Skip to main content
SpringerLink
Log in

VEGF Inhibitor Induced Oxidative Stress in Retinal Ganglion Cells

  • Chapter
  • First Online:
Studies on Retinal and Choroidal Disorders

  • 1113 Accesses

Abstract

Oxidative stress mediated toxicity is common to several sight-threatening ocular conditions, in which vascular endothelial growth factor (VEGF) plays both a pathologic and protective role. Anti-VEGF therapy can negate the protective role of endogenous VEGF and enhance oxidative stress and thus should be administered with caution as long-term intravitreal usage of bevacizumab may have collateral negative effects on retinal cells.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 279.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Kumar DM, Agarwal N (2007) Oxidative stress in glaucoma: a burden of evidence. J Glaucoma 16(3):334–343

    Article  PubMed  Google Scholar 

  2. Madsen-Bouterse SA, Kowluru RA (2008) Oxidative stress and diabetic retinopathy: pathophysiological mechanisms and treatment perspectives. Rev Endocr Metab Disord 9(4):315–327

    Article  PubMed  CAS  Google Scholar 

  3. Beatty S, Koh H, Phil M et al (2000) The role of oxidative stress in the pathogenesis of age-related macular degeneration. Surv Ophthalmol 45:115–134

    Article  PubMed  CAS  Google Scholar 

  4. Ferrara N, Mass RD, Campa C et al (2007) Targeting VEGF-A to treat cancer and age-related macular degeneration. Annu Rev Med 58:491–504

    Article  PubMed  CAS  Google Scholar 

  5. Duh EJ, Yang HS, Haller JA et al (2004) Vitreous levels of pigment epithelium-derived factor and vascular endothelial growth factor: implications for ocular angiogenesis. Am J Ophthalmol 137:668–674

    PubMed  CAS  Google Scholar 

  6. Chan WM, Lai TY, Chan KP et al (2008) Changes in aqueous vascular endothelial growth factor and pigment epithelial-derived growth factor levels following intravitreal bevacizumab injections for choroidal neovascularization secondary to age-related macular degeneration or pathologic myopia. Retina 28(9):1308–1313

    Article  PubMed  Google Scholar 

  7. Aiello LP, Avery RL, Arrigg PG et al (1994) Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med 331:1480–1487

    Article  PubMed  CAS  Google Scholar 

  8. Grover S, Gupta S, Sharma R et al (2009) Intracameral bevacizumab effectively reduces aqueous vascular endothelial growth factor concentrations in neovascular glaucoma. Br J Ophthalmol 93(2):273–274

    Article  PubMed  CAS  Google Scholar 

  9. Sharma RK, Rogojina AT, Chalam KV (2010) Bevacizumab therapy normalizes the pathological intraocular environment beyond neutralizing VEGF. Mol Vis 16:2175–2184

    PubMed  CAS  Google Scholar 

  10. Campochiaro PA, Choy DF, Do DV et al (2009) Monitoring ocular drug therapy by analysis of aqueous samples. Ophthalmology 116(11):2158–2164

    Article  PubMed  Google Scholar 

  11. Gragoudas ES, Adamis AP, Cunningham ET Jr et al (2004) Pegaptanib for neovascular age-related macular degeneration. N Engl J Med 351:2805–2816

    Article  PubMed  CAS  Google Scholar 

  12. Brown DM, Kaiser PK, Michels M et al (2006) Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med 355:1432–1444

    Article  PubMed  CAS  Google Scholar 

  13. Arevalo JF, Fromow-Guerra J, Quiroz-Mercado H et al (2007) Primary intravitreal bevacizumab (avastin) for diabetic macular edema: results from the Pan-American Collaborative Retina Study Group at 6-month follow-up. Ophthalmology 114(4):743–750

    Article  PubMed  Google Scholar 

  14. Kook D, Wolf A, Kreutzer T et al (2008) Long-term effect of intravitreal bevacizumab (avastin) in patients with chronic diffuse diabetic macular edema. Retina 28(8):1053–1060

    Article  PubMed  Google Scholar 

  15. Costa RA, Jorge R, Calucci D et al (2007) Intravitreal bevacizumab (avastin) for central and hemicentral retinal vein occlusions: IBeVO study. Retina 27(2):141–149

    Article  PubMed  Google Scholar 

  16. Charbel Issa P, Finger RP, Holz FG et al (2008) Eighteen-month follow-up of intravitreal bevacizumab in type 2 idiopathic macular telangiectasia. Br J Ophthalmol 92(7):941–945

    Article  PubMed  CAS  Google Scholar 

  17. Arevalo JF, Garcia-Amaris RA, Roca JA et al (2007) Primary intravitreal bevacizumab for the management of pseudophakic cystoid macular edema: pilot study of the Pan-American Collaborative Retina Study Group. J Cataract Refract Surg 33(12):2098–2105

    Article  PubMed  Google Scholar 

  18. Mirshahi A, Namavari A, Djalilian A et al (2009) Intravitreal bevacizumab (avastin) for the treatment of cystoid macular edema in Behçet disease. Ocul Immunol Inflamm 17(1):59–64

    Article  PubMed  Google Scholar 

  19. Chalam KV, Gupta SK, Grover S et al (2008) Intracameral avastin dramatically resolves iris neovascularization and reverses neovascular glaucoma. Eur J Ophthalmol 18(2):255–262

    PubMed  CAS  Google Scholar 

  20. Rosenfeld PJ, Moshfeghi AA, Puliafito CA (2005) Optical coherence tomography findings after an intravitreal injection of bevacizumab (avastin) for neovascular age-related macular degeneration. Ophthalmic Surg Lasers Imaging 36(4):331–335

    PubMed  Google Scholar 

  21. Avery RL, Pieramici DJ, Rabena MD et al (2006) Intravitreal bevacizumab (avastin) for neovascular age-related macular degeneration. Ophthalmology 113(3):363–372

    Article  PubMed  Google Scholar 

  22. Sun Y, Jin K, Xie L et al (2003) VEGF-induced neuroprotection, neurogenesis, and angiogenesis after focal cerebral ischemia. J Clin Invest 111(12):1843–1851

    PubMed  CAS  Google Scholar 

  23. Tolosa L, Mir M, Asensio VJ et al (2008) Vascular endothelial growth factor protects spinal cord motoneurons against glutamate-induced excitotoxicity via phosphatidylinositol 3-kinase. J Neurochem 105(4):1080–1090

    Article  PubMed  CAS  Google Scholar 

  24. Nishijima K, Ng YS, Zhong L et al (2007) Vascular endothelial growth factor-A is a survival factor for retinal neurons and a critical neuroprotectant during the adaptive response to ischemic injury. Am J Pathol 171(1):53–67

    Article  PubMed  CAS  Google Scholar 

  25. Kilic U, Kilic E, Järve A et al (2006) Human vascular endothelial growth factor protects axotomized retinal ganglion cell in vivo by activating ERK-1/2 and Akt pathways. J Neurosci 26:12439–12446

    Article  PubMed  CAS  Google Scholar 

  26. Lambrechts D, Storkebaum E, Morimoto M et al (2003) VEGF is a modifier of amyotrophic lateral sclerosis in mice and humans and protects motoneurons against ischemic death. Nat Genet 34(4):383–394

    Article  PubMed  CAS  Google Scholar 

  27. Wang Y, Mao XO, Xie L et al (2007) Vascular endothelial growth factor overexpression delays neurodegeneration and prolongs survival in amyotrophic lateral sclerosis mice. J Neurosci 27(2):304–307

    Article  PubMed  Google Scholar 

  28. Storkebaum E, Lambrechts D, Dewerchin M et al (2005) Treatment of motoneuron degeneration by intracerebroventricular delivery of VEGF in a rat model of ALS. Nat Neurosci 8(1):85–92

    Article  PubMed  CAS  Google Scholar 

  29. Zheng C, Nennesmo I, Fadeel B et al (2004) Vascular endothelial growth factor prolongs ­survival in a transgenic mouse model of ALS. Ann Neurol 56(4):564–567

    Article  PubMed  CAS  Google Scholar 

  30. Azzouz M, Ralph GS, Storkebaum E et al (2004) VEGF delivery with retrogradely transported lentivector prolongs survival in a mouse ALS model. Nature 429(6990):413–417

    Article  PubMed  CAS  Google Scholar 

  31. Brar VS, Sharma RK, Murthy RK et al (2010) Bevacizumab neutralizes the protective effect of vascular endothelial growth factor on retinal ganglion cells. Mol Vis 16:1848–1853

    PubMed  CAS  Google Scholar 

  32. Byeon SH, Lee SC, Choi SH et al (2010) Vascular endothelial growth factor as an autocrine survival factor for retinal pigment epithelial cells under oxidative stress via the VEGF-R2/PI3K/Akt. Invest Ophthalmol Vis Sci 51(2):1190–1197

    Article  PubMed  Google Scholar 

  33. Saint-Geniez M, Maharaj ASR, Walshe TE et al (2008) Endogenous VEGF is required for visual function: evidence for a survival role on Müller cells and photoreceptors. PLoS One 3(11):e3554

    Article  PubMed  Google Scholar 

  34. Cedrone C, Mancino R, Cerulli A et al (2008) Epidemiology of primary glaucoma: prevalence, incidence, and blinding effects. Prog Brain Res 173:3–14

    Article  PubMed  Google Scholar 

  35. Ferreira SM, Lerner SF, Brunzini R et al (2004) Oxidative stress markers in aqueous humor of glaucoma patients. Am J Ophthalmol 137(1):62–69

    Article  PubMed  CAS  Google Scholar 

  36. Zanon-Moreno V, Garcia-Medina JJ, Gallego-Pinazo R et al (2009) Antioxidant status modifications by topical administration of dorzolamide in primary open-angle glaucoma. Eur J Ophthalmol 19(4):565–571

    PubMed  Google Scholar 

  37. Organisciak DT, Darrow RM, Barsalou L et al (1998) Light history and age-related changes in retinal light damage. Invest Ophthalmol Vis Sci 39:1107–1116

    PubMed  CAS  Google Scholar 

  38. Balaiya S, Murthy RK, Brar VS et al (2010) Evaluation of ultraviolet light toxicity on cultured retinal pigment epithelial and retinal ganglion cells. Clin Ophthalmol 4:33–39

    PubMed  Google Scholar 

  39. Maher P, Hanneken A (2005) The molecular basis of oxidative stress-induced cell death in an immortalized retinal ganglion cell line. Invest Ophthalmol Vis Sci 46(2):749–757

    Article  PubMed  Google Scholar 

  40. Baltmr A, Duggan J, Nizari S et al (2010) Neuroprotection in glaucoma—is there a future role? Exp Eye Res 91(5):554–566

    Article  PubMed  CAS  Google Scholar 

  41. Belforte NA, Moreno MC, de Zavalía N et al (2010) Melatonin: a novel neuroprotectant for the treatment of glaucoma. J Pineal Res 48(4):353–364

    Article  PubMed  CAS  Google Scholar 

  42. Mozaffarieh M, Grieshaber MC, Orgül S et al (2008) The potential value of natural antioxidative treatment in glaucoma. Surv Ophthalmol 53(5):479–505

    Article  PubMed  CAS  Google Scholar 

  43. Klein BE (2007) Overview of epidemiologic studies of diabetic retinopathy. Ophthalmic Epidemiol 14(4):179–183

    Article  PubMed  Google Scholar 

  44. Giacco F, Brownlee M (2010) Oxidative stress and diabetic complications. Circ Res 107(9):1058–1070

    Article  PubMed  CAS  Google Scholar 

  45. Gabbay KH (1975) Hyperglycemia, polyol metabolism, and complications of diabetes mellitus. Annu Rev Med 26:521–536

    Article  PubMed  CAS  Google Scholar 

  46. Dagher Z, Park YS, Asnaghi V et al (2004) Studies of rat and human retinas predict a role for the polyol pathway in human diabetic retinopathy. Diabetes 53(9):2404–2411

    Article  PubMed  CAS  Google Scholar 

  47. Bravi MC, Pietrangeli P, Laurenti O et al (1997) Polyol pathway activation and glutathione redox status in non-insulin-dependent diabetic patients. Metabolism 46(10):1194–1198

    Article  PubMed  CAS  Google Scholar 

  48. Xu Y, Wang S, Feng L, Zhu Q, Xiang P, He B (2010) Blockade of PKC-beta protects HUVEC from advanced glycation end products induced inflammation. Int Immunopharmacol 10(12): 1552–1559

    Article  PubMed  CAS  Google Scholar 

  49. PKC-DRS2 Group, Aiello LP, Davis MD, Girach A et al (2006) Effect of ruboxistaurin on visual loss in patients with diabetic retinopathy. Ophthalmology 113(12):2221–2230

    Article  PubMed  Google Scholar 

  50. Resnikoff S, Pascolini D, Etya’ale D et al (2004) Global data on visual impairment in the year 2002. Bull World Health Organ 82(11):844–851

    PubMed  Google Scholar 

  51. Jin GF, Hurst JS, Godley BF (2001) Hydrogen peroxide stimulates apoptosis in cultured human retinal pigment epithelial cells. Curr Eye Res 22:165–173

    Article  PubMed  CAS  Google Scholar 

  52. Rozanowska M, Jarvis-Evans J, Korytowski W et al (1995) Blue light-induced reactivity of retinal age pigment. In vitro generation of oxygen-reactive species. J Biol Chem 270:18825–18830

    Article  PubMed  CAS  Google Scholar 

  53. Winkler BS, Boulton ME, Gottsch JD et al (1999) Oxidative damage and age-related macular degeneration. Mol Vis 5:32

    PubMed  CAS  Google Scholar 

  54. Khandhadia S, Lotery A (2010) Oxidation and age-related macular degeneration: insights from molecular biology. Expert Rev Mol Med 12:e34

    Article  PubMed  Google Scholar 

  55. Tate DJ, Miceli MV, Newsome DA (1995) Phagocytosis and H2O2 induce catalase and metallothionein gene expression in human retinal pigment epithelial cells. Invest Ophthalmol Vis Sci 36:1271–1279

    PubMed  Google Scholar 

  56. Kannan R, Zhang N, Sreekumar PG et al (2006) Stimulation of apical and basolateral VEGF-A and VEGF-C secretion by oxidative stress in polarized retinal pigment epithelial cells. Mol Vis 12:1649–1659

    PubMed  CAS  Google Scholar 

  57. Ferrara N, Henzel WJ (1989) Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. Biochem Biophys Res Commun 161:851–859

    Article  PubMed  CAS  Google Scholar 

  58. Keck PJ, Hauser SD, Krivi G et al (1989) Vascular permeability factor, an endothelial cell mitogen related to PDGF. Science 246:1309–1312

    Article  PubMed  CAS  Google Scholar 

  59. Ferrara N, Damico L, Shams N et al (2006) Development of ranibizumab, an anti-vascular endothelial growth factor antigen binding fragment, as therapy for neovascular age-related macular degeneration. Retina 26(8):859–870

    Article  PubMed  Google Scholar 

  60. Darland DC, Massingham LJ, Smith SR et al (2003) Pericyte production of cell-associated VEGF is differentiation-dependent and is associated with endothelial survival. Dev Biol 264:275–288

    Article  PubMed  CAS  Google Scholar 

  61. Saint-Geniez M, Maldonado AE, D’Amore PA (2006) VEGF expression and receptor activation in the choroid during development and in the adult. Invest Ophthalmol Vis Sci 47:3135–3142

    Article  PubMed  Google Scholar 

  62. Shima DT, Adamis AP, Ferrara N et al (1995) Hypoxic induction of endothelial cell growth factors in retinal cells: identification and characterization of vascular endothelial growth factor (VEGF) as the mitogen. Mol Med 1(2):182–193

    PubMed  CAS  Google Scholar 

  63. Castilla MA, Caramelo C, Gazapo RM et al (2000) Role of vascular endothelial growth factor (VEGF) in endothelial cell protection against cytotoxic agents. Life Sci 67:1003–1013

    Article  PubMed  CAS  Google Scholar 

  64. Sathasivam S (2008) VEGF and ALS. Neurosci Res 62(2):71–77

    Article  PubMed  CAS  Google Scholar 

  65. Abid MR, Schoots IG, Spokes KC et al (2004) Vascular endothelial growth factor-mediated induction of manganese superoxide dismutase occurs through redox-dependent regulation of forkhead and IkappaB/NF-kappaB. J Biol Chem 279(42):44030–44038

    Article  PubMed  CAS  Google Scholar 

  66. Madhavan L, Ourednik V, Ourednik J (2008) Neural stem/progenitor cells initiate the formation of cellular networks that provide neuroprotection by growth factor-modulated antioxidant expression. Stem Cells 26:254–265

    Article  PubMed  CAS  Google Scholar 

  67. Siner JM, Jiang G, Cohen ZI et al (2007) VEGF-induced heme oxygenase-1 confers cytoprotection from lethal hyperoxia in vivo. FASEB J 21:1422–1432

    Article  PubMed  CAS  Google Scholar 

  68. González-Pacheco FR, Deudero JJ, Castellanos MC et al (2006) Mechanisms of endothelial response to oxidative aggression: protective role of autologous VEGF and induction of VEGFR2 by H2O2. Am J Physiol Heart Circ Physiol 291(3):H1395–H1401

    Article  PubMed  Google Scholar 

  69. Li B, Xu W, Luo C et al (2003) VEGF-induced activation of the PI3-K/Akt pathway reduces mutant SOD1-mediated motor neuron cell death. Brain Res Mol Brain Res 111(1–2): 155–164

    Article  PubMed  CAS  Google Scholar 

  70. Takahashi T, Shimizu H, Morimatsu H et al (2007) Heme oxygenase-1: a fundamental guardian against oxidative tissue injuries in acute inflammation. Mini Rev Med Chem 7(7): 745–753

    Article  PubMed  CAS  Google Scholar 

  71. Morse D, Lin L, Choi AM et al (2009) Heme oxygenase-1, a critical arbitrator of cell death pathways in lung injury and disease. Free Radic Biol Med 47(1):1–12

    Article  PubMed  CAS  Google Scholar 

  72. Wooten MW (1999) Function for NF-kB in neuronal survival: regulation by atypical protein kinase C. J Neurosci Res 58(5):607–611

    Article  PubMed  CAS  Google Scholar 

  73. Kim AH, Khursigara G, Sun X et al (2001) Akt phosphorylates and negatively regulates apoptosis signal-regulating kinase 1. Mol Cell Biol 21(3):893–901

    Article  PubMed  CAS  Google Scholar 

  74. Rosenfeld PJ, Brown DM, Heier JS et al (2006) Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 355(14):1419–1431

    Article  PubMed  CAS  Google Scholar 

  75. Xu W, Wang H, Wang F et al (2010) Testing toxicity of multiple intravitreal injections of bevacizumab in rabbit eyes. Can J Ophthalmol 45(4):386–392

    Article  PubMed  Google Scholar 

  76. Pedersen KB, Møller F, Sjølie AK et al (2010) Electrophysiological assessment of retinal function during 6 months of bevacizumab treatment in neovascular age-related macular degeneration. Retina 30(7):1025–1033

    Article  PubMed  Google Scholar 

  77. Thaler S, Fiedorowicz M, Choragiewicz TJ et al (2010) Toxicity testing of the VEGF inhibitors bevacizumab, ranibizumab and pegaptanib in rats both with and without prior retinal ganglion cell damage. Acta Ophthalmol 88(5):e170–e176

    PubMed  Google Scholar 

  78. Guo B, Wang Y, Hui Y et al (2010) Effects of anti-VEGF agents on rat retinal Müller glial cells. Mol Vis 16:793–799

    PubMed  CAS  Google Scholar 

  79. Brar VS, Sharma RK, Murthy RK et al (2009) Evaluation of differential toxicity of varying doses of bevacizumab on retinal ganglion cells, retinal pigment epithelial cells, and vascular endothelial growth factor-enriched choroidal endothelial cells. J Ocul Pharmacol Ther 25(6):507–511

    Article  PubMed  CAS  Google Scholar 

  80. Frassetto LJ, Schlieve CR, Lieven CJ et al (2006) Kinase-dependent differentiation of a retinal ganglion cell precursor. Invest Ophthalmol Vis Sci 47:427–438

    Article  PubMed  Google Scholar 

  81. Robbins ME, Zhao W (2004) Chronic oxidative stress and radiation-induced late normal tissue injury: a review. Int J Radiat Biol 80(4):251–259, Review

    Article  PubMed  CAS  Google Scholar 

  82. Avila MP, Farah ME, Santos A et al (2009) Twelve-month short-term safety and visual-acuity results from a multicentre prospective study of epiretinal strontium-90 brachytherapy with bevacizumab for the treatment of subfoveal choroidal neovascularisation secondary to age-related macular degeneration. Br J Ophthalmol 93(3):305–309

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Ophthalmology, University of Florida College of Medicine, 580 West 8th Street, Plaza II 3rd floor, Jacksonville, FL, 32209, USA

    Vikram S. Brar & K. V. Chalam

Authors
  1. Vikram S. Brar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. K. V. Chalam
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Vikram S. Brar .

Editor information

Editors and Affiliations

  1. W. Southwinds Blvd. 1250, Vero Beach, 32963, Florida, USA

    Robert D. Stratton

  2. Department of Ophthalmology, University of Florida, SW Archer Road 1600, Gainesville, 32610, Florida, USA

    William W. Hauswirth

  3. Molecular and Integrative Physiology, Ophthalmology and Visual Sciences, Kellogg Eye Center, Wall Street 1000, Ann Arbor, 17033-2390, Michigan, USA

    Thomas W. Gardner

Rights and permissions

Reprints and permissions

Copyright information

© 2012 Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Brar, V.S., Chalam, K.V. (2012). VEGF Inhibitor Induced Oxidative Stress in Retinal Ganglion Cells. In: Stratton, R., Hauswirth, W., Gardner, T. (eds) Studies on Retinal and Choroidal Disorders. Oxidative Stress in Applied Basic Research and Clinical Practice. Humana Press. https://doi.org/10.1007/978-1-61779-606-7_29

Download citation

Publish with us

Policies and ethics

Search

Navigation