Documenta Ophthalmologica

, Volume 97, Issue 3–4, pp 251–260 | Cite as

Regulators of vascular permeability: potential sites for intervention in the treatment of macular edema

  • Mark C. Gillies

Abstract

Rather than being a non-specific reaction to a noxious stimulus, breakdown of the capillary blood-retinal barrier causing macular edema appears to be dependent on a number of active processes which may be open to pharmacological manipulation. Extracellular influences which may affect barrier function include serum and neighboring cell types, which act though cytokines, such as vascular endothelial growth factor and transforming growth factor-ß, and other factors. A number of intracellular pathways acting on the cytoskeleton and components of the intercellular junctional complexes have been identified which mediate agonist-induced leak of the vascular endothelium. The further elucidation of these processes may be useful in the development of better treatments for breakdown of the inner blood-retinal barrier.

blood-retinal barrier drug therapy endothelium vascular permeability protein kinase C tyrosine phosphorylation 

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References

  1. 1.
    Lum H, Malik AB. Regulation of vascular endothelial barrier function. Am J Physiol 1994; 267: 1223-41.Google Scholar
  2. 2.
    Aiello LP, Bursell SE, Clermont A, Duh E, Ishii H, Takagi C, Mori F, Ciulla TA, Ways K, Jirousek M, Smith LE, King GL. Vascular endothelial growth factor-induced retinal permeability is mediated by protein kinase C in vivo and suppressed by an orally effective beta-isoform-selective inhibitor. Diabetes 1997; 46: 1473-80.PubMedGoogle Scholar
  3. 3.
    Greenwood J. Astrocyes, cerebral endothelium, and cell culture. The pursuit of an in vitro blood-brain barrier. Ann NY Acad Sci 1991; 633: 426-1.PubMedGoogle Scholar
  4. 4.
    Takakura Y, Audus K, Borchardt RT. Blood-brain barrier: transport studies in isolated brain capillaries and in cultured brain endothelial cells. Adv Pharmacol 1991; 22: 137-65.PubMedGoogle Scholar
  5. 5.
    Cereijido M, Robbins ES, Dolan WJ, Rotunno CA, Sabatini DD. Polarized monolayers formed by epithelial cells on a permeable and translucent support. J Cell Biol 1978; 77: 853-80.PubMedCrossRefGoogle Scholar
  6. 6.
    Gillies M, Su T, Naidoo D. Electrical resistance and macromolecular permeability of retinal capillary endothelial cells in vitro. Curr Eye Res 1995; 14: 435-42.PubMedGoogle Scholar
  7. 7.
    Yaccino JA, Chang YS, Hollis TM, Gardner TW, Tarbell JM. Physiological transport properties of cultured retinal microvascular endothelial cell monolayers. Curr Eye Res 1997; 16: 761-8.PubMedCrossRefGoogle Scholar
  8. 8.
    Beck DW, Vinters HV, HartMN, Cancilla PA. Glial cells influence polarity of the bloodbrain barrier. J Neuropathol Exp Neurol 1984; 43: 219-24.PubMedGoogle Scholar
  9. 9.
    Provis JM, Kannah G, Leech JN, Gillies M, Penfold PL. Modulation of human vascular endothelial cell resistivity in vitro by conditioned media (ARVO abstract). Invest Ophthalmol Vis Sci 1996; 37: S796.Google Scholar
  10. 10.
    Gardner TW, Lieth E, Khin SA, Barber AJ, Bonsall DJ, Lesher T, Rice K, Brennan WA Jr. Astrocytes increase barrier properties and ZO-1 expression in retinal vascular endothelial cells. Invest Ophthalmol Vis Sci 1997; 38: 2423-7.PubMedGoogle Scholar
  11. 11.
    Langford-Smith J, Gillies M, Billson F. Barrier activity of fractionated human serum. Aust NZ J Ophthalmol 1997; 25(Suppl 1): S85-6.Google Scholar
  12. 12.
    Gillies M, Su T. Interferon alpha 2b enhances barrier function of bovine retinal microvascular endothelium in vitro. Microvasc Res 1995; 49: 277-88.PubMedCrossRefGoogle Scholar
  13. 13.
    Levitzki A, Gazit A. Tyrosine kinase inhibition: an approach to drug development. Science 1995; 267: 1782-8.PubMedGoogle Scholar
  14. 14.
    Volberg T, Geiger B, Dror R, Zick Y. Modulation of intercellular adherens-type junctions and tyrosine phosphorylation of their components in RSV-transformed cultured chick lens cells. Cell Regul 1991; 2: 105-20.PubMedGoogle Scholar
  15. 15.
    Matsuyoshi, N Hamaguchi M, Taniguchi A, Tsukitas S, Takeichi M. Cadherin-mediated cell-cell adhesion is perturbed by v-src tyrosine phosphorylation in metastatic fibroblasts. J Cell Biol 1992; 118: 703.PubMedCrossRefGoogle Scholar
  16. 16.
    Volberg T, Zick Y, Dror R, Sabanay I, Gilon C, Levitzki A, Geiger B. The effect of tyrosine-specific protein phosphorylation on the assembly of adherens-type junctions. EMBO J 1992; 11: 1733.PubMedGoogle Scholar
  17. 17.
    Gumbiner B, Stevenson B, Grimaldi A. The role of the cell adhesion molecule uvomorulin in the formation and maintenance of the epithelial junctional complex. J Cell Biol 1988; 107: 1575-87.PubMedCrossRefGoogle Scholar
  18. 18.
    Ozawa M, Baribault H, Kemler R. The cytoplasmic domain of the cell adhesion molecule uvomorulin associates with three independent proteins structurally related in different species. EMBO J 1989; 8: 1711-7.PubMedGoogle Scholar
  19. 19.
    Dejana E, Corada M, Lampugnani MG. Endothelial cell-to-cell junctions. FASEB J 1995; 9: 910-8.PubMedGoogle Scholar
  20. 20.
    Abedi H, Zachary I. Vascular endothelial growth factor stimulates tyrosine phosphorylation and recruitment to new focal adhesions of focal adhesion kinase and paxillin in endothelial cells. J Biol Chem 1997; 272: 15442-51.PubMedCrossRefGoogle Scholar
  21. 21.
    Lynch JJ, Ferro TJ, Blumenstock FA, Brockenauer AM, Malik AB. Increased endothelial albumin permeability mediated by protein kinase C activation. J Clin Invest 1990; 85: 1991-8.PubMedGoogle Scholar
  22. 22.
    Hug H, Sarre TF. Protein kinase C isoenzymes: divergence in signal transduction? Biochem J 1993; 291: 329-43.PubMedGoogle Scholar
  23. 23.
    Shiba T, Inoguchi T, Sportsman JR. Correlation of diacylglycerol level and protein kinase C activity in rat retina to retinal circulation. Am J Physiol 1993; 265: E783-93.PubMedGoogle Scholar
  24. 24.
    Lynch JJ, Ferro TJ, Blumenstock TA, Brockenauer AM, Malik AB. Increased endothelial albumin permeability mediated by protein kinase C activation. J Clin Invest 1990: 85: 1991-8.PubMedGoogle Scholar
  25. 25.
    Wolf BA, Williamson JR, Easom RA, Chang K, Sherman WR, Turk J. Diacylglycerol accumulation and microvascular abnormalities induced by elevated glucose levels. J Clin Invest 1990; 87: 31-8.CrossRefGoogle Scholar
  26. 26.
    Thurston G, Turner D. Thrombin-induced increase of F-actin in human umbilical vein endothelial cells. Microvasc Res 1994; 47: 1-20.PubMedCrossRefGoogle Scholar
  27. 27.
    Citi S. Protein kinase inhibitors prevent junction dissociation induced by low extracellular calcium in MDCK cells. J Cell Biol 1992; 117: 169-78.PubMedCrossRefGoogle Scholar
  28. 28.
    Balda MS, Gonazalez-Mariscal L, Contreras RG, Macias-Silva M, Torres-Marquez ME, Garcia-Sainz JA, Cereijido M. Assembly and sealing of tight junctions: possible participation of G-proteins, phospholipase C, protein kinase C and calmodulin. J Membr Biol 1991; 122: 193-202.PubMedCrossRefGoogle Scholar
  29. 29.
    Stasek JE Jr, Patterson CE, Garcia JG. Protein kinase C phosphorylates caldesmon77 and vimentin and enhances albumin permeability across cultured bovine pulmonary artery endothelial cell monolayers. J Cell Physiol 1992; 153: 62-75.PubMedCrossRefGoogle Scholar
  30. 30.
    Werth DK, Niedel JE, Pastan I. Vinculin, a cytoskeletal substrate of protein kinase C. J Biol Chem 1983; 258: 11423-6.Google Scholar
  31. 31.
    Oliver JA. Adenylate cyclase and protein kinase C mediate opposite actions on endothelial junctions. J Cell Physiol 1990; 145: 536-42.PubMedCrossRefGoogle Scholar
  32. 32.
    Garcia JGN, Schaphorst KL. Regulation of endothelial cell gap formation and paracellular permeability. J Invest Med 1995; 43: 117-26.Google Scholar
  33. 33.
    Lee T-S, Saltsman KA, Ohashi H, King GL. Activation of protein kinase C by elevated glucose concentration: proposal for a mechanism in the development of diabetic vascular complications. Proc Natl Acad Sci USA 1989; 86: 5141-5.PubMedCrossRefGoogle Scholar
  34. 34.
    Van den Enden MK, Nyengaard JR, Ostrow E, Burgan JH, Williamson JR. Elevated glucose levels increase retinal glycolysis and sorbitol pathway metabolism. Implications for diabetic retinopathy. Invest Ophthalmol Vis Sci 1995; 36: 1675-85.PubMedGoogle Scholar
  35. 35.
    Xia P, Inoguchi T, Kern TS, Engerman RL, Oates PJ, King GL. Characterization of the mechanism for chronic activation of diacylglycerol-protein kinase C pathway in diabetes and hypergalactosemia. Diabetes 1994; 43: 1122-9.PubMedGoogle Scholar
  36. 36.
    Gillies MC, Su T, Stayt J, Simpson JM, Naidoo D, Salonikas C. Effect of high glucose on permeability of retinal capillary endothelium in vitro. Invest Ophthalmol Vis Sci 1997; 38: 635-42.PubMedGoogle Scholar
  37. 37.
    Stelzner TJ, Weil JV, O'Brien RF. Role of cyclic adenosine monophosphate in the induction of endothelial barrier properties. J Cell Physiol 1989; 139: 157-66.PubMedCrossRefGoogle Scholar
  38. 38.
    Minnear FL, DeMichele MA, Leonhardt S, Andersen TT, Teitler M. Isoproterenol antagonizes endothelial permeability induced by thrombin and thrombin receptor peptide. J Appl Physiol 1993; 75: 1171-9.PubMedGoogle Scholar
  39. 39.
    Mayhan WG, Joyner WL. The effect of altering the external calcium concentration and a calcium channel blocker, verapamil, on microvascular leaky sites and dextran clearance in the hamster cheek pouch. Microvasc Res 1984; 28: 159-79.PubMedCrossRefGoogle Scholar
  40. 40.
    Lum H, Del Vecchio PJ, Schneider AS, Goligorsky MS, Malik AB. Calcium dependence of the thrombin-induced increase in endothelial albumin permeability. J Appl Physiol 1989; 66: 1471-6.PubMedCrossRefGoogle Scholar
  41. 41.
    Garcia JG, Schaphorst KL, Shi S, Verin AD, Hart CM, Callahan KS, Patterson CE. Mechanisms of ionomycin-induced endothelial cell barrier dysfunction. Am J Physiol 1997; 273: L172-84.Google Scholar
  42. 42.
    Fleming I, Fisslthaler B, Busse R. Interdependence of calcium signaling and protein tyrosine phosphorylation in human endothelial cells. J Biol Chem 1996; 271: 11009-15.PubMedCrossRefGoogle Scholar
  43. 43.
    Curry FE. Modulation of venular microvessel permeability by calcium influx into endothelial cells. FASEB J 1992; 6: 2456-66.PubMedGoogle Scholar

Copyright information

© Kluwer Academic Publishers 1999

Authors and Affiliations

  • Mark C. Gillies
    • 1
  1. 1.Save Sight InstituteSydney UniversitySydneyAustralia

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