Documenta Ophthalmologica

, Volume 120, Issue 1, pp 67–86 | Cite as

The significance of neuronal and glial cell changes in the rat retina during oxygen-induced retinopathy

  • Erica L. Fletcher
  • Laura E. Downie
  • Kate Hatzopoulos
  • Kirstan A. Vessey
  • Michelle M. Ward
  • Chee L. Chow
  • Michael J. Pianta
  • Algis J. Vingrys
  • Michael Kalloniatis
  • Jennifer L. Wilkinson-Berka
Review Article


Retinopathy of prematurity is a devastating vascular disease of premature infants. A number of studies indicate that retinal function is affected in this disease. Using the rat model of oxygen-induced retinopathy, it is possible to explore more fully the complex relationship between neuronal, glial and vascular pathology in this condition. This review examines the structural and functional changes that occur in the rat retina following oxygen-induced retinopathy. We highlight that vascular pathology in rats is characterized by aberrant growth of blood vessels into the vitreous at the expense of blood vessel growth into the body of the retina. Moreover, amino acid neurochemistry, a tool for examining neuronal changes in a spatially complete manner reveals widespread changes in amacrine and bipolar cells. In addition, neurochemical anomalies within inner retinal neurons are highly correlated with the absence of retinal vessels. The key cell types that link blood flow with neuronal function are macroglia. Macroglia cells, which in the retina include astrocytes and Müller cells, are affected by oxygen-induced retinopathy. Astrocyte loss occurs in the peripheral retina, while Müller cells show signs of reactive gliosis that is highly localized to regions that are devoid of intraretinal blood vessels. Finally, we propose that treatments, such as blockade of the renin–angiotensin system, that not only targets pathological angiogenesis, but that also promotes re-vascularization of the retina are likely to prove important in the treatment of those with retinopathy of prematurity.


Müller cell Astrocyte Photoreceptor Amacrine cell Electroretinogram Neovascularization 



This work was supported by the National Health and Medical Research Council of Australia (NHMRC grant #566815 to E. L. F. and #350224 to A. J. V., and #299974 to J. W.-B. & E. L. F.) J. W.-B. is an NHMRC Senior Research Fellow B.


  1. 1.
    Good WV, Hardy RJ, Dobson V, Palmer EA, Phelps DL, Quintos M et al (2005) The incidence and course of retinopathy of prematurity: findings from the early treatment for retinopathy of prematurity study. Pediatrics 116(1):15–23PubMedCrossRefGoogle Scholar
  2. 2.
    O’Connor AR, Stephenson T, Johnson A, Tobin MJ, Moseley MJ, Ratib S et al (2002) Long-term ophthalmic outcome of low birth weight children with and without retinopathy of prematurity. Pediatrics 109(1):12–18PubMedCrossRefGoogle Scholar
  3. 3.
    Slidsborg C, Olesen HB, Jensen PK, Jensen H, Nissen KR, Greisen G et al (2008) Treatment for retinopathy of prematurity in Denmark in a ten-year period (1996–2005): is the incidence increasing? Pediatrics 121(1):97–105PubMedCrossRefGoogle Scholar
  4. 4.
    Barnaby AM, Hansen RM, Moskowitz A, Fulton AB (2007) Development of scotopic visual thresholds in retinopathy of prematurity. Invest Ophthalmol Vis Sci 48(10):4854–4860PubMedCrossRefGoogle Scholar
  5. 5.
    Fulton AB, Hansen RM (1996) Photoreceptor function in infants and children with a history of mild retinopathy of prematurity. J Opt Soc Am 13(3):566–571CrossRefGoogle Scholar
  6. 6.
    Fulton AB, Hansen RM, Petersen RA, Vanderveen DK (2001) The rod photoreceptors in retinopathy of prematurity: an electroretinographic study. Arch Ophthalmol 119(4):499–505PubMedGoogle Scholar
  7. 7.
    Akula JD, Hansen RM, Martinez-Perez ME, Fulton AB (2007) Rod photoreceptor function predicts blood vessel abnormality in retinopathy of prematurity. Invest Ophthalmol Vis Sci 48(9):4351–4359PubMedCrossRefGoogle Scholar
  8. 8.
    Liu K, Akula JD, Falk C, Hansen RM, Fulton AB (2006) The retinal vasculature and function of the neural retina in a rat model of retinopathy of prematurity. Invest Ophthalmol Vis Sci 47(6):2639–2647PubMedCrossRefGoogle Scholar
  9. 9.
    Ames A 3rd, Li YY, Heher EC, Kimble CR (1992) Energy metabolism of rabbit retina as related to function: high cost of Na+ transport. J Neurosci 12(3):840–853PubMedGoogle Scholar
  10. 10.
    Bringmann A, Pannicke T, Grosche J, Francke M, Wiedemann P, Skatchkov SN et al (2006) Muller cells in the healthy and diseased retina. Prog Retin Eye Res 25(4):397–424PubMedCrossRefGoogle Scholar
  11. 11.
    Dorrell MI, Friedlander M (2006) Mechanisms of endothelial cell guidance and vascular patterning in the developing mouse retina. Prog Retin Eye Res 25(3):277–295PubMedCrossRefGoogle Scholar
  12. 12.
    Anderson CM, Nedergaard M (2003) Astrocyte-mediated control of cerebral microcirculation. Trends Neurosci 26(7):340–344 author reply 4–5PubMedCrossRefGoogle Scholar
  13. 13.
    Metea MR, Newman EA (2006) Glial cells dilate and constrict blood vessels: a mechanism of neurovascular coupling. J Neurosci 26(11):2862–2870PubMedCrossRefGoogle Scholar
  14. 14.
    Mulligan SJ, MacVicar BA (2004) Calcium transients in astrocyte endfeet cause cerebrovascular constrictions. Nature 431(7005):195–199PubMedCrossRefGoogle Scholar
  15. 15.
    Hanisch UK, Kettenmann H (2007) Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci 10(11):1387–1394PubMedCrossRefGoogle Scholar
  16. 16.
    Checchin D, Sennlaub F, Levavasseur E, Leduc M, Chemtob S (2006) Potential role of microglia in retinal blood vessel formation. Invest Ophthalmol Vis Sci 47(8):3595–3602PubMedCrossRefGoogle Scholar
  17. 17.
    Davies MH, Eubanks JP, Powers MR (2006) Microglia and macrophages are increased in response to ischemia-induced retinopathy in the mouse retina. Mol Vis 12:467–477PubMedGoogle Scholar
  18. 18.
    Zhao L, Ma W, Fariss RN, Wong WT (2009) Retinal vascular repair and neovascularization are not dependent on CX3CR1 signaling in a model of ischemic retinopathy. Exp Eye Res 88(6):1004–1013PubMedCrossRefGoogle Scholar
  19. 19.
    Lutty GA, Chan-Ling T, Phelps DL, Adamis AP, Berns KI, Chan CK et al (2006) Proceedings of the third international symposium on retinopathy of prematurity: an update on ROP from the lab to the nursery (November 2003, Anaheim, California). Mol Vis 12:532–580PubMedGoogle Scholar
  20. 20.
    Penn JS, Henry MM, Wall PT, Tolman BL (1995) The range of PaO2 variation determines the severity of oxygen-induced retinopathy in newborn rats. Invest Ophthalmol Vis Sci 36(10):2063–2070PubMedGoogle Scholar
  21. 21.
    Penn JS, Tolman BL, Lowery LA, Koutz CA (1992) Oxygen-induced retinopathy in the rat: hemorrhages and dysplasias may lead to retinal detachment. Curr Eye Res 11(10):939–953PubMedCrossRefGoogle Scholar
  22. 22.
    Penn JS, Tolman BL, Henry MM (1994) Oxygen-induced retinopathy in the rat: relationship of retinal nonperfusion to subsequent neovascularization. Invest Ophthalmol Vis Sci 35(9):3429–3435PubMedGoogle Scholar
  23. 23.
    van Wijngaarden P, Brereton HM, Coster DJ, Williams KA (2007) Genetic influences on susceptibility to oxygen-induced retinopathy. Invest Ophthalmol Vis Sci 48(4):1761–1766PubMedCrossRefGoogle Scholar
  24. 24.
    van Wijngaarden P, Brereton HM, Gibbins IL, Coster DJ, Williams KA (2007) Kinetics of strain-dependent differential gene expression in oxygen-induced retinopathy in the rat. Exp Eye Res 85(4):508–517PubMedCrossRefGoogle Scholar
  25. 25.
    Hellstrom A, Perruzzi C, Ju M, Engstrom E, Hard AL, Liu JL et al (2001) Low IGF-I suppresses VEGF-survival signaling in retinal endothelial cells: direct correlation with clinical retinopathy of prematurity. Proc Natl Acad Sci USA 98(10):5804–5808PubMedCrossRefGoogle Scholar
  26. 26.
    Oshima Y, Oshima S, Nambu H, Kachi S, Takahashi K, Umeda N et al (2005) Different effects of angiopoietin-2 in different vascular beds: new vessels are most sensitive. FASEB J 19(8):963–965PubMedGoogle Scholar
  27. 27.
    Xia XB, Xiong SQ, Song WT, Luo J, Wang YK, Zhou RR (2008) Inhibition of retinal neovascularization by siRNA targeting VEGF(165). Mol Vis 14:1965–1973PubMedGoogle Scholar
  28. 28.
    Downie LE, Pianta MJ, Vingrys AJ, Wilkinson-Berka JL, Fletcher EL (2008) AT1 receptor inhibition prevents astrocyte degeneration and restores vascular growth in oxygen-induced retinopathy. Glia 56(10):1076–1090PubMedCrossRefGoogle Scholar
  29. 29.
    Provis JM (2001) Development of the primate retinal vasculature. Prog Retin Eye Res 20(6):799–821PubMedCrossRefGoogle Scholar
  30. 30.
    Dorrell MI, Aguilar E, Friedlander M (2002) Retinal vascular development is mediated by endothelial filopodia, a preexisting astrocytic template and specific R-cadherin adhesion. Invest Ophthalmol Vis Sci 43(11):3500–3510PubMedGoogle Scholar
  31. 31.
    Fruttiger M, Calver AR, Kruger WH, Mudhar HS, Michalovich D, Takakura N et al (1996) PDGF mediates a neuron-astrocyte interaction in the developing retina. Neuron 17(6):1117–1131PubMedCrossRefGoogle Scholar
  32. 32.
    Stone J, Itin A, Alon T, Pe’er J, Gnessin H, Chan-Ling T et al (1995) Development of retinal vasculature is mediated by hypoxia-induced vascular endothelial growth factor (VEGF) expression by neuroglia. J Neurosci 15(7 Pt 1):4738–4747PubMedGoogle Scholar
  33. 33.
    Stone J, Chan-Ling T, Pe’er J, Itin A, Gnessin H, Keshet E (1996) Roles of vascular endothelial growth factor and astrocyte degeneration in the genesis of retinopathy of prematurity. Invest Ophthalmol Vis Sci 37(2):290–299PubMedGoogle Scholar
  34. 34.
    Palmer EA, Hardy RJ, Dobson V, Phelps DL, Quinn GE, Summers CG et al (2005) 15-year outcomes following threshold retinopathy of prematurity: final results from the multicenter trial of cryotherapy for retinopathy of prematurity. Arch Ophthalmol 123(3):311–318PubMedCrossRefGoogle Scholar
  35. 35.
    Reisner DS, Hansen RM, Findl O, Petersen RA, Fulton AB (1997) Dark-adapted thresholds in children with histories of mild retinopathy of prematurity. Invest Ophthalmol Vis Sci 38(6):1175–1183PubMedGoogle Scholar
  36. 36.
    Bloomfield SA, Dacheux RF (2001) Rod vision: pathways and processing in the mammalian retina. Prog Retin Eye Res 20(3):351–384PubMedCrossRefGoogle Scholar
  37. 37.
    Mills SL, Massey SC (1999) AII amacrine cells limit scotopic acuity in central macaque retina: a confocal analysis of calretinin labeling. J Comp Neurol 411(1):19–34PubMedCrossRefGoogle Scholar
  38. 38.
    Weymouth AE, Vingrys AJ (2008) Rodent electroretinography: methods for extraction and interpretation of rod and cone responses. Prog Retin Eye Res 27(1):1–44PubMedCrossRefGoogle Scholar
  39. 39.
    Akula JD, Mocko JA, Moskowitz A, Hansen RM, Fulton AB (2007) The oscillatory potentials of the dark-adapted electroretinogram in retinopathy of prematurity. Invest Ophthalmol Vis Sci 48(12):5788–5797PubMedCrossRefGoogle Scholar
  40. 40.
    Fulton AB, Hansen RM, Moskowitz A, Barnaby AM (2005) Multifocal ERG in subjects with a history of retinopathy of prematurity. Doc Ophthalmol 111(1):7–13PubMedCrossRefGoogle Scholar
  41. 41.
    Reynaud X, Hansen RM, Fulton AB (1995) Effect of prior oxygen exposure on the electroretinographic responses of infant rats. Invest Ophthalmol Vis Sci 36(10):2071–2079PubMedGoogle Scholar
  42. 42.
    Daniele LL, Sauer B, Gallagher SM, Pugh EN Jr, Philp NJ (2008) Altered visual function in monocarboxylate transporter 3 (Slc16a8) knockout mice. Am J Physiol 295(2):C451–C457CrossRefGoogle Scholar
  43. 43.
    Yu DY, Cringle SJ (2001) Oxygen distribution and consumption within the retina in vascularised and avascular retinas and in animal models of retinal disease. Prog Retin Eye Res 20(2):175–208PubMedCrossRefGoogle Scholar
  44. 44.
    Cringle SJ, Yu PK, Su EN, Yu DY (2006) Oxygen distribution and consumption in the developing rat retina. Invest Ophthalmol Vis Sci 47(9):4072–4076PubMedCrossRefGoogle Scholar
  45. 45.
    Sherry DM, Wang MM, Bates J, Frishman LJ (2003) Expression of vesicular glutamate transporter 1 in the mouse retina reveals temporal ordering in development of rod vs. cone and ON vs. OFF circuits. J Comp Neurol 465(4):480–498PubMedCrossRefGoogle Scholar
  46. 46.
    Fulton AB, Hansen RM, Moskowitz A (2008) The cone electroretinogram in retinopathy of prematurity. Invest Ophthalmol Vis Sci 49(2):814–819PubMedCrossRefGoogle Scholar
  47. 47.
    Lachapelle P, Dembinska O, Rojas LM, Benoit J, Almazan G, Chemtob S (1999) Persistent functional and structural retinal anomalies in newborn rats exposed to hyperoxia. Can J Physiol Pharmacol 77(1):48–55PubMedCrossRefGoogle Scholar
  48. 48.
    Dembinska O, Rojas LM, Varma DR, Chemtob S, Lachapelle P (2001) Graded contribution of retinal maturation to the development of oxygen-induced retinopathy in rats. Invest Ophthalmol Vis Sci 42(5):1111–1118PubMedGoogle Scholar
  49. 49.
    Dembinska O, Rojas LM, Chemtob S, Lachapelle P (2002) Evidence for a brief period of enhanced oxygen susceptibility in the rat model of oxygen-induced retinopathy. Invest Ophthalmol Vis Sci 43(7):2481–2490PubMedGoogle Scholar
  50. 50.
    Downie LE, Pianta MJ, Vingrys AJ, Wilkinson-Berka JL, Fletcher EL (2007) Neuronal and glial cell changes are determined by retinal vascularization in retinopathy of prematurity. J Comp Neurol 504(4):404–417PubMedCrossRefGoogle Scholar
  51. 51.
    Kalloniatis M, Tomisich G (1999) Amino acid neurochemistry of the vertebrate retina. Prog Retin Eye Res 18(6):811–866PubMedCrossRefGoogle Scholar
  52. 52.
    Fletcher EL, Kalloniatis M (1996) Neurochemical architecture of the normal and degenerating rat retina. J Comp Neurol 376(3):343–360PubMedCrossRefGoogle Scholar
  53. 53.
    Kalloniatis M, Marc RE, Murry RF (1996) Amino acid signatures in the primate retina. J Neurosci 16(21):6807–6829PubMedGoogle Scholar
  54. 54.
    Marc RE, Murry RF, Fisher SK, Linberg KA, Lewis GP, Kalloniatis M (1998) Amino acid signatures in the normal cat retina. Invest Ophthalmol Vis Sci 39(9):1685–1693PubMedGoogle Scholar
  55. 55.
    Robin LN, Kalloniatis M (1992) Interrelationship between retinal ischaemic damage and turnover and metabolism of putative amino acid neurotransmitters, glutamate and GABA. Doc Ophthalmol 80(4):273–300PubMedCrossRefGoogle Scholar
  56. 56.
    Bui BV, Vingrys AJ, Kalloniatis M (2003) Correlating retinal function and amino acid immunocytochemistry following post-mortem ischemia. Exp Eye Res 77(2):125–136PubMedCrossRefGoogle Scholar
  57. 57.
    Bui BV, Vingrys AJ, Wellard JW, Kalloniatis M (2004) Monocarboxylate transport inhibition alters retinal function and cellular amino acid levels. Eur J Neurosci 20(6):1525–1537PubMedCrossRefGoogle Scholar
  58. 58.
    Fletcher EL, Kalloniatis M (1997) Neurochemical development of the degenerating rat retina. J Comp Neurol 388(1):1–22PubMedCrossRefGoogle Scholar
  59. 59.
    Fletcher EL, Kalloniatis M (1997) Localisation of amino acid neurotransmitters during postnatal development of the rat retina. J Comp Neurol 380(4):449–471PubMedCrossRefGoogle Scholar
  60. 60.
    Kalloniatis M, Fletcher EL (1993) Immunocytochemical localization of the amino acid neurotransmitters in the chicken retina. J Comp Neurol 336(2):174–193PubMedCrossRefGoogle Scholar
  61. 61.
    Kalloniatis M, Napper GA (2002) Retinal neurochemical changes following application of glutamate as a metabolic substrate. Clin Exp Optom 85(1):27–36PubMedCrossRefGoogle Scholar
  62. 62.
    Napper GA, Kalloniatis M (1999) Neurochemical changes following postmortem ischemia in the rat retina. Vis Neurosci 16(6):1169–1180PubMedCrossRefGoogle Scholar
  63. 63.
    Sun D, Bui BV, Vingrys AJ, Kalloniatis M (2007) Alterations in photoreceptor-bipolar cell signaling following ischemia/reperfusion in the rat retina. J Comp Neurol 505(1):131–146PubMedCrossRefGoogle Scholar
  64. 64.
    Sun D, Kalloniatis M (2004) Quantification of amino acid neurochemistry secondary to NMDA or betaxolol application. Clin Experiment Ophthalmol 32(5):505–517PubMedCrossRefGoogle Scholar
  65. 65.
    Sun D, Vingrys AJ, Kalloniatis M (2007) Metabolic and functional profiling of the ischemic/reperfused rat retina. J Comp Neurol 505(1):114–130PubMedCrossRefGoogle Scholar
  66. 66.
    Sun D, Vingrys AJ, Kalloniatis M (2007) Metabolic and functional profiling of the normal rat retina. J Comp Neurol 505(1):92–113PubMedCrossRefGoogle Scholar
  67. 67.
    Marc RE, Jones BW (2003) Retinal remodeling in inherited photoreceptor degenerations. Mol Neurobiol 28(2):139–147PubMedCrossRefGoogle Scholar
  68. 68.
    Marc RE, Jones BW, Anderson JR, Kinard K, Marshak DW, Wilson JH et al (2007) Neural reprogramming in retinal degeneration. Invest Ophthalmol Vis Sci 48(7):3364–3371PubMedCrossRefGoogle Scholar
  69. 69.
    Marc RE, Jones BW, Watt CB, Strettoi E (2003) Neural remodeling in retinal degeneration. Prog Retin Eye Res 22(5):607–655PubMedCrossRefGoogle Scholar
  70. 70.
    Marc RE, Murry RF, Fisher SK, Linberg KA, Lewis GP (1998) Amino acid signatures in the detached cat retina. Invest Ophthalmol Vis Sci 39(9):1694–1702PubMedGoogle Scholar
  71. 71.
    Tout S, Chan-Ling T, Hollander H, Stone J (1993) The role of Muller cells in the formation of the blood-retinal barrier. Neuroscience 55(1):291–301PubMedCrossRefGoogle Scholar
  72. 72.
    Chan-Ling T, Stone J (1992) Degeneration of astrocytes in feline retinopathy of prematurity causes failure of the blood-retinal barrier. Invest Ophthalmol Vis Sci 33(7):2148–2159PubMedGoogle Scholar
  73. 73.
    Pow DV, Robinson SR (1994) Glutamate in some retinal neurons is derived solely from glia. Neuroscience 60(2):355–366PubMedCrossRefGoogle Scholar
  74. 74.
    Kalloniatis M, Napper GA (1996) Glutamate metabolic pathways in displaced ganglion cells of the chicken retina. J Comp Neurol 367(4):518–536PubMedCrossRefGoogle Scholar
  75. 75.
    Napper GA, Pianta MJ, Kalloniatis M (2001) Localization of amino acid neurotransmitters following in vitro ischemia and anoxia in the rat retina. Vis Neurosci 18(3):413–427PubMedCrossRefGoogle Scholar
  76. 76.
    Chan-Ling T, McLeod DS, Hughes S, Baxter L, Chu Y, Hasegawa T et al (2004) Astrocyte-endothelial cell relationships during human retinal vascular development. Invest Ophthalmol Vis Sci 45(6):2020–2032PubMedCrossRefGoogle Scholar
  77. 77.
    Zhang Y, Stone J (1997) Role of astrocytes in the control of developing retinal vessels. Invest Ophthalmol Vis Sci 38(9):1653–1666PubMedGoogle Scholar
  78. 78.
    Penn JS, Thum LA, Rhem MN, Dell SJ (1988) Effects of oxygen rearing on the electroretinogram and GFA-protein in the rat. Invest Ophthalmol Vis Sci 29(11):1623–1630PubMedGoogle Scholar
  79. 79.
    Haydon PG (2001) GLIA: listening and talking to the synapse. Nat Rev 2(3):185–193CrossRefGoogle Scholar
  80. 80.
    Newman EA (2004) Glial modulation of synaptic transmission in the retina. Glia 47(3):268–274PubMedCrossRefGoogle Scholar
  81. 81.
    Gordon GR, Choi HB, Rungta RL, Ellis-Davies GC, MacVicar BA (2008) Brain metabolism dictates the polarity of astrocyte control over arterioles. Nature 456(7223):745–749PubMedCrossRefGoogle Scholar
  82. 82.
    Gordon GR, Mulligan SJ, MacVicar BA (2007) Astrocyte control of the cerebrovasculature. Glia 55(12):1214–1221PubMedCrossRefGoogle Scholar
  83. 83.
    Nimmerjahn A, Kirchhoff F, Helmchen F (2005) Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308(5726):1314–1318PubMedCrossRefGoogle Scholar
  84. 84.
    Lee JE, Liang KJ, Fariss RN, Wong WT (2008) Ex vivo dynamic imaging of retinal microglia using time-lapse confocal microscopy. Invest Ophthalmol Vis Sci 49(9):4169–4176PubMedCrossRefGoogle Scholar
  85. 85.
    Davies MH, Stempel AJ, Powers MR (2008) MCP-1 deficiency delays regression of pathologic retinal neovascularization in a model of ischemic retinopathy. Invest Ophthalmol Vis Sci 49(9):4195–4202PubMedCrossRefGoogle Scholar
  86. 86.
    Ambati J, Anand A, Fernandez S, Sakurai E, Lynn BC, Kuziel WA et al (2003) An animal model of age-related macular degeneration in senescent Ccl-2- or Ccr-2-deficient mice. Nat Med 9(11):1390–1397PubMedCrossRefGoogle Scholar
  87. 87.
    El Khoury J, Toft M, Hickman SE, Means TK, Terada K, Geula C et al (2007) Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like disease. Nat Med 13(4):432–438PubMedCrossRefGoogle Scholar
  88. 88.
    Yoshida S, Yoshida A, Ishibashi T, Elner SG, Elner VM (2003) Role of MCP-1 and MIP-1alpha in retinal neovascularization during postischemic inflammation in a mouse model of retinal neovascularization. J Leukoc Biol 73(1):137–144PubMedCrossRefGoogle Scholar
  89. 89.
    Biber K, Neumann H, Inoue K, Boddeke HW (2007) Neuronal ‘On’ and ‘Off’ signals control microglia. Trends Neurosci 30(11):596–602PubMedCrossRefGoogle Scholar
  90. 90.
    Block ML, Zecca L, Hong JS (2007) Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev 8(1):57–69CrossRefGoogle Scholar
  91. 91.
    Lalancette-Hebert M, Gowing G, Simard A, Weng YC, Kriz J (2007) Selective ablation of proliferating microglial cells exacerbates ischemic injury in the brain. J Neurosci 27(10):2596–2605PubMedCrossRefGoogle Scholar
  92. 92.
    Cardona AE, Pioro EP, Sasse ME, Kostenko V, Cardona SM, Dijkstra IM et al (2006) Control of microglial neurotoxicity by the fractalkine receptor. Nat Neurosci 9(7):917–924PubMedCrossRefGoogle Scholar
  93. 93.
    Danser AH, van den Dorpel MA, Deinum J, Derkx FH, Franken AA, Peperkamp E et al (1989) Renin, prorenin, and immunoreactive renin in vitreous fluid from eyes with and without diabetic retinopathy. J Clin Endocrinol Metab 68(1):160–167PubMedCrossRefGoogle Scholar
  94. 94.
    Moravski CJ, Kelly DJ, Cooper ME, Gilbert RE, Bertram JF, Shahinfar S et al (2000) Retinal neovascularization is prevented by blockade of the renin-angiotensin system. Hypertension 36(6):1099–1104PubMedGoogle Scholar
  95. 95.
    Wilkinson-Berka JL, Fletcher EL (2004) Angiotensin and bradykinin: targets for the treatment of vascular and neuro-glial pathology in diabetic retinopathy. Curr Pharm Des 10(27):3313–3330PubMedCrossRefGoogle Scholar
  96. 96.
    Berka JL, Stubbs AJ, Wang DZ, DiNicolantonio R, Alcorn D, Campbell DJ et al (1995) Renin-containing Muller cells of the retina display endocrine features. Invest Ophthalmol Vis Sci 36(7):1450–1458PubMedGoogle Scholar
  97. 97.
    Sarlos S, Wilkinson-Berka JL (2005) The renin-angiotensin system and the developing retinal vasculature. Invest Ophthalmol Vis Sci 46(3):1069–1077PubMedCrossRefGoogle Scholar
  98. 98.
    Yokota H, Nagaoka T, Mori F, Hikichi T, Hosokawa H, Tanaka H et al (2007) Prorenin levels in retinopathy of prematurity. Am J Ophthalmol 143(3):531–533PubMedCrossRefGoogle Scholar
  99. 99.
    Lonchampt M, Pennel L, Duhault J (2001) Hyperoxia/normoxia-driven retinal angiogenesis in mice: a role for angiotensin II. Invest Ophthalmol Vis Sci 42(2):429–432PubMedGoogle Scholar
  100. 100.
    Wilkinson-Berka JL (2004) Diabetes and retinal vascular disorders: role of the renin-angiotensin system. Expert Rev Mol Med 6(15):1–18PubMedCrossRefGoogle Scholar
  101. 101.
    Nagai N, Noda K, Urano T, Kubota Y, Shinoda H, Koto T et al (2005) Selective suppression of pathologic, but not physiologic, retinal neovascularization by blocking the angiotensin II type 1 receptor. Invest Ophthalmol Vis Sci 46(3):1078–1084PubMedCrossRefGoogle Scholar
  102. 102.
    Wilkinson-Berka JL, Tan G, Jaworski K, Miller AG (2009) Identification of a retinal aldosterone system and the protective effects of mineralocorticoid receptor antagonism on retinal vascular pathology. Circ Res 104(1):124–133PubMedCrossRefGoogle Scholar
  103. 103.
    Satofuka S, Ichihara A, Nagai N, Koto T, Shinoda H, Noda K et al (2007) Role of nonproteolytically activated prorenin in pathologic, but not physiologic, retinal neovascularization. Invest Ophthalmol Vis Sci 48(1):422–429PubMedCrossRefGoogle Scholar
  104. 104.
    Sarlos S, Rizkalla B, Moravski CJ, Cao Z, Cooper ME, Wilkinson-Berka JL (2003) Retinal angiogenesis is mediated by an interaction between the angiotensin type 2 receptor, VEGF, and angiopoietin. Am J Pathol 163(3):879–887PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Erica L. Fletcher
    • 1
  • Laura E. Downie
    • 1
    • 2
  • Kate Hatzopoulos
    • 1
  • Kirstan A. Vessey
    • 1
  • Michelle M. Ward
    • 1
  • Chee L. Chow
    • 1
  • Michael J. Pianta
    • 2
  • Algis J. Vingrys
    • 2
  • Michael Kalloniatis
    • 1
    • 4
  • Jennifer L. Wilkinson-Berka
    • 3
  1. 1.Department of Anatomy and Cell BiologyThe University of MelbourneParkvilleAustralia
  2. 2.Department of Optometry and Vision SciencesThe University of MelbourneParkvilleAustralia
  3. 3.Department of ImmunologyMonash UniversityPrahranAustralia
  4. 4.Department of Optometry and Vision ScienceUniversity of AucklandAucklandNew Zealand

Personalised recommendations