Vascularisation of the cornea may occur as a sight-threatening response to various insults to the cornea, such as infection, trauma and inflammation, and is a well-recognised risk factor for rejection and subsequent failure of corneal grafts. Various different treatment modalities have been used in the past, with varying levels of success. In this review, we discuss the pathogenesis of corneal neovascularisation, look at recent advances in the assessment of these patients and give an overview of currently available treatment options, both medical and surgical. We also discuss current experimental treatment for corneal neovascularisation, such as gene therapy, which may provide further treatment options in the future.
Corneal neovascularisation, haemangiogenesis, lymphangiogenesis, anterior segment angiography, in vivo confocal microscopy, anti-VEGF, fine-needle diathermy
Natasha Spiteri, Matthias Brunner, Bernhard Steger, Vito Romano and Stephen B Kaye have nothing to disclose in relation to this article. No funding was received in the publication of this article.
Authorship: All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship of this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published.
This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit
October 17, 2016 Accepted:
December 06, 2016
Natasha Spiteri, Sydney Hospital and Sydney Eye Hospital Macquarie Street, Sydney NSW 2000, Australia. E: email@example.com
Corneal neovascularisation (CoNV) is a sight-threatening condition caused by new vessel formation from the limbal vascular plexus and marginal corneal arcades and invasion into the cornea in response to inflammation, infection, trauma and hypoxia.1,2 CoNV may lead to profound visual decline by compromising corneal clarity. Pathologic vessel formation may compromise corneal transparency by blocking and diffracting light, causing lipid and protein exudation and serving as a conduit for inflammatory cells that damage the structural integrity of the cornea leading to scarring (see Figure 1).3 As one of the main causes of corneal blindness in developed countries and a major risk factor for immune allograft rejection after corneal transplantation, CoNV represents a major health burden to the public.4 Although the global impact of CoNV is not known, the incidence rate has been estimated to be 1.4 million per year in the United States.5 Current treatment options of CoNV are limited and prevention of visual loss remains the main challenge for clinicians when facing patients with CoNV. Recent investigations, however, have improved our understanding of the complex mechanisms involved in corneal haem- and lymphangiogenesis and new insights into molecular pathways have opened new doors for potential future treatment strategies.6''
Corneal angiogenic privilege
The cornea is a complex sensory organ and its transparency, which presupposes the absence of blood and lymph vessels, is critical for optimal vision. Corneal avascularity is maintained by a highly regulated and delicate balance of naturally occurring pro- and anti-angiogenic factors (angiogenic privilege). Various signaling cascades and molecular mechanisms maintain corneal avascularity under homeostatic conditions.7 Corneal and limbal epithelial cells have an angiostatic effect on the cornea and limbal epithelial cells further function as a barrier against haem-and lymphangiogenesis.8,9 It has been demonstrated that different cytokine traps for angiogenic and inflammatory factors are constitutively expressed by the intact corneal epithelium: soluble vascular endothelial growth factor (VEGF)-A receptor-1 (sVEGFR1) acts as a decoy receptor for secreted VEGF and inactivates membrane-bound VEGF-A receptors 1 and 2 by heterodimerisation;10 VEGFR3 binds and inhibits activation of VEGF-C and VEGF-D which promote lymphangiogenesis;11 and sVEGFR2 controls the ingrowth of lymphatic vessels.12 Other inhibitors of angiogenesis found in the corneal epithelium include angiostatin, which plays a role in the maintenance of corneal avascularity after wounding,13 and pigment epithelium derived factor (PEDF), a serine protease inhibitor responsible for excluding vessels from invading the cornea.14 Furthermore, the cornea actively counteracts hypoxia-driven upregulation of VEGF by low, if any expression of hypoxia inducible factor (HIF)-1a and by expression of IPAS, an inhibitor of hypoxia-driven HIF-1a-signaling.14 The corneal epithelial basement membrane (EBM) also plays an important role in regulating angiogenic privilege: Potent anti-angiogenic factors such as endostatin, thrombospondins (TSP-1 and -2), and tissue inhibitor of metalloproteinase-3 are derived from the extracellular matrix component of the EBM.15–17 Endostatin inhibits the endothelial cell cycle in G1 phase and mitogenic activities of VEGF in vascular endothelial cells by inhibiting binding of VEGF to surface receptors (KDR/Flk-1) and blocking downstream signaling events.18 TSP-1 inhibits angiogenesis
by inducing vascular endothelial cell apoptosis through binding to CD36 receptors19 and binding to CD36 on the surface of macrophages suppresses the TGF-b induced expression of VEGF-C and VEGF-D, which are potent promoters of lymphangiogenesis.20 TSP-2 inhibits cell-cycle progression in endothelial cells in the absence of apoptosis.21 Moreover, heparan sulfate proteoglycans in the EBM have been shown to bind and inhibit VEGF and fibroblast growth factor (FGF-2) and sequester their proinflammatory and angiogenic effects.17 The lower temperature of the cornea, the extensive innervation, and aqueous humor factors further contribute to the avascular state of the healthy cornea.22
Pathogenesis of corneal neovascularisation
Disruption of the balance between pro- and anti-angiogenic factors and overweighing of proangiogenic factors results in pathological vessel formation.1 Although many regulatory factors have been identified, not all mechanisms involved in the development of CoNV are completely understood. Inflammation and macrophage recruitment play a key role for corneal angiogenesis: activated macrophages are known to secrete inflammatory cytokines such as tumour necrosis factor alpha (TNF-α) and VEGF-A, -C, and -D, resulting in the induction of both haem- and lymphangiogenesis and further macrophage infiltration.23–25 VEGF-A is considered to be one of the most important members of the VEGF family and a main driver for pathologic haemangiogenesis.26 Apart from macrophages, corneal fibroblasts and epithelial cells are the most important sources of VEGF-A.27 The action of VEGF on conjunctival blood and lymphatic vessels is thought to be mainly via VEGFR-2 and VEGFR-328 with resultant budding from pre- existing blood vessels at the limbal vascular plexus or from vascular endothelial progenitor cells that express VEGFR-2 (Flk-1), CD34 antigen (a cell-cell adhesion protein) and Tie-2, a receptor for angiopoietin-1.24,30 Further promotors of corneal angiogenesis include FGF, platelet-derived growth factors (PDGF), angiopoietins, matrix metalloproteinases (MMP-2, -9, and -14) and inflammatory mediators such as interleukins (IL-1, -6, and -8), tumour necrosis factor (TNF-α), and transforming growth factor (TGFβ).30
1. Chang J, Gabison E, Kato T, Azar DT, Corneal neovascularization, Curr Opin Ophthalmol, 2001;12:242–9.
2. Zheng Y, Kaye AE, Boker A, et al., Marginal corneal vascular arcades, Invest Ophthalmol Vis Sci, 2013;54:7470–7.
3. Giménez F, Suryawanshi A, Rouse BT, Pathogenesis of herpes stromal keratitis - A focus on corneal neovascularization, Prog Retin Eye Res, 2013;33:1–9.
4. Bachmann B, Taylor RS, Cursiefen C, Corneal neovascularization as a risk factor for graft failure and rejection after keratoplasty: an evidence-based meta-analysis, Ophthalmology, 2010;117:1300–5.
5. Dana MR, Scharmberg DA, Kowal VO, et al., Corneal neovascularization after penetrating keratoplasty, Cornea, 1995;14:604–609.
6. Abdelfattah NS, Amgad M, Zayed AA, et al., Clinical correlates of common corneal neovascular diseases: a literature review, Int J Ophthalmol, 2015;8:182–93.
7. Cursiefen C, Immune privilege and angiogenic privilege of the cornea, Chem Immunol Allergy, 2007;92:50–7.
8. Ma DH, Tsai RJ, Chu WK, Kao CH, Chen JK, Inhibition of vascular endothelial cell morphogenesis in cultures by limbal epithelial cells, Invest Ophthalmol Vis Sci, 1999;40:1822–8.
9. Schlötzer-Schrehardt U, Kruse FE, Identification and characterization of limbal stem cells, Exp Eye Res, 2005;81:247–64.
10. Ambati BK, Patterson E, Jani P, et al., Soluble vascular endothelial growth factor receptor-1 contributes to the corneal antiangiogenic barrier, Br J Ophthalmol, 2007;91:505–8.
11. Cursiefen C, Chen L, Saint-Geniez M, et al., Nonvascular VEGF receptor 3 expression by corneal epithelium maintains avascularity and vision, Proc Natl Acad Sci USA, 2006;103:11405–10.
12. Albuquerque RJ, Hayashi T, Cho WG, et al., Alternatively spliced vascular endothelial growth factor receptor-2 is an essential endogenous inhibitor of lymphatic vessel growth, Nat Med, 2009;15:1023–30.
13. Gabison E, Chang JH, Hernández-Quintela E, et al., Antiangiogenic role of angiostatin during corneal wound healing, Exp Eye Res, 2004;78:579–89.
14. Makino Y, Cao R, Svensson K, et al., Inhibitory PAS domain protein is a negative regulator of hypoxia-inducible gene expression, Nature, 2001;414:550–4.
15. Lin HC, Chang JH, Jain S, Get al., Matrilysin cleavage of corneal collagen type XVIII NC1 domain and generation of a 28-kDa fragment, Invest Ophthalmol Vis Sci, 2001;42:2517–24.
16. Cursiefen C, Masli S, Ng TF, et al., Roles of thrombospondin-1 and -2 in regulating corneal and iris angiogenesis, Invest Ophthalmol Vis Sci, 2004;45:1117–24.
17. Ma DH, Chen HC, Lai JY, et al., Matrix revolution: molecular mechanism for inflammatory corneal neovascularization and restoration of corneal avascularity by epithelial stem cell transplantation, Ocul Surf, 2009;7:128–44.
18. Kim YM, Hwang S, Kim YM, et al., Endostatin blocks vascular endothelial growth factor-mediated signaling via direct interaction with KDR/Flk-1, J Biol Chem, 2002;277:27872–9.
19. Jiménez B, Volpert OV, Crawford SE, et al., Signals leading to apoptosis-dependent inhibition of neovascularization by thrombospondin-1, Nat Med, 2000;6:41–8.
20. Cursiefen C, Maruyama K, Bock F, et al., Thrombospondin 1 inhibits inflammatory lymphangiogenesis by CD36 ligation on monocytes, J Exp Med, 2011;208:1083–92.
21. Armstrong LC, Bornstein P, Thrombospondins 1 and 2 function as inhibitors of angiogenesis, Matrix Biol, 2003;22:63–71.
22. Bock F, Maruyama K, Regenfuss B, et al., Novel anti(lymph) angiogenic treatment strategies for corneal and ocular surface diseases, Prog Retin Eye Res, 2013;34:89–124.
23. Cursiefen C, Chen L, Borges LP, et al., VEGF-A stimulates lymphangiogenesis and hemangiogenesis in inflammatory neovascularization via macrophage recruitment, J Clin Inves, 2004;113:1040–50.
24. Maruyama K, Ii M, Cursiefen C, Jackson DG, et al., Inflammationinduced lymphangiogenesis in the cornea arises from CD11bpositive macrophages, J Clin Invest, 2005;115:2363–72.
25. Fukumoto A, Maruyama K, Walsh T, et al., Intracellular thiol redox status regulates lymphangiogenesis and dictates corneal limbal graft survival, Invest Ophthalmol Vis Sci, 2010;51:2450–8.
26. Stuttfeld E, Ballmer-Hofer K, Structure and function of VEGF receptors, IUBMB Life, 2009;61:915–22.
27. Sivak JM, Ostriker AC, Woolfenden A, et al., Pharmacologic uncoupling of angiogenesis and inflammation during initiation of pathological corneal neovascularization, J Biol Chem, 2011;286:44965–75.
28. Mimura T, Amano S, Usui T, et al., Expression of vascular endothelial growth factor C and vascular endothelial growth factor receptor 3 in corneal lymphangiogenesis, Exp Eye Res, 2001;72:71–8.
29. Yamashita J, Itoh H, Hirashima M,et al., Flk1-positive cells derived from embryonic stem cells serve as vascular progenitors, Nature, 2000;408:92–6.
30. Stevenson W, Cheng SF, Dastjerdi MH, Ferrari G, Dana R, Corneal neovascularization and the utility of topical VEGF inhibition: ranibizumab (Lucentis) vs bevacizumab (Avastin), Ocul Surf, 2012;10:67–83.
31. Dastjerdi MH, Al-Arfaj KM, Nallasamy N, et al., Topical bevacizumab in the treatment of corneal neovascularization: results of a prospective, open-label, noncomparative study, Arch Ophthalmol, 2009;127:381–389.
32. Faraj LA, Said DG, Al-Aqaba M, Otri AM, Dua HS, Clinical evaluation and characterisation of corneal vascularization, Br J Ophthalmol, 2016;100:315–22.
33. Anijeet DR, Zheng Y, Tey A, et al.,. Imaging and evaluation of corneal vascularization using fluorescein and indocyanine green angiography, Invest Ophthalmol Vis Sci, 2012;53:650–8.
34. Kirwan RP, Zheng Y, Tey A, et al., Quantifying changes in corneal neovascularization using fluorescein and indocyanine green angiography, Am J Ophthalmol, 2012;154:850–8.
35. Steger B, Romano V, Kaye SB, Corneal indocyanine green angiography to guide medical and surgical management of corneal neovascularization, Cornea, 2016;35:41–5.
36. Easty DL, Bron AJ, Fluorescein angiography of the anterior segment: its value in corneal disease, Br J Ophthalmol, 1971;55:671–682.
37. Chaoran Z, Zhirong L, Gezhi X, Combination of vascular endothelial growth factor receptor/platelet-derived growth factor receptor inhibition markedly improves the antiangiogenic efficacy for advanced stage mouse corneal neovascularization, Graefes Arch Clin Exp Ophthalmol, 2011;249:1493–501.
38. Spiteri N, Romano V, Zheng Y, et al., Corneal angiography for guiding and evaluating fine-needle diathermy treatment of corneal neovascularization, Ophthalmology, 2015;122:1079–84.
39. Romano V, Steger B, Zheng Y, et al., Angiographic and In Vivo Confocal Microscopic Characterization of Human Corneal Blood and Presumed Lymphatic Neovascularization: A Pilot Study, Cornea, 2015;34:1459–65. 40. Ang M, Sim DA, Keane PA, et al., Optical Coh
erence Tomography Angiography for Anterior Segment Vasculature Imaging, Ophthalmology, 2015;122:1740–7.
41. Ang M, Cai Y, Shahipasand S, et al., En face optical coherence tomography angiography for corneal neovascularization, Br J Ophthalmol, 2016;100:616–21.
42. Ang M, Cai Y, MacPhee B, et al., Optical coherence tomography angiography and indocyanine green angiography for corneal vascularization, Br J Ophthalmol, 2016;28.
43. Yaylali V, Ohta T, Kaufman SC, Maitchouk DY, Beuerman RW, In vivo confocal imaging of corneal neovascularization, Cornea, 1998;17:646–53.
44. Peebo BB, Fagerholm P, Traneus-Röckert C, Lagali N, Cellularlevel characterization of lymph vessels in live, unlabeled corneas by in vivo confocal microscopy, Invest Ophthalmol Vis Sci, 2010;51:830–5.
45. Peebo BB, Fagerholm P, MD, Lagali N, An in Vivo Method for Visualizing Flow Dynamics of Cells within Corneal Lymphatics, Lymphat Res Biol, 2013;11: 93–100.
46. Gupta D, Illingworth C, Treatments for corneal neovascularization: a review, Cornea, 2011;30:927–38.
47. Boneham GC, Collin HB, Steroid inhibition of limbal blood and lymphatic vascular cell growth, Curr Eye Res, 1995;14:1–10.
48. Qazi Y, Wong G, Monson B, Stringham J, Ambati BK, Corneal transparency: genesis, maintenance and dysfunction, Brain Res Bull, 2009;27;198–210.
49. Snyder DS, Unanue ER, Corticosteroids inhibit murine macrophage Ia expression and interleukin 1 production, J Immunol, 1982;129:1803–1805.
50. Wahl SM, Corticosteroid inhibition of chemotactic lymphokine production by T and B lymphocytes, Ann N Y Acad Sci, 1975;256:375–85.
51. Hori Y, Hu DE, Yasui K, et al., Differential effects of angiostatic steroids and dexamethasone on angiogenesis and cytokine levels in rat sponge implants, Br J Pharmacol, 1996;118:1584–1591.
52. Robin JB, Regis-Pacheco LF, Kash RL, Schanzlin DJ, The histopathology of corneal neovascularization. Inhibitor effects, Arch Ophthalmol, 1985;103:284–287.
53. Jørgensen KA, Stoffersen E, Hydrocortisone inhibits platelet prostaglandin and endothelial prostacyclin production, Pharmacol Res Commun, 1981;13:579–586.
54. McNatt LG, Weimer JY, Clark AF, Angiostatic activity of steroids in the chick embryo CAM and the rabbit cornea models of neovascularization, J Ocul Pharmacol Ther, 1999;15:413–423.
55. Castro MR, Lutz D, Edelman JL, Effect of COX inhibitors on VEGF-induced retinal vascular leakage and experimental corneal and choroidal neovascularization, Exp Eye Res, 2004;79:275–285.
56. Takahashi K, Saishin Y, Saishin Y, et al., Topical nepafenac inhibits ocular neovascularization, Invest Ophthalmol Vis Sci, 2003;44:409–15.
57. Yamada M, Kawai M, Kawai Y, Mashima Y, The effect of selective cyclooxygenase-2 inhibitor on corneal angiogenesis in the rat, Curr Eye Res, 1999;19:300–304.
58. Guidera AC, Luchs JI, Udell IJ, Keratitis, ulceration, and perforation associated with topical nonsteroidal antiinflammatory drugs, Ophthalmology, 2001;108:936–44.
59. Lipman RM, Epstein RJ, Hendricks RL, Suppression of corneal neovascularization with cyclosporine, Arch Ophthalmol, 1992;110:405–7.
60. Benelli U, Ross JR, Nardi M, Klintworth GK, Corneal neovascularization induced by xenografts or chemical cautery. Inhibition by cyclosporin A, Invest Ophthalmol Vis Sci, 1997;38:274–82.
61. Hernandez GL, Volpert OV, Iniguez MA, et al., Selective inhibition of vascular endothelial growth factor-mediated angiogenesis by cyclosporin A: roles of the nuclear factor of activated T cells and cyclooxygenase 2, J Exp Med, 2001;193: 607–20.
62. Birnbaum F, Bohringer D, Sokolovska Y, Sundmacher R, Reinhard T, Immunosuppression with cyclosporine A and mycophenolate mofetil after penetrating high-risk keratoplasty: a retrospective study, Transplantation, 2005;79:964–8.
63. Pillai CT, Dua HS, Hossain P. Fine needle diathermy occlusion of corneal vessels, Invest Ophthalmol Vis Sci, 2000;41:2148–2153.
64. Shimazaki J, Den S, Omoto M, et al., Prospective, randomized study of the efficacy of systemic cyclosporine in high-risk corneal transplantation, Am J Ophthalmol, 2011;152:33–39.
65. Bock F, Matthaei M, Reinhard T, et al., High-dose subconjunctival cyclosporine a implants do not affect corneal neovascularization after high-risk keratoplasty, Ophthalmology, 2014;121:1677–82.
66. Gottsch JD, Akpek, EK, Topical cyclosporin stimulates neovascularization in resolving sterile rheumatoid central corneal ulcers, Trans Am Ophthalmol Soc, 2000;98:81–7.
67. Gan L, Fagerholm P, Palmblad J, Vascular endothelial growth factor (VEGF) and its receptor VEGFR-2 in the regulation of corneal neovascularization and wound healing, Acta Ophthalmol Scand, 2004;82: 557–563.
68. Philipp W, Speicher L, Humpel C, Expression of vascular endothelial growth factor and its receptors in inflamed and vascularized human corneas, Invest Ophthalmol Vis Sci, 2000;41:2514–2522.
69. Maddula S, Davis DK, Maddula S, Burrow MK, Ambati BK, Horizons in therapy for corneal angiogenesis, Ophthalmology, 2011;118:591–9.
70. Papathanassiou M, Theodoropoulou S, Analitis A, Tzonou A, Theodossiadis PG, Vascular endothelial growth factor inhibitors for treatment of corneal neovascularization: a meta-analysis, Cornea, 2013;32:435–44.
71. Chang JH, Garg NK, Lunde E, et al., Corneal neovascularization: an anti-VEGF therapy review, Surv Ophthalmol, 2012;57:415–29.
72. Pieramici DJ, Rabena MD, Anti-VEGF therapy: comparison of current and future agents, Eye (Lond), 2008;22):1330–6.
73. Lipp M, Bucher F, Parthasarathy A, et al., Blockade of the VEGF isoforms in inflammatory corneal hemangiogenesis and lymphangiogenesis, Graefes Arch Clin Exp Ophthalmol, 2014;252:943–9.
74. Ferrara N, Hillan KJ, Novotny W, Bevacizumab (Avastin), a humanized anti-VEGF monoclonal antibody for cancer therapy, Biochem Biophys Res Commun, 2005;333:328–35.
75. Evoy KE, Abel SR, Aflibercept: newly approved for the treatment of macular edema following central retinal vein occlusion, Ann Pharmacother, 2013;47:819–27.
76. Stewart MW, Rosenfeld PJ, Predicted biological activity of intravitreal VEGF Trap, Br J Ophthalmol, 2008;92:667–8.
77. Dastjerdi MH, Saban DR, Okanobo A, et al., Effects of topical and subconjunctival bevacizumab in high-risk corneal transplant survival, Invest Ophthalmol Vis Sci, 2010;51:2411–2417.
78. Kim SW, Ha BJ, Kim EK, Tchah H, Kim TI, The effect of topical bevacizumab on corneal neovascularization, Ophthalmology, 2008;115:e33–8.
79. Bock F, König Y, Kruse F, Baier M, Cursiefen C, Bevacizumab (Avastin) eye drops inhibit corneal neovascularization, Graefes Arch Clin Exp Ophthalmol, 2008;246:281–4.
80. Bucher F, Parthasarathy A, Bergua A, et al., Topical Ranibizumab inhibits inflammatory corneal hem- and lymphangiogenesis, Acta Ophthalmol, 2014;92:143–8.
81. Türkcü FM, Cinar Y, Türkcü G, et al., Topical and subconjunctival ranibizumab (lucentis) for corneal neovascularization in experimental rat model, Cutan Ocul Toxicol, 2014;33:138–44.
82. Ferrari G, Dastjerdi MH, Okanobo A, et al., Topical ranibizumab as a treatment of corneal neovascularization, Cornea, 2013;32:992–7.
83. Petsoglou C, Balaggan KS, Dart JK, et al., Subconjunctival bevacizumab induces regression of corneal neovascularisation: a pilot randomised placebo-controlled double-masked trial, Br J Ophthalmol, 2013;97:28–32.
84. Hashemian MN, Z-Mehrjardi H, Moghimi S, Tahvildari M, Mojazi- Amiri H, Prevention of corneal neovascularization: comparison of different doses of subconjunctival bevacizumab with its topical form in experimental rats, Ophthalmic Res, 2011;46:50–4.
85. Kim EK, Kong SJ, Chung SK, Comparative study of ranibizumab and bevacizumab on corneal neovascularization in rabbits, Cornea, 2014;33:60–4.
86. Dastjerdi MH, Sadrai Z, Saban DR, Zhang Q, Dana R, Corneal penetration of topical and subconjunctival bevacizumab, Invest Ophthalmol Vis Sci, 2011;52:8718–23.
87. Mandalos A, Tsakpinis D, Karayannopoulou G, et al., The effect of subconjunctival ranibizumab on primary pterygium: a pilot study, Cornea, 2010;29:1373–9.
88. Koenig Y, Bock F, Horn F, et al., Short- and long-term safety profile and efficacy of topical bevacizumab (Avastin) eye drops against corneal neovascularization, Graefes Arch Clin Exp Ophthalmol, 2009;247:1375–82.
89. Sarah B, Ibtissam H, Mohammed B, Hasna S, Abdeljalil M, Intrastromal injection of bevacizumab in the management of corneal neovascularization: About 25 eyes, J Ophthalmol, 2016;2016:6084270. Epub 2016 Aug 17.
90. Hashemian MN, Zare MA, Rahimi F, Mohammadpour M, Deep intrastromal bevacizumab injection for management of corneal stromal vascularization after deep anterior lamellar keratoplasty, a novel technique, Cornea, 2011;30:215–8.
91. Oh JY, Kim MK, Wee WR, Subconjunctival and intracorneal bevacizumab injection for corneal neovascularization in lipid keratopathy, Cornea, 2009;28:1070–3.
92. Ahn YJ, Hwang HB, Chung SK, Ranibizumab injection for corneal neovascularization refractory to bevacizumab treatment, Korean J Ophthalmol, 2014;28:177–80.
93. Asena L, Akova YA, Cetinkaya A, Kucukerdonmez C, The effect of topical bevacizumab as an adjunctive therapy for corneal neovascularization, Acta Ophthalmol, 2013;91:246–8.
94. Greenberg JI, Cheresh DA, VEGF as an inhibitor of tumor vessel maturation: implications for cancer therapy, Expert Opin Biol Ther, 2009;9:1347–56.
95. Bergers G, Song S, The role of pericytes in blood-vessel formation and maintenance, Neuro Oncol, 2005;7:452–64.
96. Gal-Or O, Livny E, Sella R, et al., Efficacy of subconjunctival aflibercept versus bevacizumab for prevention of corneal neovascularization in a rat model, Cornea, 2016;35:991–6.
97. Park YR, Chung SK, Inhibitory effect of topical aflibercept on corneal neovascularization in rabbits, Cornea, 2015;34:1303–7.
98. Al-Mahmood S, Colin S, Farhat N, et al., Potent in vivo antiangiogenic effects of GS–101 (5'-TATCCGGAGGGCTCGCCATGCTGCT-3'), an antisense oligonucleotide preventing the expression of insulin receptor substrate-1, J Pharmacol Exp Ther, 2009;329:496–504.
99. Berdugo M, Andrieu-Soler C, Doat M, et al., Downregulation of IRS-1 expression causes inhibition of corneal angiogenesis, Invest Ophthalmol Vis Sci, 2005;46:4072–8.
100. Cursiefen C, Viaud E, Bock F, et al.,. Aganirsen antisense oligonucleotide eye drops inhibit keratitis-induced corneal neovascularization and reduce need for transplantation: the I-CAN study, Ophthalmology, 2014;121:1683–92.
101. Reed JW, Fromer C, Klintworth GK, Induced corneal vascularization remission with argon laser therapy, Arch Ophthalmol, 1975;93:1017–1019.
102. Marsh RJ, Argon laser treatment of lipid keratopathy, Br J Ophthalmol, 1988;72:900–904.
103. Pillai CT, Dua HS, Hossain P, Fine needle diathermy occlusion of corneal vessels, Invest Ophthalmol Vis Sci, 2000;41:2148–2153.
104. Sheppard JD Jr, Epstein RJ, Lattanzio FA Jr, et al., Argon laser photodynamic therapy of human corneal neovascularization after intravenous administration of dihematoporphyrin ether, Am J Ophthalmol, 2006;141:524–529.
105. Cherry PM, Garner A, Corneal neovascularization treated with argon laser, Br J Ophthalmol, 1976;60:464–472.
106. Marsh RJ, Marshall J, Treatment of lipid keratopathy with the argon laser, Br J Ophthalmol, 1982;66:127–135.
107. Gerten G, Bevacizumab (Avastin) and argon laser to treat neovascularization in corneal transplant surgery, Cornea, 2008;27:1195–1199.
108. Nirankari VS, Baer JC, Corneal argon laser photocoagulation for neovascularization in penetrating keratoplasty, Ophthalmology, 1986;93:1304–1309.
109. Epstein RJ, Strutling RD, Hendricks RL, et al. Corneal neovascularization: pathogenesis and inhibition. Cornea, 1987;6:250–257.
110. Pai VH, Handary SV, Necrotizing scleritis following laser therapy for corneal vascularization, Ann Ophthalmol, 2009;41:50–51.
111. Mosier MA, Champion J, Liaw JH, et al., Retinal effects of frequency doubled nd:YAG (532 nm) laser: histopathological comparision with argon laser, Laser Surg Med, 1985;5:377–404.
112. Nirankari VS, Laser photocoagulation for corneal stromal vascularization, Trans Am Ophthalmol Soc, 1992;90:595–669.
113. Krasnick NM, Spigelman AV, Comparison of yellow dye, continuous wave Nd:YAG, and argon green laser on experimentally induced corneal neovascularization, J Refract Surg, 1995;11:45–49.
114. Chan WM, Lim TH, Pece A, Silva R, Yoshimura N, Verteporfin PDT for non-standard indications - a review of current literature, Graefes Arch Clin Exp Ophthalmol, 2010;248:613–26.
115. Hassan AA, Ghoneim DF, El-dib AA, Ahmed SA, Abdel- Salam AM, Photothrombosis of Corneal Neovascularization by Photodynamic Therapy Utilizing Verteporfin and Diode Laser, J Lasers Med Sci, 2013;4:131–139.
116. Brooks BJ, Ambati BK, Marcus DM, Ratanasit A, Photodynamic therapy for corneal neovascularisation and lipid degeneration, Br J Ophthalmol, 2004;88:840.
117. Yoon KC, You IC, Kang IS, et al.,. Photodynamic therapy with verteporfin for corneal neovascularization, Am J Ophthalmol, 2007;144:390–395.
118. Al-Torbak AA, Photodynamic therapy with verteporfin for corneal neovascularization, Middle East Afr J Ophthalmol, 2012;19:185–9.
119. You IC, Im SK, Lee SH, Yoon KC, Photodynamic therapy with verteporfin combined with subconjunctival injection of bevacizumab for corneal neovascularization, Cornea, 2011;30:30–3.
120. Veritti D, Vergallo S, Lanzetta P, Triple therapy for corneal neovascularization: a case report, Eur J Ophthalmol, 2012;22(Suppl 7):S126–8.
121. Corrent G, Roussel TJ, Tseng SCG, et al., Promotion of graft survival by photothrombotic occlusion of corneal neovascularization, Arch Ophthalmol, 1989;107:1051–1056.
122. Gordon YJ, Mann RK, Mah TS, et al., Fluorescein-potentiated argon laser therapy improves symptoms and appearance of corneal neovascularization, Cornea, 2002;21:770–773.
123. Romano V, Steger B, Brunner M, et al., Method for Angiographically guided fine-needle diathermy in the treatment of corneal neovascularization, Cornea, 2016 May 4. [Epub ahead of print]
124. Romano V, Steger B, Kaye SB, Fine-needle diathermy guided by angiography, Cornea, 2015;34:e29–30.
125. Feldman ST, Ellis W, Frucht-Pery J, et al., Experimental radial thermokeratoplasty in rabbits, Arch Ophthalmol, 1990;108:997–1000.
126. Ehrlich JS, Manche EE, Regression of effect over long-term follow-up of conductive keratoplasty to correct mild to moderate hyperopia, J Cataract Refract Surg, 2009;35:1591–1596.
127. Barsam A, Patmore A, Muller D, et al., Keratorefractive effect of microwave keratoplasty on human corneas, J Cataract Refract Surg, 2010;36:472–476.
128. Junghans BM, Collin HB, The limbal vascular response to corneal injury. An autoradiographic study, Cornea, 1989;8:141–149.
129. Cursiefen C, Hofmann-Rummelt C, Kuchle M, et al., Pericyte recruitment in human corneal angiogenesis: an ultrastructural study with clinicopathological correlation, Br J Ophthalmol, 2003;87:101–106.
130. Romano V, Spiteri N, Kaye SB, Angiographic-guided treatment of corneal neovascularization, JAMA Ophthalmol, 2015;133:e143544.
131. Koenig Y, Bock F, Kruse FE, et al., Angioregressive pretreatment of mature corneal blood vessels before keratoplasty: fineneedle vessel coagulation combined with anti-VEGFs, Cornea, 2012;31:887–892.
132. Kather JN, Kroll J, Transgenic mouse models of corneal neovascularization: new perspectives for angiogenesis research, Invest Ophthalmol Vis Sci, 2014;55: 7637–51.
133. Guzman-Aranguez A, Loma P, Pintor J, Small-interfering RNAs (siRNAs) as a promising tool for ocular therapy, Br J Pharmacol, 2013;170:730–47.
134. Kim B, Tang Q, Biswas PS, et al., Inhibition of ocular angiogenesis by siRNA targeting vascular endothelial growth factor pathway genes: therapeutic strategy for herpetic stromal keratitis, Am J Pathol, 2004;165:2177–85.
135. Rho CR, Choi J-S, Seo M, Lee SK, Joo C-K, Inhibition of lymphangiogenesis and hemangiogenesis in corneal inflammation by subconjunctival Prox1 siRNA injection in rats, Invest Ophthalmol Vis Sci, 2015;56:5871–9.
136. Chen P, Yin H, Wang Y, Wang Y, Xie L, Inhibition of VEGF expression and corneal neovascularization by shRNA targeting HIF-1α in a mouse model of closed eye contact lens wear, Mol Vis, 2012;18:864–73.
137. Zong R, Zhou T, Lin Z, et al., Down-Regulation of MicroRNA-184 Is Associated With Corneal Neovascularization, Invest Ophthalmol Vis Sci, 2016;57:1398–407.
138. Mulik S, Xu J, Reddy PBJ, et al., Role of miR-132 in angiogenesis after ocular infection with herpes simplex virus, Am J Pathol, 2012;181:525–34.
139. Vadlapatla RK, Vadlapudi AD, Mitra AK, Hypoxia-inducible factor-1 (HIF-1): a potential target for intervention in ocular neovascular diseases, Curr Drug Targets, 2013;14:919–35.
140. Hasskarl J, Everolimus, Recent Results Cancer Res, 2014;201:373–92.
141. Porta C, Paglino C, Mosca A, Targeting PI3K/Akt/mTOR signaling in cancer, Front Oncol, 2014; 4: 64.
142. Kim S, Ding W, Zhang L, Tian W, Chen S, Clinical response to sunitinib as a multitargeted tyrosine-kinase inhibitor (TKI) in solid cancers: a review of clinical trials, OncoTargets Ther, 2014;7:719–28.
143. Imbulgoda A, Heng DYC, Kollmannsberger C, Sunitinib in the treatment of advanced solid tumors, Recent Results Cancer Res, 2014;201:165–84.
144. Çakmak H, Ergin K, Bozkurt G, Kocatürk T, Evliçoglu GE, The effects of topical everolimus and sunitinib on corneal neovascularization, Cutan Ocul Toxicol, 2016;35: 97–103.
145. Huminiecki L, Gorn M, Suchting S, Poulsom R, Bicknell R, Magic roundabout is a new member of the roundabout receptor family that is endothelial specific and expressed at sites of active angiogenesis, Genomics, 2002;79:547–52.
146. Okada Y, Yano K, Jin E, et al., A three-kilobase fragment of the human Robo4 promoter directs cell type-specific expression in endothelium, Circ Res, 2007;100:1712–22.
147. Gimenez F, Mulik S, Veiga-Parga T, Bhela S, Rouse BT, Robo 4 counteracts angiogenesis in herpetic stromal keratitis, PloS One, 2015;10: e0141925.
148. Li YN, Pinzón-Duarte G, Dattilo M, et al., The expression and function of netrin-4 in murine ocular tissues, Exp Eye Res, 2012;96:24–35.
149. Yang Y, Zou L, Wang Y, et al., Axon guidance cue Netrin-1 has dual function in angiogenesis, Cancer Biol Ther, 2007;6:743–8.
150. Han Y, Shao Y, Lin Z, et al., Netrin-1 simultaneously suppresses corneal inflammation and neovascularization, Invest Ophthalmol Vis Sci, 2012;53:1285–95.
151. Han Y, Shao Y, Liu T, Qu Y-L, Li W, Liu Z, Therapeutic effects of topical netrin-4 inhibits corneal neovascularization in alkaliburn rats, PloS One, 2015;10:e0122951.
152. Lai L-J, Xiao X, Wu JH, Inhibition of corneal neovascularization with endostatin delivered by adeno-associated viral (AAV) vector in a mouse corneal injury model, J Biomed Sci, 2007;14:313–22.
153. Ning TH, Chao CJ, Ying MG, Min X, Shan WF, Preparation, characterization and anti-angiogenesis activity of endostatin covalently modified by polysulfated heparin, Pharm, 2012; 67:622–7.
154. Li Z-N, Yuan Z-F, Mu G-Y, et al., Inhibitory effect of polysulfated heparin endostatin on alkali burn induced corneal neovascularization in rabbits, Int J Ophthalmol, 2015;8:234–8.
155. Yoshida J, Wicks RT, Zambrano AI, et al., Inhibition of corneal neovascularization by subconjunctival injection of Fcendostatin, a novel inhibitor of angiogenesis, J Ophthalmol, 2015;2015:137136.
156. Ferrari G, Bignami F, Rama P, Tumor necrosis factor-α inhibitors as a treatment of corneal hemangiogenesis and lymphangiogenesis, Eye Contact Lens, 2015;41:72–6.
157. Kim JW, Chung SK, The effect of topical infliximab on corneal neovascularization in rabbits, Cornea, 2013;32:185–90.
158. Voiculescu OB, Voinea LM, Infliximab eye drops treatment in corneal neovascularization, J Med Life, 2015;8:566–7.
159. Kubota M, Shimmura S, Kubota S, et al., Hydrogen and N-acetyl- L-cysteine rescue oxidative stress-induced angiogenesis in a mouse corneal alkali-burn model, Invest Ophthalmol Vis Sci, 2011;52:427–33.
160. Iwasaki H, Okamoto R, Kato S, et al., High glucose induces plasminogen activator inhibitor-1 expression through Rho/ Rho-kinase-mediated NF-kappaB activation in bovine aortic endothelial cells, Atherosclerosis, 2008;196:22–8.
161. Lu Y, Li H, Jian W, et al., The Rho/Rho-associated protein kinase inhibitor fasudil in the protection of endothelial cells against advanced glycation end products through the nuclear factor κB pathway, Exp Ther Med, 2013;6:310–6.
162. Zeng P, Pi R-B, Li P, et al., Fasudil hydrochloride, a potent ROCK inhibitor, inhibits corneal neovascularization after alkali burns in mice, Mol Vis, 2015;21:688–98.
163. Kim DW, Lee SH, Shin MJ, et al., PEP-1-FK506BP inhibits alkali burn-induced corneal inflammation on the rat model of corneal alkali injury, BMB Rep, 2015;48: 618–23.