Advertisement

Pathophysiology of Diabetic Retinopathy

  • Michael W. Stewart
Chapter

Abstract

The retina was first described by Herophilus of Chalcedon around 300 bc. It was named by Rufos of Ephesus (c. 110 ad) and appeared to early anatomists as a surrounding net which supported the vitreous. Though Galen noted structural similarities to the brain, he was unable to provide further understanding regarding its function. It was Kepler who first suggested that the retina served as the eye’s primary photoreceptor tissue. By using alcohol fixation, Treviranus (1835) performed the first detailed microscopic retinal studies. Only with the subsequent development of electron microscopy, trypsin digest, clinical fluorescein angiography, and optical coherence tomography have scientists been able to understand the retina’s cellular connections, ultrastructure, and retinal vasculature, as well as correlate anatomical and clinical findings.1

Keywords

Vascular Endothelial Growth Factor Diabetic Retinopathy Macular Edema Vascular Endothelial Growth Factor Level Diabetic Macular Edema 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. 1.
    Sigelman J, Ozanics V. Retina. In Duane’s Foundations of Clinical Ophthalmology. Philadelphia: Lippincott; 1990.Google Scholar
  2. 2.
    Hogan MJ, Alvarado JA, Weddell JE. The retina. In Histology of the Human Eye. Philadelphia: WB Saunders; 1971:393–522.Google Scholar
  3. 3.
    Zinn KM, Marmor MF, eds. The Retinal Pigment Epithelium. Cambridge, MA: Harvard University Press; 1979.Google Scholar
  4. 4.
    Pfeffer BA. Improved methodology for cell culture of human and monkey retinal pigment epithelium. Prog Retinal Res. 1991;10:251.Google Scholar
  5. 5.
    Feeney-Burns L, Burns RP, Gao C-L. Age-related macular changes in humans over 90 years old. Am J Ophthalmol. 1990;109:265–278.PubMedGoogle Scholar
  6. 6.
    Handelman GJ, Snodderly DM, Krinsky NI, et al. Biological control of primate macular pigment – biochemical and densitometric studies. Invest Ophthalmol Vis Sci. 1991;32:257–267.PubMedGoogle Scholar
  7. 7.
    Wald G, Brown PK. Human rhodopsin. Science. 1958;127:222–226.PubMedGoogle Scholar
  8. 8.
    Adler AJ, Severin KM. Proteins of the bovine interphotoreceptor matrix – tissues of origin. Exp Eye Res. 1981;2: 755–769.Google Scholar
  9. 9.
    Dowling JE, Boycott BB. Organization of the primate retina – electron microscopy. Proc R Soc Ser B. 1966;166: 80–111.Google Scholar
  10. 10.
    Curcio CA, Allen KA. Topography of ganglion cells in human retina. J Comp Neurol. 1990;300:5–25.PubMedGoogle Scholar
  11. 11.
    Pollock SC, Miller NR. The retinal nerve fiber layer. Int Ophthalmol Clin. 1986;26:201–221.PubMedGoogle Scholar
  12. 12.
    McLeod D. Why cotton wool spots should not be regarded as retinal nerve fiber layer infarcts. Br J Ophthalmol. 2005;89:229–237.PubMedGoogle Scholar
  13. 13.
    Ogden TE. The glia of the retina. In: Ryan SJ, Ogden TE, eds. Retina, Vol. 1. St. Louis: CV Mosby; 1989:53–56.Google Scholar
  14. 14.
    Smelser GK, Ishikawa T, Pei YF. Electron microscopic studies of intra-retinal spaces – diffusion of particulate materials. In Rohen JW, ed. Structure of the Eye, II Symp. Stuttgart: Schattauer-Verlag; 1965:109–121.Google Scholar
  15. 15.
    Hewitt AT, Adler R. The retinal pigment epithelium and interphotoreceptor matrix – structure and specialized functions. In: Ryan SJ, Ogden TE, eds. Retina, Vol. 1. St. Louis: CV Mosby; 1989:57–64.Google Scholar
  16. 16.
    Jerdan JA, Kao L, Glaser BM. The inner limiting membrane: a modified basement membrane? Invest Ophthalmol Vis Sci (suppl). 1986;27:230a.Google Scholar
  17. 17.
    Yamada E. Some structural features of the fovea centralis in the human retina. Arch Ophthalmol. 1969;82: 151–159.PubMedGoogle Scholar
  18. 18.
    Archer D, Krill AE, Newell FW. Fluorescein studies of normal choroidal circulation. Am J Ophthalmol. 1970;69: 543–554.PubMedGoogle Scholar
  19. 19.
    Ernest JT. Macrocirculation and microcirculation of the retina. In: Ryan SJ, Ogden TE, eds. Retina, Vol. 1. St. Louis: CV Mosby; 1989:65–66.Google Scholar
  20. 20.
    Ferrari-Dileo G, Davis EB, Anderson DR. Response of retinal vasculature to phenylephrine. Invest Ophthalmol Vis Sci. 1990;30:1181–1182.Google Scholar
  21. 21.
    Shin DH, Tsai CS, Parrow KA, et al. Vasoconstrictive effect of topical timolol on human retinal arteries. Graefes Arch Clin Exp Ophthalmol. 1991;229:298–299.PubMedGoogle Scholar
  22. 22.
    Shakib M, Cunha-Vaz JG. Studies on the permeability of the blood–retinal barrier. IV. Junctional complexes of the retinal vessels and their role in the permeability of the blood–retinal barrier. Exp Eye Res. 1966;5:229–234.PubMedGoogle Scholar
  23. 23.
    Hogan MJ, Feeney L. Ultrastructure of the retinal vessels. Part 1. The larger vessels. J Ultrastruct Res. 1963;9:10–28.Google Scholar
  24. 24.
    Henkind P. New observations on the radial peripapillary capillaries. Invest Ophthalmol. 1967;6:103.PubMedGoogle Scholar
  25. 25.
    Wise GN, Dollery CT, Henkind P. The Retinal Circulation. New York: Harper & Row; 1971.Google Scholar
  26. 26.
    Chakravarthy U, Gardiner TA, Anderson P, et al. The effect of endothelin I on the retinal microvascular pericyte. Microvasc Res. 1992;43:241–254.PubMedGoogle Scholar
  27. 27.
    Dodge AB, Hechtman HB, Shepro D. Microvascular endothelial-derived autacoids regulate pericyte contractility. Cell Motil Cytoskel. 1991;18:180–188.Google Scholar
  28. 28.
    Matsugi T, Chen Q, Anderson DR. Contractile responses of cultured bovine retinal pericytes to angiotensin II. Arch Ophthalmol. 1997;115:1281–1285.PubMedGoogle Scholar
  29. 29.
    Cogan DG, Toussaint D, Kuwabara T. Retinal vascular patterns. Part IV. Diabetic retinopathy. Arch Ophthalmol. 1961;66:366–378.PubMedGoogle Scholar
  30. 30.
    Matthews DR, Stratton IM, Aldington SJ, et al. Risks of progression of retinopathy and vision loss related to tight blood pressure control in type 2 diabetes mellitus: UKPDS 69. Arch Ophthalmol. 2004;122:1631–1640.PubMedGoogle Scholar
  31. 31.
    Stratton IM, Kohner EM, Aldington SJ, et al. UKPDS 50: risk factors for incidence and progression of retinopathy in Type II diabetes over 6 years from diagnosis. Diabetologia. 2001;44:156–163.PubMedGoogle Scholar
  32. 32.
    Stefannson E, Landers MB 3rd, Wolbarsht ML. Increased retinal oxygen supply following pan-retinal photocoagulation and vitrectomy and lensectomy. Trans Am Ophthalmol Soc. 1981;79:307–334.Google Scholar
  33. 33.
    Stefansson E. The therapeutic effects of retinal laser treatment and vitrectomy. A theory based on oxygen and vascular physiology. Acta Ophthalmol Scand. 2001; 79:435–440.PubMedGoogle Scholar
  34. 34.
    Stefansson E. Ocular oxygenation and the treatment of diabetic retinopathy. Surv Ophthalmol. 2006;51:364–380.PubMedGoogle Scholar
  35. 35.
    Kristinsson JK, Gottfredsdotter MS, Stefannson E. Retinal vessel dilatation and elongation precedes diabetic macular oedema. Br J Ophthalmol. 1997;81:274–278.PubMedGoogle Scholar
  36. 36.
    Kokame GT, de Leon MD, Tanji T. Serous retinal detachment and cystoid macular edema in hypotony maculopathy. Am J Ophthalmol. 2001;131:384–386.PubMedGoogle Scholar
  37. 37.
    Lewis H, Abrams GW, Blumenkranz MS, Campo RV. Vitrectomy for diabetic macular traction and edema associated with posterior hyaloid traction. Ophthalmology. 1992;99:753–759.PubMedGoogle Scholar
  38. 38.
    Patel JI, Tombran-Tink J, Hykin PG, et al. Vitreous and aqueous concentrations of proangiogenic, antiangiogenic factors and other cytokines in diabetic retinopathy patients with macular edema: implications for structural differences in macular profiles. Exp Eye Res. 2006;82: 798–806.PubMedGoogle Scholar
  39. 39.
    Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature. 2001;414:813–820.PubMedGoogle Scholar
  40. 40.
    Lucis AJ. Atherosclerosis. Nature. 2000;407:233–241.Google Scholar
  41. 41.
    Hseuh WA, Law RE. Cardiovascular risk continuum: implications of insulin resistance and diabetes. Am J Med. 1998;105:4S–14S.Google Scholar
  42. 42.
    Guigliano D, Ceriello A, Paolisso G. Oxidative stress and diabetic vascular complications. Diabetes Care. 1996; 19:257–267.Google Scholar
  43. 43.
    Du XL, Edelstein D, Dimmeler S, et al. Hyperglycemia inhibits endothelial nitric oxide synthase activity by posttranslational modification at the Akt site. J Clin Invest. 2001;108:1341–1348.PubMedGoogle Scholar
  44. 44.
    Giardino I, Edelstein D, Brownlee M. BCL-2 expression or antioxidants prevent hyperglycemia-induced formation of intracellular advanced glycation endproducts in bovine endothelial cells. J Clin Invest. 1996;97:1422–1428.PubMedGoogle Scholar
  45. 45.
    Du XL, Edelstein D, Rossetti L, et al. Hyperglycemia-induced mitochondrial superoxide overproduction activates the hexosamine pathway and induces plasminogen activator inhibitor-1 expression by increasing Sp1 glycosylation. Proc Natl Acad Sci USA. 2000;97:12222–12226.PubMedGoogle Scholar
  46. 46.
    Yamagishi SI, Edelstein D, Du XL, Brownlee M. Hyperglycemia potentiates collagen-induced platelet activation through mitochondrial superoxide overproduction. Diabetes. 2001;50:1491–1494.PubMedGoogle Scholar
  47. 47.
    Craven PA, Phillip SL, Melham MF, et al. Overexpression of Mn2+ superoxide dismutase increases in collagen accumulation induced by culture in mesangial cells in high-media glucose. Metabolism. 2001;50:1043–1048.PubMedGoogle Scholar
  48. 48.
    Williamson JR, Chang K, Frangos M, et al. Hyperglycemic pseudohypoxia and diabetic complications. Diabetes. 1993;42:801–813.PubMedGoogle Scholar
  49. 49.
    Engerman RL, Kern TX, Larson ME. Nerve conduction and aldose reductase inhibition during 5 years of diabetes or galactosaemia in dogs. Diabetologia. 1994;37:141–144.PubMedGoogle Scholar
  50. 50.
    Greene DA, Arezzo JC, Brown MB. Effect of aldose reductase inhibition on nerve conduction and morphometry in diabetic neuropathy. Zenarestat study group. Neurology. 1999;53:580–591.PubMedGoogle Scholar
  51. 51.
    Stitt AW, Li YM, Gardiner TA, et al. Advanced glycation end products (AGEs) co-localize with AGE receptors in the retinal vasculature of diabetic and of AGE-infused rats. Am J Pathol. 1997;150:523–528.PubMedGoogle Scholar
  52. 52.
    Horie K, Miyata T, Maeda K, et al. Immunohistochemical colocalization of glycoxidation products and lipid peroxidation products in diabetic renal glomerular lesions. Implication for glycoxidative stress in the pathogenesis of diabetic nephropathy. J Clin Invest. 1997;100:2995–3004.PubMedGoogle Scholar
  53. 53.
    Degenhardt TP, Thorpe SR, Baynes JW. Chemical modification of proteins by methylglyoxal. Cell Mol Biol. 1998;44:1139–1145.PubMedGoogle Scholar
  54. 54.
    Wells-Knecht KJ, Zyzak DV, Litchfield JE, et al. Mechanism of autoxidative glycosylation: identification of glyoxal and arabinose as intermediates in the autoxidative modification of proteins by glucose. Biochemistry. 1995;34:3702–3709.PubMedGoogle Scholar
  55. 55.
    Thornalley PJ. The glyoxalase system: new developments towards functional characterization of a metabolic pathway fundamental to biological life. Biochem J. 1990;269: 1–11.PubMedGoogle Scholar
  56. 56.
    Soulis-Liparota T, Cooper M, Papazoglou D, et al. Retardation by aminoguanidine of development of albuminuria, mesangial expansion, and tissue fluorescence in streptozocin-induced diabetic rat. Diabetes. 1991;40: 1328–1334.PubMedGoogle Scholar
  57. 57.
    Bolton WK, Cattran DC, Williams ME, et al. Randomized trial of an inhibitor of advanced glycation end products in diabetic nephropathy. Am J Nephrol. 2004;24: 32–40.PubMedGoogle Scholar
  58. 58.
    Huijberts MSP, Wolffenbuttel BH, Boudier HA, et al. Aminoguanidine treatment increases elasticity and decreases fluid filtration of large arteries from diabetic rats. J Clin Invest. 1993;92:1407–1411.PubMedGoogle Scholar
  59. 59.
    Tsilibary EC, Charonis AS, Reger LA, et al. The effect of nonenzymatic glucosylation on the binding of the main noncollagenous NC1 domain to type IV collagen. J Biol Chem. 1988;263:4302–4308.PubMedGoogle Scholar
  60. 60.
    Charonis AS, Reger LA, Dege JE, et al. Laminin alterations after in vitro nonenzymatic glucosylation. Diabetes. 1990;39:807–814.PubMedGoogle Scholar
  61. 61.
    Federoff HJ, Lawrence D, Brownlee M. Nonenzymatic glycosylation of laminin and the laminin peptide CIKVAVS inhibits neurite outgrowth. Diabetes. 1993;42: 590–513.Google Scholar
  62. 62.
    Lu M, Kuroki M, Amano S, et al. Advanced glycation end products increase retinal vascular endothelial growth factor expression. J Clin Invest. 1998;101:1219–1224.PubMedGoogle Scholar
  63. 63.
    Koya D, King GL. Protein kinase C activation and the development of diabetic complications. Diabetes. 1998;47: 859–866.PubMedGoogle Scholar
  64. 64.
    Portilla D, Dai G, Peters JM, et al. Etomoxir-induced PPARalpha-modulated enzymes protect during acute renal failure. Am J Physiol Renal Physiol. 2000;278: F667–F675.PubMedGoogle Scholar
  65. 65.
    Keough RJ, Dunlop ME, Larkins RG. Effect of inhibition of aldose reductase on glucose flux, diacylglycerol formation, protein kinase C, and phospholipase A2 activation. Metabolism. 1997;46:41–47.Google Scholar
  66. 66.
    Ishii H, Jirousek MR, Koya D, et al. Amelioration of vascular dysfunctions in diabetic rats by an oral PKC beta inhibitor. Science. 1996;272:728–731.PubMedGoogle Scholar
  67. 67.
    Williams B, Gallacher B, Patel H, Orme C. Glucose-induced protein kinase C activation of protein kinase C alpha. Circ Res. 1997;46:1497–1503.Google Scholar
  68. 68.
    Craven PA, Studer RK, Felder J, et al. Nitric oxide inhibition of transforming growth factor-beta and collagen synthesis in mesangial cells. Diabetes. 1997;46:671–681.PubMedGoogle Scholar
  69. 69.
    Pieper GM, Riaz-ul-Haq J. Activation of nuclear factor-kappaB in cultured endothelial cells by increased glucose concentration: prevention by calphostin C. Cardiovasc Pharmacol. 1997;30:528–532.Google Scholar
  70. 70.
    Yerneni KK, Bai W, Khan BV, et al. Hyperglycemia-induced activation of nuclear transcription factor kappaB in vascular smooth muscle cells. Diabetes. 1999;48: 855–864.PubMedGoogle Scholar
  71. 71.
    Koya D, Haneda M, Nakagawa H, et al. Amelioration of accelerated diabetic mesangial expansion by treatment with a PKC beta inhibitor in diabetic db/db mice, a rodent model for type 2 diabetes. FASEB J. 2000;14:439–447.PubMedGoogle Scholar
  72. 72.
    Hart GW. Dynamic O-linked glycosylation of nuclear and cytoskeletal proteins. Annu Rev Biochem. 1997;66: 315–335.PubMedGoogle Scholar
  73. 73.
    Fine BS, Brucker AJ. Macular edema and cystoid macular edema. Am J Ophthalmol. 1981;92:466–481.PubMedGoogle Scholar
  74. 74.
    Gass JDM, Anderson DR, Davis EB. A clinical, fluorescein angiographic, and electron microscopic correlation of cystoid macular edema. Am J Ophthalmol. 1985; 100:82–86.PubMedGoogle Scholar
  75. 75.
    Arend O, Remky A, Harris A, et al. Macular microcirculation in cystoid maculopathy of diabetic patients [see comments]. Br J Ophthalmol. 1995;79:628–632.PubMedGoogle Scholar
  76. 76.
    Smith RT, Lee CM, Charles HC, et al. Quantification of diabetic macular edema. Arch Ophthalmol. 1987;105: 218–222.PubMedGoogle Scholar
  77. 77.
    Antcliff RJ, Marshall J. The pathogenesis of edema in diabetic maculopathy. Semin Ophthalmol. 1999;14:223–232.PubMedGoogle Scholar
  78. 78.
    Sinclair SH. Macular retinal capillary hemodynamics in diabetic patients. Ophthalmology. 1991;98:1580–1586.PubMedGoogle Scholar
  79. 79.
    Langham ME, Grebe R, Hopkins S, et al. Choroidal blood flow in diabetic retinopathy. Exp Eye Res. 1991; 52:167–173.PubMedGoogle Scholar
  80. 80.
    Weinberger D, Fink-Cohen S, Gaton DD, et al. Non-retinovascular leakage in diabetic maculopathy. Br J Ophthalmol. 1995;79:728–731.PubMedGoogle Scholar
  81. 81.
    Fukushima I, McLeod DS, Lutty GA. Intrachoroidal microvascular abnormality: a previously unrecognized form of choroidal neovascularization. Am J Ophthalmol. 1997;124:473–487.PubMedGoogle Scholar
  82. 82.
    Lanigan LP. Impaired autoregulation of the retinal vasculature and microalbuminuria in diabetes mellitus. Eye. 1990;4:174–180.PubMedGoogle Scholar
  83. 83.
    Schmetterer L, Salomon A, Rheinberger A, et al. Fundus pulsation measurements in diabetic retinopathy. Graefe’s Arch Clin Exp Ophthalmol. 1997;235:283–287.Google Scholar
  84. 84.
    Ohno-Matsui K, Yoshida T, Uetama T, et al. Vascular endothelial growth factor upregulates pigment epithelium-derived factor expression via VEGFR-1 in human retinal pigment epithelial cells. Biochem Biophys Res Commun. 2003;303:962–967.PubMedGoogle Scholar
  85. 85.
    Christinger HW, Fuh G, de Vos AM, Wiesmann C. The crystal structure of placental growth factor in complex with domain 2 of vascular endothelial growth factor receptor-1. J Biol Chem. 2004;279:10382–10388.PubMedGoogle Scholar
  86. 86.
    Miyamoto N, de Kozak Y, Jeanny JC, et al. Placental growth factor-1 and epithelial haemato-retinal barrier breakdown: potential implication in the pathogenesis of diabetic retinopathy. Diabetologia. 2007;50: 461–470.PubMedGoogle Scholar
  87. 87.
    Bensaoula T, Ottlecz A. Biochemical and ultrastructural studies in the neural retina and retinal pigment epithelium of STZ-diabetic rats: effect of captopril. J Ocular Pharmacol Ther. 2001;17:573–586.Google Scholar
  88. 88.
    Tso MO. Pathology of cystoid macular edema. Ophthalmology. 1982;89:902–915.PubMedGoogle Scholar
  89. 89.
    Tso MO. Pathological study of cystoid macular oedema. Trans OSUK. 1980;100:408–413.Google Scholar
  90. 90.
    Matter K, Balda MS. Occludin and the functions of tight junctions. Int Rev Cytol. 1999;186:117–146.PubMedGoogle Scholar
  91. 91.
    Kiuchi-Saichin Y, Gotoh S, Furuse M, et al. Differential expression patterns of claudins, tight junction membrane proteins, in mouse nephron segments. J Am Soc Nephrol. 2002;13:875–886.Google Scholar
  92. 92.
    Antonetti DA, Barber AJ, Khin S, et al. 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. 1998;47:1953–1959.PubMedGoogle Scholar
  93. 93.
    Nitta T, Hata M, Gotoh S, et al. Size-selective loosening of the blood–brain barrier in claudin-5 deficient mice. J Cell Biol. 2003;161:653–660.PubMedGoogle Scholar
  94. 94.
    Felinski EA, Antonetti DA. Glucocorticoid regulation of endothelial cell tight junction gene expression: novel treatments for diabetic retinopathy. Curr Eye Res. 2005; 30:949–957.PubMedGoogle Scholar
  95. 95.
    Fanning AS, Ma TY, Anderson JM. Isolation and functional characterization of the actin binding region in the tight junction protein ZO-1. FASEB J. 2002;16:1835–1837.PubMedGoogle Scholar
  96. 96.
    Gardner TW, Lieth E, Khin SA, et al. Astrocytes increase barrier properties and ZO-1 expression in retinal vascular endothelial cells. Invest Ophthalmol Vis Sci. 1997;38:2423–2427.PubMedGoogle Scholar
  97. 97.
    Ebnet K, Suzuki A, Ohno S, Vestweber D. Junctional adhesion molecules (JAMs): more molecules with dual functions? J Cell Sci. 2004;117:19–29.PubMedGoogle Scholar
  98. 98.
    Stevenson BR, Keon BH. The tight junction: morphology to molecules. Annu Rev Cell Dev Biol. 1998;14:89–109.PubMedGoogle Scholar
  99. 99.
    Cunha-Vaz J, Faria de Abreu JR, Campos AJ. Early breakdown of the blood–retinal barrier in diabetes. Br J Ophthalmol. 1975;59:649–656.PubMedGoogle Scholar
  100. 100.
    Jones CW, Cunha-Vaz J, Zweig KO, Stein M. Kinetic vitreous fluorophotometry in experimental diabetes. Arch Ophthalmol. 1979;97:1941–1943.PubMedGoogle Scholar
  101. 101.
    Bates DO, Hillman NJ, Williams B, et al. Regulation of microvascular permeability by vascular endothelial growth factors. J Anat. 2002;200:581–597.PubMedGoogle Scholar
  102. 102.
    Wang W, Dentler WL, Borchardt RT. VEGF increases BMED monolayer permeability by affecting occludin expression and tight junction assembly. Am J Physiol Heart Circ Physiol. 2001;280:H434–H440.PubMedGoogle Scholar
  103. 103.
    Giebel SJ, Menicucci G, McGuire PG, Das A. Matrix metalloproteinases in early diabetic retinopathy and their role in alteration of the blood–retinal barrier. Lab Invest. 2005;85:597–607.PubMedGoogle Scholar
  104. 104.
    Vinores SA, Van Niel E, Swerrdloff IL, et al. 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;57:723–735.PubMedGoogle Scholar
  105. 105.
    Gillies MC, Su T, Stayl J, et al. Effect of high glucose on permeability on retinal capillary endothelium in vitro. Invest Ophthalmol Vis Sci. 1997;38:635–642.PubMedGoogle Scholar
  106. 106.
    Gardner TW, Lieth E, Khin SA, et al. Astrocytes increase barrier properties and ZO-1 expression in retinal vascular endothelial cells. Invest Ophthalmol Vis Sci. 1997;38:2423–2427.PubMedGoogle Scholar
  107. 107.
    Xia P, Aiello LP, Ishii H, et al. Characterization of vascular endothelial growth factor’s effect on the activation of protein kinase C, its isoforms, and endothelial cell growth. J Clin Invest. 1996;98:2018–2026.PubMedGoogle Scholar
  108. 108.
    Zachary I, Gliki G. Signaling transduction mechanisms mediating biological actions of the vascular endothelial growth factor family. Cardiovasc Res. 2001;49:568–581.PubMedGoogle Scholar
  109. 109.
    Karkkainan MJ, Makinen T, Alitalo K. Lymphatic endothelium: a new frontier of metastasis research. Nat Cell Biol. 2002;4:E2–E5.Google Scholar
  110. 110.
    Gerber HP, Condorelli F, Park J, Ferrara N. Differential transcriptional regulation of the two VEGF receptor genes, Flt-1, but not Flk-a/KDR, is up-regulated by hypoxia. J Biol Chem. 1997;272:23659–23667.PubMedGoogle Scholar
  111. 111.
    Ferrara N. Vascular endothelial growth factor: basic science and clinical progress. Endocrin Rev. 2004;25:581–611.Google Scholar
  112. 112.
    Spanel-Borowski K, Mayerhofer A. Formation and regression of capillary sprouts in corpora lutea of immature superstimulated golden hamsters. Acta Anat (Basel). 1987;128:227–235.Google Scholar
  113. 113.
    Dejana E, Spagnuolo R, Bazzoni G. Interendothelial junctions and their role in the control of angiogenesis, vascular permeability and leukocyte transmigration. Thromb Haemost. 2001;86:308–315.PubMedGoogle Scholar
  114. 114.
    Abell RG. The permeability of blood capillary sprouts and newly formed blood capillaries as compared to that of older capillaries. Am J Physiol. 1946;147:231–241.Google Scholar
  115. 115.
    Schoefl GI. Studies on inflammation. III. Growing capillaries: their structure and permeability. Virchows Arch Pathol Anat. 1963;337:97–141.Google Scholar
  116. 116.
    Saishin Y, Saishin Y, Takahashi K, et al. VEGF-TRAP(R1R2) suppresses choroidal neovascularization and VEGF-induced breakdown of the blood–retinal barrier. J Cell Physiol. 2003;195:241–248.PubMedGoogle Scholar
  117. 117.
    Gehlbach P, Demetriades AM, Yamamoto S, et al. Periocular gene transfer of sFlt-1 suppresses ocular neovascularization and VEGF-induced breakdown of the blood–retinal barrier. Hum Gene Ther. 2003;14:129–141.PubMedGoogle Scholar
  118. 118.
    Bainbridge JW, Mistry A, De Alwis M, et al. Inhibition of retinal neovascularization by gene transfer of soluble VEGF receptor sFlt-1. Gene Ther. 2002;9:320–326.PubMedGoogle Scholar
  119. 119.
    Tobe T, Ortega S, Luna JD, et al. Targeted disruption of the FGF2 gene does not prevent choroidal neovascularization in a murine model. Am J Path. 1998;153:1641–1646.PubMedGoogle Scholar
  120. 120.
    Oshima Y, Oshima S, Nambu H, et al. Increased expression of VEGF in retinal pigmented epithelial cells is not sufficient to cause choroidal neovascularization. J Cell Physiol. 2004;201:393–400.PubMedGoogle Scholar
  121. 121.
    Ozaki H, Hayashi H, Vinores SA, et al. 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;64:505–517.PubMedGoogle Scholar
  122. 122.
    Bates DO, Curry FE. Vascular endothelial growth factor increases hydraulic conductivity of isolated perfused microvessels. Am J Physiol. 1996;271:H2520–H2528.PubMedGoogle Scholar
  123. 123.
    Wu HM, Huang Q, Yuan Y, Granger HJ. VEGF induces NO-dependent hyperpermeability in coronary venules. Am J Physiol. 1996;271:H2735–H2739.PubMedGoogle Scholar
  124. 124.
    Bates DO. The chronic effect of vascular endothelial growth factor on individually perfused frog mesenteric microvessels. J Physiol. 1998;513:225–233.PubMedGoogle Scholar
  125. 125.
    Fukumura D, Gohongi T, Kadambi A, et al. Predominant role of endothelial nitric oxide synthase in vascular endothelial growth factor-induced angiogenesis and vascular permeability. Proc Natl Acad Sci USA. 2001;98:2604–2609.PubMedGoogle Scholar
  126. 126.
    Lu M, Perez VL, Ma N, et al. VEGF increases retinal vascular ICAM-1 expression in vivo. Invest Ophthalmol Vis Sci. 1999;40:1808–1812.PubMedGoogle Scholar
  127. 127.
    Gaudry M, Bregerie O, Andrieu V, et al. Intracellular pool of vascular endothelial growth factor in human neutrophils. Blood. 1997;90:4153–4161.PubMedGoogle Scholar
  128. 128.
    Miyamoto K, Khosrof S, Bursell SE, et al. Prevention of leukostasis and vascular leakage in streptozotocin-induced diabetic retinopathy via intercellular adhesion molecule-1 inhibition. Proc Natl Acad Sci USA. 1999; 96:10836–10841.PubMedGoogle Scholar
  129. 129.
    Bolton SJ, Anthony DC, Perry VH. Loss of the tight junction proteins occludin and zonula occludens-1 from cerebral vascular endothelium during neutrophil-induced blood–brain barrier breakdown in vivo. Neuroscience. 1998;86:1245–1257.PubMedGoogle Scholar
  130. 130.
    Brooks HL Jr., Caballero S Jr., Newell CK, et al. Vitreous levels of vascular endothelial growth factor and stromal-derived factor 1 in patients with diabetic retinopathy and cystoid macular edema before and after intraocular injection of triamcinolone. Arch Ophthalmol. 2004;122:1801–1807.PubMedGoogle Scholar
  131. 131.
    Funatsu H, Yamashita H, Ikeda T, et al. Vitreous levels of interleukin-6 and vascular endothelial growth factor are related to diabetic macular edema. Ophthalmology. 2003;110:1690–1696.PubMedGoogle Scholar
  132. 132.
    Semenza G. Signal transduction to hypoxia-inducible factor 1. Biochem Pharmacol. 2002;64:993–998.PubMedGoogle Scholar
  133. 133.
    Jaakkola P, Mole DR, Tian YM, et al. Targeting of HIF-alpha to the von Hippel–Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science. 2001;292:468–472.PubMedGoogle Scholar
  134. 134.
    Safran M, Kaelin WG Jr. HIF hydroxylation and the mammalian oxygen-sensing pathway. J Clin Invest. 2003; 779–783.Google Scholar
  135. 135.
    Wang GL, Jiang BH, Rue EA, Semenza GL. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci. 1995;92:5510–5514.PubMedGoogle Scholar
  136. 136.
    Weiner CM, Booth G, Semenza GL. In vivo expression of mRNAs encoding hypoxia-inducible factor 1. Biochem Biophys Res Commun. 1996;225:485–488.Google Scholar
  137. 137.
    Schroedl C, McClintock DS, Budinger GR, Chandel NS. Hypoxic but not anoxic stabilization of HIF-1alpha requires mitochondrial reactive oxygen species. Am J Physiol Lung Cell Mol Physiol. 2002;283: L922–L931.PubMedGoogle Scholar
  138. 138.
    Poulaki V, Qin W, Joussen AM, et al. Acute intensive insulin therapy exacerbates diabetic blood–retinal barrier breakdown via hypoxia-inducible factor-1alpha and VEGF. J Clin Invest. 2002;109:805–815.PubMedGoogle Scholar
  139. 139.
    Paul SA, Simons JW, Mabjeesh NJ. HIF at the crossroads between ischemia and carcinogenesis. J Cell Physiol. 2004;200:20–30.PubMedGoogle Scholar
  140. 140.
    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.PubMedGoogle Scholar
  141. 141.
    Clarke H, Marano CW, Peralta Soler A, Mullin JM. Modification of tight junction function by protein kinase C isoforms. Adv Drug Deliv Rev. 2000;41:283–301.PubMedGoogle Scholar
  142. 142.
    Studer RK, Craven PA, DeRubertis FR. Role for protein kinase C in the mediation of increased fibronectin accumulation by mesangial cells grown in high-glucose medium. Diabetes. 1993;42:118–126.PubMedGoogle Scholar
  143. 143.
    Aiello LP, Bursell SE, Clermont A, et al. 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;46:1473–1480.PubMedGoogle Scholar
  144. 144.
    Williams B, Gallacher B, Patel H, Orme C. Glucose-induced protein kinase C activation regulates vascular permeability factor mRNA expression and peptide production by human vascular smooth muscle cells in vitro. Diabetes. 1997;46:1497–1503.PubMedGoogle Scholar
  145. 145.
    Miller JW, Adamis AP, Aiello LP. Vascular endothelial growth factor in ocular neovascularization and proliferative diabetic retinopathy. Diabetes Metab Rev. 1997;13: 37–50.PubMedGoogle Scholar
  146. 146.
    Liu H, Ren JG, Cooper WL, et al. Identification of the antivasopermeability effect of pigment epithelium-derived factor and its active site. Proc Natl Acad Sci. 2004;101:6605–6610.PubMedGoogle Scholar
  147. 147.
    Zhang SX, Wang JJ, Gao G, et al. Pigment epithelium-derived factor downregulates vascular endothelial growth factor (VEGF) expression and inhibits VEGF–VEGF receptor 2 binding in diabetic retinopathy. J Mol Endocrinol. 2006;37:1–12.PubMedGoogle Scholar
  148. 148.
    Kim S, Iwao H. Molecular and cellular mechanisms of angiotensin II-mediated cardiovascular and renal diseases. Pharmacol Rev. 2000;52:11–34.PubMedGoogle Scholar
  149. 149.
    Aguilera G, Kiss A. Regulation of the hypothalamic–pituitary–adrenal axis and vasopressin secretion. Role of angiotensin II. Adv Exp Med Biol. 1996;396:105–112.PubMedGoogle Scholar
  150. 150.
    Culman J, Hohle S, Qadri F, et al. Angiotensin as neuromodulator/neurotransmitter in central control of body fluid and electrolyte homeostasis. Clin Exp Hypertens. 1995;17:281–293.PubMedGoogle Scholar
  151. 151.
    Ito M, Oliverio MI, Mannon PJ, et al. Regulation of blood pressure by the type 1A angiotensin II receptor gene. Proc Natl Acad Sci USA. 1995;92:3521–3525.PubMedGoogle Scholar
  152. 152.
    Kato H, Suzuki H, Tajima S, et al. Angiotensin II stimulates collagen synthesis in cultured vascular smooth muscle cells. J Hypertens. 1991;9:17–22.PubMedGoogle Scholar
  153. 153.
    Otani A, Takagi H, Oh H, et al. Angiotensin II induces expression of the Tie2 receptor ligand, angiopoietin-2, in bovine retinal endothelial cells. Diabetes. 2001;50:867–875.PubMedGoogle Scholar
  154. 154.
    Otani A, Takagi H, Suzuma K, Honda Y. Angiotensin II potentiates endothelial growth factor-induced angiogenic activity in retinal microcapillary endothelial cells. Circ Res. 1998;82:619–628.PubMedGoogle Scholar
  155. 155.
    Suzuki Y, Ruiz-Ortega M, Lorenzo O, et al. Inflammation and angiotensin II. Int J Biochem Cell Biol. 2003; 35:881–900.PubMedGoogle Scholar
  156. 156.
    Nagai N, Noda K, Urano T, et al. Selective suppression of pathologic, but not physiologic, retinal neovascularization by blocking the angiotensin II type 1 receptor. Invest Ophthalmol Vis Sci. 2005;46:1078–1084.PubMedGoogle Scholar
  157. 157.
    Tamura K, Nyui N, Tamura N, et al. Mechanism of angiotensin II-mediated regulation of fibronectin gene in rat vascular smooth muscle cells. J Biol Chem. 1998; 273:26487–26496.PubMedGoogle Scholar
  158. 158.
    Wilkinson-Berka J. Angiotensin and diabetic retinopathy. Int J Biochem Cell Biol. 2006;38:752–765.PubMedGoogle Scholar
  159. 159.
    Kawamura H, Kobayashi M, Li Q, et al. Effects of angiotensin II on the pericyte-containing microvasculature of the rat retina. J Physiol. 2004;561:671–683.PubMedGoogle Scholar
  160. 160.
    Ferrara N. Role of vascular endothelial growth factor in the regulation of angiogenesis. Kidney Int. 1999;56:794–814.PubMedGoogle Scholar
  161. 161.
    Zhang J-Z. Captopril inhibits capillary degeneration the early stages of diabetic retinopathy. Curr Eye Res. 2007;32:883–889.PubMedGoogle Scholar
  162. 162.
    Gilbert RD, Kelly DJ, Cox AJ, et al. Angiotensin converting enzyme inhibition reduces retinal overexpression of vascular endothelial growth factor and hyperpermeability in experimental diabetes. Diabetologia. 2000;43:1360–1367.PubMedGoogle Scholar
  163. 163.
    Chaturvedi N, Sjolie AK, Stephenson JM, et al. Effect of lisinopril on progression of retinopathy in normotensive people with type 1 diabetes. The EUCLID study group. EURODIAB controlled trial of Lisinopril in insulin-dependent diabetes mellitus. Lancet. 1998;351:28–31.PubMedGoogle Scholar
  164. 164.
    Funatsu H, Yamashita H, Ikeda T, et al. Angiotensin II and vascular endothelial growth factor in the vitreous fluid of patients with proliferative diabetic retinopathy. Br J Ophthalmol. 2002;86:311–315.PubMedGoogle Scholar
  165. 165.
    Nagai N, Izumi-Nagai K, Oike Y, et al. Suppression of diabetes-induced retinal inflammation by blocking the angiotensin II type 1 receptor or its downstream nuclear factor-κB pathway. Invest Oph Vis Sci. 2007;48: 4342–4350.Google Scholar
  166. 166.
    Mizutani M, Kern TS, Lorenzi M. Accelerated death of retinal microvascular cells in human and experimental diabetic retinopathy. J Clin Invest. 1996;97:2883–2890.PubMedGoogle Scholar
  167. 167.
    Benjamin LE. Glucose, VEGF-A, and diabetic complications. Am J Pathol. 2001;158:1181–1184.PubMedGoogle Scholar
  168. 168.
    Aiello L, Avery R, Arrigg P, et al. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med. 1994;331:1480–1487.PubMedGoogle Scholar
  169. 169.
    Adamis AP, Miller JW, Bernal MT, et al. Increased vascular endothelial growth factor levels in the vitreous of eyes with proliferative diabetic retinopathy. Am J Ophthalmol. 1994;118:445–450.PubMedGoogle Scholar
  170. 170.
    Simo R, Carrasco E, Garcia-Ramirez M, Hernandez C. Angiogenic and antiangiogenic factors in proliferative diabetic retinopathy. Curr Diabetes Rev. 2006;2:71–98.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Department of OphthalmologyMayo School of MedicineJacksonvilleUSA

Personalised recommendations