Skip to main content
SpringerLink
Log in

Pathophysiology of Neovascular Glaucoma

  • Chapter
  • First Online:
Neovascular Glaucoma

Part of the book series: Essentials in Ophthalmology ((ESSENTIALS))

  • 276 Accesses

Abstract

Neovascular glaucoma (NVG) is an aggressive form of secondary glaucoma characterized by anterior segment fibrovascular proliferation into the angle, leading to secondary synechial angle closure and glaucomatous optic nerve damage due to often rapid and extreme intraocular pressure elevations. Iris neovessels that grow in the setting of neovascular glaucoma are driven by molecular signaling pathways similar to those that govern vascularization during development but are coopted by pathologies that feature tissue hypoxia, such as cancer and retinal ischemia. These neovessels are distinct from their developmental counterparts in their disorganized pattern, leakiness, and association with contractile myofibroblasts. Vascular endothelial growth factor (VEGF) is chief among the pathogenic proangiogenic signals. VEGFs are a family of proangiogenic ligands released by ischemic retina in various disease states. Both panretinal laser photocoagulation and anti-VEGF therapy can induce regression of anterior segment neovessels in early disease prior to synechial angle closure. The persistence of retinal, iris, and angle neovascularization despite anti-VEGF treatment in some patients has driven research on additional vasoproliferative factors, including platelet-derived growth factor (PDGF), angiopoietin-4, erythropoietin, and many others. This chapter reviews the clinical, histological, molecular, and cellular pathophysiology of anterior segment neovascularization leading to intraocular pressure elevation in neovascular glaucoma.

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

Access this chapter

Log in via an institution
eBook
USD 16.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 16.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 129.99
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. Weiss DI, Shaffer RN, Nehrenberg TR. Neovascular glaucoma complicating carotid-cavernous fistula. Arch Ophthalmol. 1963;69:304–7.

    Article  CAS  Google Scholar 

  2. Barac IR, Pop MD, Gheorghe AI, Taban C. Neovascular secondary glaucoma, etiology and pathogenesis. Rom J Ophthalmol. 2015;59:24–8.

    Google Scholar 

  3. Ishibashi S, Tawara A, Sohma R, Kubota T, Toh N. Angiographic Changes in Iris and Iridocorneal Angle Neovascularization After Intravitreal Bevacizumab Injection. Arch Ophthalmol. 2010;128:1539–45.

    Article  CAS  Google Scholar 

  4. John T, Sassani JW, Eagle RC. The myofibroblastic component of rubeosis iridis. Ophthalmology. 1983;90:721–8.

    Article  CAS  Google Scholar 

  5. Wakabayashi T, Oshima Y, Sakaguchi H, Ikuno Y, Miki A, Gomi F, Otori Y, Kamei M, Kusaka S, Tano Y. Intravitreal bevacizumab to treat iris neovascularization and neovascular glaucoma secondary to ischemic retinal diseases in 41 consecutive cases. Ophthalmology. 2008;115:1571–1580.e3.

    Article  Google Scholar 

  6. Eilken HM, Adams RH. Dynamics of endothelial cell behavior in sprouting angiogenesis. Curr Opin Cell Biol. 2010;22:617–25.

    Article  CAS  Google Scholar 

  7. Stahl A, Connor KM, Sapieha P, et al. The mouse retina as an angiogenesis model. Invest Ophthalmol Vis Sci. 2010;51:2813–26.

    Article  Google Scholar 

  8. Hillen F, Griffioen AW. Tumour vascularization: sprouting angiogenesis and beyond. Cancer Metastasis Rev. 2007;26:489–502.

    Article  Google Scholar 

  9. Siemerink MJ, Klaassen I, Noorden CJFV, Schlingemann RO. Endothelial tip cells in ocular angiogenesis potential target for anti-angiogenesis therapy. J Histochem Cytochem. 2013;61:101–15.

    Article  Google Scholar 

  10. Iruela-Arispe ML, Davis GE. Cellular and molecular mechanisms of vascular lumen formation. Dev Cell. 2009;16:222–31.

    Article  CAS  Google Scholar 

  11. Bock KD, Smet FD, Oliveira RLD, Anthonis K, Carmeliet P. Endothelial oxygen sensors regulate tumor vessel abnormalization by instructing phalanx endothelial cells. J Mol Med. 2009;87:561–9.

    Article  Google Scholar 

  12. Nork TM, Tso MOM, Duvall J, Hayreh SS. Cellular mechanisms of iris neovascularization secondary to retinal vein occlusion. Arch Ophthalmol. 1989;107:581–6.

    Article  CAS  Google Scholar 

  13. Hayreh SS, Rojas P, Podhajsky P, Montague P, Woolson RF. Ocular neovascularization with retinal vascular occlusion-III incidence of ocular neovascularization with retinal vein occlusion. Ophthalmology. 1983;90:488–506.

    Article  CAS  Google Scholar 

  14. Michaelson IC. The mode of development of the vascular system of the retina, with some observations on its significance for certain retinal disease. Trans Ophthalmol Soc U K. 1948;68:137–80.

    Google Scholar 

  15. Aiello LP. Vascular endothelial growth factor and the eye: past, present, and future. Arch Ophthalmol. 1996;114:1252–4.

    Article  CAS  Google Scholar 

  16. Folkman J, Merler E, Abernathy C, Williams G. Isolation of a tumor factor responsible for angiogenesis. J Exp Med. 1971;133:275–88.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  18. Shima DT, Gougos A, Miller JW, Tolentino M, Robinson G, Adamis AP, D’Amore PA. Cloning and mRNA expression of vascular endothelial growth factor in ischemic retinas of Macaca fascicularis. Invest Ophthalmol Vis Sci. 1996;37:1334–40.

    CAS  Google Scholar 

  19. Behzadian MA, Wang XL, Al-Shabrawey M, Shabrawey M, Caldwell RB. Effects of hypoxia on glial cell expression of angiogenesis-regulating factors VEGF and TGF-β. Glia. 1998;24:216–25.

    Article  CAS  Google Scholar 

  20. Koch S, Claesson-Welsh L. Signal transduction by vascular endothelial growth factor receptors. Cold Spring Harb Perspect Med. 2012;2:a006502.

    Article  Google Scholar 

  21. Ho QT, Kuo CJ. Vascular endothelial growth factor: biology and therapeutic applications. Int J Biochem Cell Biol. 2007;39:1349–57.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  23. Tripathi RC, Lixa J, Tripathi BJ, Chalam KV, Adamis AP. Increased level of vascular endothelial growth factor in aqueous humor of patients with neovascular glaucoma. Ophthalmology. 1998;105:232–7.

    Article  CAS  Google Scholar 

  24. Tolentino MJ, Miller JW, Gragoudas ES, Chatzistefanou K, Ferrara N, Adamis AP. Vascular endothelial growth factor is sufficient to produce iris neovascularization and neovascular glaucoma in a nonhuman primate. Arch Ophthalmol. 1996;114:964–70.

    Article  CAS  Google Scholar 

  25. Adamis AP, Shima DT, Tolentino MJ, Gragoudas ES, Ferrara N, Folkman J, D’Amore PA, Miller JW. Inhibition of vascular endothelial growth factor prevents retinal ischemia—associated iris neovascularization in a nonhuman primate. Arch Ophthalmol. 1996;114:66–71.

    Article  CAS  Google Scholar 

  26. Wand M, Dueker DK, Aiello LM, Grant WM. Effects of panretinal photocoagulation on rubeosis iridis, angle neovascularization, and neovascular glaucoma. Am J Ophthalmol. 1978;86:332–9.

    Article  CAS  Google Scholar 

  27. Shinoda K, Ishida S, Kawashima S, Wakabayashi T, Uchita M, Matsuzaki T, Takayama M, Shinmura K, Yamada M. Clinical factors related to the aqueous levels of vascular endothelial growth factor and hepatocyte growth factor in proliferative diabetic retinopathy. Curr Eye Res. 2000;21:655–61.

    Article  CAS  Google Scholar 

  28. Grisanti S, Biester S, Peters S, Tatar O, Ziemssen F, Bartz-Schmidt KU, Group TTBS. Intracameral bevacizumab for iris rubeosis. Am J Ophthalmol. 2006;142:158–60.

    Article  CAS  Google Scholar 

  29. Iliev ME, Domig D, Wolf-Schnurrbursch U, Wolf S, Sarra G-M. Intravitreal bevacizumab (avastin®) in the treatment of neovascular glaucoma. Am J Ophthalmol. 2006;142:1054–6.

    Article  CAS  Google Scholar 

  30. Yazdani S, Hendi K, Pakravan M, Mahdavi M, Yaseri M. Intravitreal bevacizumab for neovascular glaucoma. J Glaucoma. 2009;18:632–7.

    Article  Google Scholar 

  31. Oshima Y, Sakaguchi H, Gomi F, Tano Y. Regression of iris neovascularization after intravitreal injection of bevacizumab in patients with proliferative diabetic retinopathy. Am J Ophthalmol. 2006;142:155–157.e1.

    Article  CAS  Google Scholar 

  32. Mason JO, Albert MA, Mays A, Vail R. Regression of neovascular iris vessels by intravitreal injection of bevacizumab. Retina. 2006;26:839–41.

    Article  Google Scholar 

  33. Grover S, Gupta S, Sharma R, Brar VS, Chalam KV. Intracameral bevacizumab effectively reduces aqueous vascular endothelial growth factor concentrations in neovascular glaucoma. Br J Ophthalmol. 2009;93:273.

    Article  CAS  Google Scholar 

  34. Akagi T, Fujimoto M, Ikeda HO. Anterior segment optical coherence tomography angiography of iris neovascularization after intravitreal ranibizumab and panretinal photocoagulation. JAMA Ophthalmol. 2020;138:e190318.

    Article  Google Scholar 

  35. Olmos LC, Sayed MS, Moraczewski AL, Gedde SJ, Rosenfeld PJ, Shi W, Feuer WJ, Lee RK. Long-term outcomes of neovascular glaucoma treated with and without intravitreal bevacizumab. Eye. 2016;30:463–72.

    Article  CAS  Google Scholar 

  36. Kumar A, Li X. PDGF-C and PDGF-D in ocular diseases. Mol Asp Med. 2018;62:33–43.

    Article  CAS  Google Scholar 

  37. Kodama T, Oku H, Kawamura H, Sakagami K, Puro DG. Platelet-derived growth factor-BB: a survival factor for the retinal microvasculature during periods of metabolic compromise. Curr Eye Res. 2001;23:93–7.

    Article  CAS  Google Scholar 

  38. Mori K, Gehlbach P, Ando A, Dyer G, Lipinsky E, Chaudhry AG, Hackett SF, Campochiaro PA. Retina-specific expression of PDGF-B versus PDGF-A: vascular versus nonvascular proliferative retinopathy. Invest Ophthalmol Vis Sci. 2002;43:2001–6.

    Google Scholar 

  39. Dong A, Seidel C, Snell D, et al. Antagonism of PDGF-BB suppresses subretinal neovascularization and enhances the effects of blocking VEGF-A. Angiogenesis. 2014;17:553–62.

    CAS  Google Scholar 

  40. Li Y, Hu D, Lv P, Xing M, Song Z, Li C, Wang Y, Hou X. Expression of platelet-derived growth factor-C in aqueous humor of patients with neovascular glaucoma and its correlation with vascular endothelial growth factor. Eur J Ophthalmol. 2019;30:500–5.

    Article  CAS  Google Scholar 

  41. Ohira S, Inoue T, Shobayashi K, Iwao K, Fukushima M, Tanihara H. Simultaneous increase in multiple proinflammatory cytokines in the aqueous humor in neovascular glaucoma with and without intravitreal bevacizumab injection aqueous humor cytokines in neovascular glaucoma. Invest Ophthalmol Vis Sci. 2015;56:3541–8.

    Article  CAS  Google Scholar 

  42. Jaffe GJ, Ciulla TA, Ciardella AP, et al. Dual antagonism of PDGF and VEGF in neovascular age-related macular degeneration a phase IIb, multicenter, randomized controlled trial. Ophthalmology. 2017;124:224–34.

    Article  Google Scholar 

  43. Jaffe GJ, Eliott D, Wells JA, Prenner JL, Papp A, Patel S. A phase 1 study of intravitreous E10030 in combination with ranibizumab in neovascular age-related macular degeneration. Ophthalmology. 2016;123:78–85.

    Article  Google Scholar 

  44. Dunn EN, Hariprasad SM, Sheth VS. An overview of the Fovista and Rinucumab trials and the fate of anti-PDGF medications. Ophthalmic Surg Lasers Imaging Retina. 2017;48:100–4.

    Article  Google Scholar 

  45. Hussain RM, Ciulla TA. Emerging vascular endothelial growth factor antagonists to treat neovascular age-related macular degeneration. Expert Opin Emerg Drugs. 2017;22:235–46.

    Article  CAS  Google Scholar 

  46. Babapoor-Farrokhran S, Jee K, Puchner B, et al. Angiopoietin-like 4 is a potent angiogenic factor and a novel therapeutic target for patients with proliferative diabetic retinopathy. Proc Natl Acad Sci. 2015;112:E3030–9.

    Article  CAS  Google Scholar 

  47. Kim JH, Shin JP, Kim IT, Park DH. Aqueous angiopoietin-like 4 levels correlate with nonperfusion area and macular edema in branch retinal vein occlusion. Invest Ophthalmol Vis Sci. 2016;57:6–11.

    CAS  Google Scholar 

  48. Chen KH, Wu CC, Roy S, Lee SM, Liu JH. Increased interleukin-6 in aqueous humor of neovascular glaucoma. Invest Ophthalmol Vis Sci. 1999;40:2627–32.

    CAS  Google Scholar 

  49. Watanabe D, Suzuma K, Matsui S, et al. Erythropoietin as a retinal angiogenic factor in proliferative diabetic retinopathy. New Engl J Med. 2005;353:782–92.

    Article  CAS  Google Scholar 

  50. Yu X-B, Sun X-H, Dahan E, Guo W-Y, Qian S-H, Meng F-R, Song Y-L, Simon GJB. Increased levels of transforming growth factor-beta1 and -beta2 in the aqueous humor of patients with neovascular glaucoma. Ophthalmic Surg Lasers Imaging. 2007;38:6–14.

    Article  Google Scholar 

  51. Tripathi RC, Borisuth NSC, Tripathi BJ. Detection, quantification, and significance of basic fibroblast growth factor in the aqueous humor of man, cat, dog and pig. Exp Eye Res. 1992;54:447–54.

    Article  CAS  Google Scholar 

  52. Gardiner TA, Gibson DS, de Gooyer TE, de la Cruz VF, McDonald DM, Stitt AW. Inhibition of tumor necrosis factor-α improves physiological angiogenesis and reduces pathological neovascularization in ischemic retinopathy. Am J Pathol. 2005;166:637–44.

    Article  CAS  Google Scholar 

  53. Gao G, Li Y, Zhang D, Gee S, Crosson C, Ma J. Unbalanced expression of VEGF and PEDF in ischemia-induced retinal neovascularization. FEBS Lett. 2001;489:270–6.

    Article  CAS  Google Scholar 

  54. Ogata N, Nishikawa M, Nishimura T, Mitsuma Y, Matsumura M. Unbalanced vitreous levels of pigment epithelium-derived factor and vascular endothelial growth factor in diabetic retinopathy. Am J Ophthalmol. 2002;134:348–53.

    Article  CAS  Google Scholar 

  55. Ogata N, Nishikawa M, Nishimura T, Mitsuma Y, Matsumura M. Inverse levels of pigment epithelium-derived factor and vascular endothelial growth factor in the vitreous of eyes with rhegmatogenous retinal detachment and proliferative vitreoretinopathy. Am J Ophthalmol. 2002;133:851–2.

    Article  CAS  Google Scholar 

  56. Spranger J, Osterhoff M, Reimann M, et al. Loss of the antiangiogenic pigment epithelium-derived factor in patients with angiogenic eye disease. Diabetes. 2001;50:2641–5.

    Article  CAS  Google Scholar 

  57. Ogata N, Tombran-Tink J, Nishikawa M, Nishimura T, Mitsuma Y, Sakamoto T, Matsumura M. Pigment epithelium-derived factor in the vitreous is low in diabetic retinopathy and high in rhegmatogenous retinal detachment. Am J Ophthalmol. 2001;132:378–82.

    Article  CAS  Google Scholar 

  58. 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 degeneration11InternetAdvance publication at ajo.com. May 7, 2002. Am J Ophthalmol. 2002;134:220–7.

    Article  CAS  Google Scholar 

  59. Gao G, Li Y, Gee S, Dudley A, Fant J, Crosson C, Ma J. Down-regulation of vascular endothelial growth factor and up-regulation of pigment epithelium-derived factor: a possible mechanism for the anti-angiogenic activity of plasminogen kringle 5*. J Biol Chem. 2002;277:9492–7.

    Article  CAS  Google Scholar 

  60. Notari L, Miller A, Martínez A, Amaral J, Ju M, Robinson G, Smith LEH, Becerra SP. Pigment epithelium–derived factor is a substrate for matrix metalloproteinase type 2 and type 9: implications for downregulation in hypoxia. Invest Ophthalmol Vis Sci. 2005;46:2736–47.

    Article  Google Scholar 

  61. Volpert OV, Zaichuk T, Zhou W, Reiher F, Ferguson TA, Stuart PM, Amin M, Bouck NP. Inducer-stimulated Fas targets activated endothelium for destruction by anti-angiogenic thrombospondin-1 and pigment epithelium–derived factor. Nat Med. 2002;8:349–57.

    Article  CAS  Google Scholar 

  62. Chen L, Zhang SS-M, Barnstable CJ, Tombran-Tink J. PEDF induces apoptosis in human endothelial cells by activating p38 MAP kinase-dependent cleavage of multiple caspases. Biochem Bioph Res Commun. 2006;348:1288–95.

    Article  CAS  Google Scholar 

  63. Ho T-C, Chen S-L, Yang Y-C, Liao C-L, Cheng H-C, Tsao Y-P. PEDF induces p53-mediated apoptosis through PPAR gamma signaling in human umbilical vein endothelial cells. Cardiovasc Res. 2007;76:213–23.

    Article  CAS  Google Scholar 

  64. del Amo EM, Rimpelä A-K, Heikkinen E, et al. Pharmacokinetic aspects of retinal drug delivery. Prog Retin Eye Res. 2017;57:134–85.

    Article  Google Scholar 

  65. Shimada H, Akaza E, Yuzawa M, Kawashima M. Concentration gradient of vascular endothelial growth factor in the vitreous of eyes with diabetic macular edema. Invest Ophthalmol Vis Sci. 2009;50:2953–5.

    Article  Google Scholar 

  66. Lee SS, Ghosn C, Yu Z, et al. Vitreous VEGF clearance is increased after vitrectomy. Invest Ophthalmol Vis Sci. 2010;51:2135–8.

    Article  Google Scholar 

  67. Aaberg TM. Clinical results in vitrectomy for diabetic traction retinal detachment. Am J Ophthalmol. 1979;88:246–53.

    Article  CAS  Google Scholar 

  68. Summanen P. Neovascular glaucoma following vitrectomy for diabetic eye disease. Acta Ophthalmol. 1988;66:110–6.

    Article  CAS  Google Scholar 

  69. Blankenship GW. The lens Influence on diabetic vitrectomy results: report of a prospective randomized study. Arch Ophthalmol. 1980;98:2196–8.

    Article  CAS  Google Scholar 

  70. Rice TA, Michels RG, Rice EF. Vitrectomy for diabetic traction retinal detachment involving the macula. Am J Ophthalmol. 1983;95:22–33.

    Article  CAS  Google Scholar 

  71. Tawara A, Kubota T, Hata Y, Sakamoto T, Honda M, Yoshikawa H, Inomata H, Ohnishi Y. Neovascularization in the anterior segment of the rabbit eye by experimental anterior ischemia. Graefes Arch Clin Exp Ophthalmol. 2002;240:144–53.

    Article  Google Scholar 

  72. Chalam KV, Brar VS, Murthy RK. Human ciliary epithelium as a source of synthesis and secretion of vascular endothelial growth factor in neovascular glaucoma. JAMA Ophthalmol. 2014;132:1350–4.

    Article  Google Scholar 

  73. Ramli N, Htoon HM, Ho CL, Aung T, Perera S. Risk factors for hypotony after transscleral diode cyclophotocoagulation. J Glaucoma. 2012;21:169–73.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Glaucoma Center of Excellence, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Qing Wang & Thomas V. Johnson

Authors
  1. Qing Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Thomas V. Johnson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Thomas V. Johnson .

Editor information

Editors and Affiliations

  1. Ophthalmology and Visual Science, University of Chicago, Chicago, IL, USA

    Mary Qiu

Rights and permissions

Reprints and permissions

Copyright information

© 2022 The Author(s), under exclusive license to Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Wang, Q., Johnson, T.V. (2022). Pathophysiology of Neovascular Glaucoma. In: Qiu, M. (eds) Neovascular Glaucoma. Essentials in Ophthalmology. Springer, Cham. https://doi.org/10.1007/978-3-031-11720-6_3

Download citation

  • DOI: https://doi.org/10.1007/978-3-031-11720-6_3

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-031-11719-0

  • Online ISBN: 978-3-031-11720-6

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation