Skip to main content

Pathogenesis of Choroidal Neovascularization

  • Chapter
  • First Online:
  • 469 Accesses

Abstract

Choroidal neovascularization (CNV) is a major cause of severe vision loss in patients with age-related macular degeneration. Despite intensive research, the pathogenesis of choroidal neovascularization is still poorly understood. Many factors were identified to be involved in the development of choroidal neovascularization. Choroidal blood flow and hemodynamic changes with consecutive impairment of the perfusion, especially of the choriocapillaris, as well as reduction of clearance of debris from the retinal pigment epithelium and Bruch’s membrane were proposed to play a role. Imbalance of the angiogenic process including different factors such as vascular endothelial growth factor, angiopoietins, basal fibroblast growth factor and pigment epithelium-derived factor as well as degradation of extracellular matrix are also important factors for the development of CNV. Transgenic and knockout studies have provided important insights into the development of CNV, the main cause of vision impairment and loss in patients with age-related macular degeneration.

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

Buying options

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   169.99
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

Learn about institutional subscriptions

References

  1. Bourne RR, Stevens GA, White RA, Smith JL, Flaxman SR, Price H, et al. Causes of vision loss worldwide, 1990–2010: a systematic analysis. Lancet Glob Health. 2013;1(6):e339–49.

    PubMed  Google Scholar 

  2. Chang TS, Freund KB, de la Cruz Z, Yannuzzi LA, Green WR. Clinicopathologic correlation of choroidal neovascularization demonstrated by indocyanine green angiography in a patient with retention of good vision for almost four years. Retina. 1994;14(2):114–24.

    CAS  PubMed  Google Scholar 

  3. Gass JD, Agarwal A, Lavina AM, Tawansy KA. Focal inner retinal hemorrhages in patients with drusen: an early sign of occult choroidal neovascularization and chorioretinal anastomosis. Retina. 2003;23(6):741–51.

    PubMed  Google Scholar 

  4. Chong NH, Keonin J, Luthert PJ, Frennesson CI, Weingeist DM, Wolf RL, et al. Decreased thickness and integrity of the macular elastic layer of Bruch’s membrane correspond to the distribution of lesions associated with age-related macular degeneration. Am J Pathol. 2005;166(1):241–51.

    PubMed  PubMed Central  Google Scholar 

  5. Ross RD, Barofsky JM, Cohen G, Baber WB, Palao SW, Gitter KA. Presumed macular choroidal watershed vascular filling, choroidal neovascularization, and systemic vascular disease in patients with age-related macular degeneration. Am J Ophthalmol. 1998;125(1):71–80.

    CAS  PubMed  Google Scholar 

  6. Pauleikhoff D, Spital G, Radermacher M, Brumm GA, Lommatzsch A, Bird AC. A fluorescein and indocyanine green angiographic study of choriocapillaris in age-related macular disease. Arch Ophthalmol. 1999;117(10):1353–8.

    CAS  PubMed  Google Scholar 

  7. Grunwald JE, Hariprasad SM, DuPont J. Effect of aging on foveolar choroidal circulation. Arch Ophthalmol. 1998;116(2):150–4.

    CAS  PubMed  Google Scholar 

  8. Grunwald JE, Hariprasad SM, DuPont J, Maguire MG, Fine SL, Brucker AJ, et al. Foveolar choroidal blood flow in age-related macular degeneration. Invest Ophthalmol Vis Sci. 1998;39(2):385–90.

    CAS  PubMed  Google Scholar 

  9. Moult EM, Alibhai AY, Rebhun C, Lee B, Ploner S, Schottenhamml J, et al. Spatial distribution of choriocapillaris impairment in eyes with choroidal neovascularization secondary to age-related macular degeneration: a quantitative OCT angiography study. Retina. 2020;40(3):428–45.

    Google Scholar 

  10. Friedman E. A hemodynamic model of the pathogenesis of age-related macular degeneration. Am J Ophthalmol. 1997;124(5):677–82.

    CAS  PubMed  Google Scholar 

  11. Friedman E. The role of the atherosclerotic process in the pathogenesis of age-related macular degeneration. Am J Ophthalmol. 2000;130(5):658–63.

    CAS  PubMed  Google Scholar 

  12. Mori F, Konno S, Hikichi T, Yamaguchi Y, Ishiko S, Yoshida A. Pulsatile ocular blood flow study: decreases in exudative age related macular degeneration. Br J Ophthalmol. 2001;85(5):531–3.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Remulla JF, Gaudio AR, Miller S, Sandberg MA. Foveal electroretinograms and choroidal perfusion characteristics in fellow eyes of patients with unilateral neovascular age-related macular degeneration. Br J Ophthalmol. 1995;79(6):558–61.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Senger DR, Galli SJ, Dvorak AM, Perruzzi CA, Harvey VS, Dvorak HF. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science. 1983;219(4587):983–5.

    CAS  PubMed  Google Scholar 

  15. Keck PJ, Hauser SD, Krivi G, Sanzo K, Warren T, Feder J, et al. Vascular permeability factor, an endothelial cell mitogen related to PDGF. Science. 1989;246(4935):1309–12.

    CAS  PubMed  Google Scholar 

  16. Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science. 1989;246(4935):1306–9.

    CAS  PubMed  Google Scholar 

  17. Shweiki D, Itin A, Soffer D, Keshet E. Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature. 1992;359(6398):843–5.

    CAS  PubMed  Google Scholar 

  18. Adamis AP, Miller JW, Bernal MT, D’Amico DJ, Folkman J, Yeo TK, et al. Increased vascular endothelial growth factor levels in the vitreous of eyes with proliferative diabetic retinopathy. Am J Ophthalmol. 1994;118(4):445–50.

    CAS  PubMed  Google Scholar 

  19. Pe’er J, Shweiki D, Itin A, Hemo I, Gnessin H, Keshet E. Hypoxia-induced expression of vascular endothelial growth factor by retinal cells is a common factor in neovascularizing ocular diseases. Lab Investig. 1995;72(6):638–45.

    PubMed  Google Scholar 

  20. Adamis AP, Shima DT, Tolentino MJ, Gragoudas ES, Ferrara N, Folkman J, et al. Inhibition of vascular endothelial growth factor prevents retinal ischemia-associated iris neovascularization in a nonhuman primate. Arch Ophthalmol. 1996;114(1):66–71.

    CAS  PubMed  Google Scholar 

  21. Amano S, Rohan R, Kuroki M, Tolentino M, Adamis AP. Requirement for vascular endothelial growth factor in wound- and inflammation-related corneal neovascularization. Invest Ophthalmol Vis Sci. 1998;39(1):18–22.

    CAS  PubMed  Google Scholar 

  22. Ferrara N, Henzel WJ. Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. Biochem Biophys Res Commun. 1989;161(2):851–8.

    CAS  PubMed  Google Scholar 

  23. Miller JW, Adamis AP, Shima DT, D’Amore PA, Moulton RS, O’Reilly MS, et al. Vascular endothelial growth factor/vascular permeability factor is temporally and spatially correlated with ocular angiogenesis in a primate model. Am J Pathol. 1994;145(3):574–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Ashton N. Retinal vascularization in health and disease: proctor award lecture of the Association for Research in Ophthalmology. Am J Ophthalmol. 1957;44(4 Pt 2):7–17.

    CAS  PubMed  Google Scholar 

  25. Shimizu K, Kobayashi Y, Muraoka K. Midperipheral fundus involvement in diabetic retinopathy. Ophthalmology. 1981;88(7):601–12.

    CAS  PubMed  Google Scholar 

  26. Blaauwgeers HG, Holtkamp GM, Rutten H, Witmer AN, Koolwijk P, Partanen TA, et al. Polarized vascular endothelial growth factor secretion by human retinal pigment epithelium and localization of vascular endothelial growth factor receptors on the inner choriocapillaris. Evidence for a trophic paracrine relation. Am J Pathol. 1999;155(2):421–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Roberts WG, Palade GE. Increased microvascular permeability and endothelial fenestration induced by vascular endothelial growth factor. J Cell Sci. 1995;108(Pt 6):2369–79.

    CAS  PubMed  Google Scholar 

  28. Suri C, Jones PF, Patan S, Bartunkova S, Maisonpierre PC, Davis S, et al. Requisite role of angiopoietin-1, a ligand for the TIE2 receptor, during embryonic angiogenesis. Cell. 1996;87(7):1171–80.

    CAS  Google Scholar 

  29. Carmeliet P. Mechanisms of angiogenesis and arteriogenesis. Nat Med. 2000;6(4):389–95.

    CAS  PubMed  Google Scholar 

  30. Potente M, Gerhardt H, Carmeliet P. Basic and therapeutic aspects of angiogenesis. Cell. 2011;146(6):873–87.

    CAS  Google Scholar 

  31. Suri C, McClain J, Thurston G, McDonald DM, Zhou H, Oldmixon EH, et al. Increased vascularization in mice overexpressing angiopoietin-1. Science. 1998;282(5388):468–71.

    CAS  PubMed  Google Scholar 

  32. Thurston G, Suri C, Smith K, McClain J, Sato TN, Yancopoulos GD, et al. Leakage-resistant blood vessels in mice transgenically overexpressing angiopoietin-1. Science. 1999;286(5449):2511–4.

    CAS  PubMed  Google Scholar 

  33. Witzenbichler B, Maisonpierre PC, Jones P, Yancopoulos GD, Isner JM. Chemotactic properties of angiopoietin-1 and -2, ligands for the endothelial-specific receptor tyrosine kinase Tie2. J Biol Chem. 1998;273(29):18514–21.

    CAS  PubMed  Google Scholar 

  34. Amin R, Puklin JE, Frank RN. Growth factor localization in choroidal neovascular membranes of age-related macular degeneration. Invest Ophthalmol Vis Sci. 1994;35(8):3178–88.

    CAS  PubMed  Google Scholar 

  35. Frank RN, Amin RH, Eliott D, Puklin JE, Abrams GW. Basic fibroblast growth factor and vascular endothelial growth factor are present in epiretinal and choroidal neovascular membranes. Am J Ophthalmol. 1996;122(3):393–403.

    CAS  PubMed  Google Scholar 

  36. Ogata N, Matsushima M, Takada Y, Tobe T, Takahashi K, Yi X, et al. Expression of basic fibroblast growth factor mRNA in developing choroidal neovascularization. Curr Eye Res. 1996;15(10):1008–18.

    CAS  PubMed  Google Scholar 

  37. Yamada H, Yamada E, Kwak N, Ando A, Suzuki A, Esumi N, et al. Cell injury unmasks a latent proangiogenic phenotype in mice with increased expression of FGF2 in the retina. J Cell Physiol. 2000;185(1):135–42.

    CAS  PubMed  Google Scholar 

  38. Mori K, Gehlbach P, Yamamoto S, Duh E, Zack DJ, Li Q, et al. AAV-mediated gene transfer of pigment epithelium-derived factor inhibits choroidal neovascularization. Invest Ophthalmol Vis Sci. 2002;43(6):1994–2000.

    PubMed  Google Scholar 

  39. Stellmach V, Crawford SE, Zhou W, Bouck N. Prevention of ischemia-induced retinopathy by the natural ocular antiangiogenic agent pigment epithelium-derived factor. Proc Natl Acad Sci USA. 2001;98(5):2593–7.

    CAS  PubMed  Google Scholar 

  40. Holekamp NM, Bouck N, Volpert O. Pigment epithelium-derived factor is deficient in the vitreous of patients with choroidal neovascularization due to age-related macular degeneration. Am J Ophthalmol. 2002;134(2):220–7.

    CAS  PubMed  Google Scholar 

  41. Gross JL, Moscatelli D, Rifkin DB. Increased capillary endothelial cell protease activity in response to angiogenic stimuli in vitro. Proc Natl Acad Sci USA. 1983;80(9):2623–7.

    CAS  PubMed  Google Scholar 

  42. Sato Y, Rifkin DB. Autocrine activities of basic fibroblast growth factor: regulation of endothelial cell movement, plasminogen activator synthesis, and DNA synthesis. J Cell Biol. 1988;107(3):1199–205.

    CAS  PubMed  Google Scholar 

  43. Asahara T, Chen D, Takahashi T, Fujikawa K, Kearney M, Magner M, et al. Tie2 receptor ligands, angiopoietin-1 and angiopoietin-2, modulate VEGF-induced postnatal neovascularization. Circ Res. 1998;83(3):233–40.

    CAS  PubMed  Google Scholar 

  44. Campochiaro PA, Soloway P, Ryan SJ, Miller JW. The pathogenesis of choroidal neovascularization in patients with age-related macular degeneration. Mol Vis. 1999;5:34.

    CAS  PubMed  Google Scholar 

  45. Murata T, He S, Hangai M, Ishibashi T, Xi XP, Kim S, et al. Peroxisome proliferator-activated receptor-gamma ligands inhibit choroidal neovascularization. Invest Ophthalmol Vis Sci. 2000;41(8):2309–17.

    CAS  PubMed  Google Scholar 

  46. Seo MS, Kwak N, Ozaki H, Yamada H, Okamoto N, Yamada E, et al. Dramatic inhibition of retinal and choroidal neovascularization by oral administration of a kinase inhibitor. Am J Pathol. 1999;154(6):1743–53.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Miller JW, Stinson WG, Folkman J. Regression of experimental iris neovascularization with systemic alpha-interferon. Ophthalmology. 1993;100(1):9–14.

    CAS  PubMed  Google Scholar 

  48. Cornelius LA, Nehring LC, Roby JD, Parks WC, Welgus HG. Human dermal microvascular endothelial cells produce matrix metalloproteinases in response to angiogenic factors and migration. J Invest Dermatol. 1995;105(2):170–6.

    CAS  PubMed  Google Scholar 

  49. Pepper MS, Vassalli JD, Montesano R, Orci L. Urokinase-type plasminogen activator is induced in migrating capillary endothelial cells. J Cell Biol. 1987;105(6 Pt 1):2535–41.

    CAS  PubMed  Google Scholar 

  50. Green WR, Key SN 3rd. Senile macular degeneration: a histopathologic study. Trans Am Ophthalmol Soc. 1977;75:180–254.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Penfold PL, Provis JM, Billson FA. Age-related macular degeneration: ultrastructural studies of the relationship of leucocytes to angiogenesis. Graefes Arch Clin Exp Ophthalmol. 1987;225(1):70–6.

    CAS  PubMed  Google Scholar 

  52. van der Schaft TL, Mooy CM, de Bruijn WC, de Jong PT. Early stages of age-related macular degeneration: an immunofluorescence and electron microscopy study. Br J Ophthalmol. 1993;77(10):657–61.

    PubMed  PubMed Central  Google Scholar 

  53. Becker MD, Kruse FE, Azzam L, Nobiling R, Reichling J, Volcker HE. In vivo significance of ICAM-1—dependent leukocyte adhesion in early corneal angiogenesis. Invest Ophthalmol Vis Sci. 1999;40(3):612–8.

    CAS  PubMed  Google Scholar 

  54. Miyamoto K, Khosrof S, Bursell SE, Moromizato Y, Aiello LP, Ogura Y, et al. Vascular endothelial growth factor (VEGF)-induced retinal vascular permeability is mediated by intercellular adhesion molecule-1 (ICAM-1). Am J Pathol. 2000;156(5):1733–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Harmey JH, Dimitriadis E, Kay E, Redmond HP, Bouchier-Hayes D. Regulation of macrophage production of vascular endothelial growth factor (VEGF) by hypoxia and transforming growth factor beta-1. Ann Surg Oncol. 1998;5(3):271–8.

    CAS  PubMed  Google Scholar 

  56. Green WR, Wilson DJ. Choroidal neovascularization. Ophthalmology. 1986;93(9):1169–76.

    CAS  PubMed  Google Scholar 

  57. Hoskin A, Sehmi K, Bird AC. Sorsby’s pseudoinflammatory macular dystrophy. Br J Ophthalmol. 1981;65(12):859–65.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Sorsby A, Mason ME. A fundus dystrophy with unusual features. Br J Ophthalmol. 1949;33(2):67–97.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Weber BH, Vogt G, Pruett RC, Stohr H, Felbor U. Mutations in the tissue inhibitor of metalloproteinases-3 (TIMP3) in patients with Sorsby’s fundus dystrophy. Nat Genet. 1994;8(4):352–6.

    CAS  PubMed  Google Scholar 

  60. Ryan SJ. Subretinal neovascularization. Natural history of an experimental model. Arch Ophthalmol. 1982;100(11):1804–9.

    CAS  PubMed  Google Scholar 

  61. Francois J, De Laey JJ, Cambie E, Hanssens M, Victoria-Troncoso V. Neovascularization after argon laser photocoagulation of macular lesions. Am J Ophthalmol. 1975;79(2):206–10.

    CAS  PubMed  Google Scholar 

  62. Grossniklaus HE, Cingle KA, Yoon YD, Ketkar N, L’Hernault N, Brown S. Correlation of histologic 2-dimensional reconstruction and confocal scanning laser microscopic imaging of choroidal neovascularization in eyes with age-related maculopathy. Arch Ophthalmol. 2000;118(5):625–9.

    CAS  PubMed  Google Scholar 

  63. Nishimura T, Goodnight R, Prendergast RA, Ryan SJ. Activated macrophages in experimental subretinal neovascularization. Ophthalmologica. 1990;200(1):39–44.

    CAS  PubMed  Google Scholar 

  64. Okamoto N, Tobe T, Hackett SF, Ozaki H, Vinores MA, LaRochelle W, et al. Transgenic mice with increased expression of vascular endothelial growth factor in the retina: a new model of intraretinal and subretinal neovascularization. Am J Pathol. 1997;151(1):281–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Schwesinger C, Yee C, Rohan RM, Joussen AM, Fernandez A, Meyer TN, et al. Intrachoroidal neovascularization in transgenic mice overexpressing vascular endothelial growth factor in the retinal pigment epithelium. Am J Pathol. 2001;158(3):1161–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Baffi J, Byrnes G, Chan CC, Csaky KG. Choroidal neovascularization in the rat induced by adenovirus mediated expression of vascular endothelial growth factor. Invest Ophthalmol Vis Sci. 2000;41(11):3582–9.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2020 Springer Nature Singapore Pte Ltd.

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Al-Sheikh, M., Barthelmes, D. (2020). Pathogenesis of Choroidal Neovascularization. In: Chhablani, J. (eds) Choroidal Neovascularization. Springer, Singapore. https://doi.org/10.1007/978-981-15-2213-0_2

Download citation

  • DOI: https://doi.org/10.1007/978-981-15-2213-0_2

  • Published:

  • Publisher Name: Springer, Singapore

  • Print ISBN: 978-981-15-2212-3

  • Online ISBN: 978-981-15-2213-0

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics