factor expression in vitro and in vivo. Lab Invest 1994; 71: 374-9.

    PubMed  CAS  Google Scholar 

  36. Hangai M, Yoshimura N, Yoshida M, Yabuuchi K, Honda Y. Interleukin-1 gene expression in transient retinal ischemia in the rat. Invest Ophthalmol Vis Sci 1995; 36: 571-8.

    PubMed  CAS  Google Scholar 

  37. Bamforth SD, Lightman SL, Greenwood J. Interleukin-1 beta-induced disruption of the retinal vascular barrier of the central nervous system is mediated through leukocyte recruitment and histamine. Am J Path 1997; 150: 329-40.

    PubMed  CAS  Google Scholar 

  38. Bamforth SD, Lightman SL, Greenwood J. Ultrastructural analysis of interleukin-1 betainduced leukocyte recruitment to the rat retina. Invest Ophthalmol Vis Sci 1997; 38: 25-35.

    PubMed  CAS  Google Scholar 

  39. Qu-Hong, Nagy JA, Senger DR, Dvorak HF, Dvorak AM. Ultrastructural localization of vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) to the albuminal plasma membrane and vesiculo-vacuolar organelles of tumor microvascular endothelium. J Histochem Cytochem 1995; 43: 381-93.

    PubMed  CAS  Google Scholar 

  40. Vinores SA, Chan C-C, Vinores MA, Matteson DM, Chen Y-S, Klein DA, Shi A, Ozaki H, Campochiaro PA. Increased vascular endothelial growth factor (VEGF) and transforming growth factor ß (TGFß) in experimental autoimmune uveoretinitis: Upregulation of VEGF without neovascularization. J Neuroimmunol 1998; 89: 43-50.

    Article  PubMed  CAS  Google Scholar 

  41. Clauss M, Weich H, Breier M, Knies U, Rockl W, Waltenberger J, Risau W. The vascular endothelial growth factor receptor Flt-1 mediates biological activities. Implications for a functional role of placenta growth factor in monocyte activation and chemotaxis. J Biol Chem 1996; 271: 17629-34.

    Article  PubMed  CAS  Google Scholar 

  42. Melder RJ, Koenig GC, Witwer BP, Safabakhsh N, Munn LL, Jain RK. During angiogenesis, vascular endothelial growth factor and basic fibroblast growth factor regulate natural killer cell adhesion to tumor endothelium. Nature Med 1996; 2: 992-7.

    Article  PubMed  CAS  Google Scholar 

  43. Melder RJ, Koenig GC, Munn LL, Jain RK. Adhesion of activated natural killer cells to tumor necrosis factor-alpha-treated endothelium under physiological flow conditions. Natural Immunity 1996-1997; 15: 154-63.

    PubMed  Google Scholar 

  44. Vinores SA, Shi A, Derevjanik NL, Whittum-Hudson JA, Campochiaro PA. Upregulation of VEGF and TGF-ß in experimental herpesvirus retinopathy. Invest Ophthalmol Vis Sci 1997; 38: S696.

    Google Scholar 

  45. Okamoto N, Tobe T, Hackett SF, Ozaki H, Vinores MA, LaRochelle W, Zack DJ, Campochiaro PA. Transgenic mice with increased expression of vascular endothelial growth factor in the retina. A new model of intraretinal and subretinal neovascularization. Am J Pathol 1997; 151: 281-91.

    PubMed  CAS  Google Scholar 

  46. Tobe T, Okamoto N, Vinores MA, Derevjanik NL, Vinores SA, Zack DJ, Campochiaro PA. Evolution of neovascularization in mice with overexpression of vascular endothelial growth factor in photoreceptors. Invest Ophthalmol Vis Sci 1998; 39: 180-8.

    PubMed  CAS  Google Scholar 

  47. Vinores SA, Herman MM, Perentes E, Nakagawa Y, Thomas CB, Innes DJ, Rubinstein LJ. The growth of two murine hemangioendotheliomas intracranially, subcutaneously, and in culture, and their comparison with human cerebellar hemangioblastomas: morphological and immunohistochemical studies. Acta Neuropathol 1992; 84: 67-77.

    Article  PubMed  CAS  Google Scholar 

  48. Vinores SA, Herman MM, Rubinstein LJ, Marangos PJ. Electron microscopic localization of neuron-specific enolase in rat and mouse brain. J Histochem Cytochem 1984; 32: 1295-302.

    PubMed  CAS  Google Scholar 

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Vinores, S.A., Derevjanik, N.L., Ozaki, H. et al. Cellular mechanisms of blood-retinal barrier dysfunction in macular edema. Doc Ophthalmol 97, 217–228 (1999). https://doi.org/10.1023/A:1002136712070

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