Skip to main content

Advertisement

SpringerLink
Log in

Therapeutic Strategies for Corneal Wound Angiogenesis

  • Wound Healing and Tissue Repair (C Yates and R Mota, Section Editors)
  • Published:
Current Pathobiology Reports

Abstract

Purpose of Review

Corneal diseases are a major cause of blindness worldwide, resulting from corneal scarring and neovascularization. There is an unmet need for developing effective therapies to prevent and/or treat corneal neovascularization.

Recent Findings

Topical steroid medication, cautery, argon and yellow dye laser, and fine needle diathermy have all been advocated with varying degrees of success. Vascular endothelial growth factor family of proteins play a pivotal role in corneal neovascularization, and current therapies are aimed at disrupting the various steps in this pathway. Advancement in cell-based therapies and regulatory molecules as a therapeutic target for treating corneal neovascularization is gaining popularity.

Summary

This review focuses on the current treatment modalities, new alternative therapies, potential new targets, and insights into the future research for this debilitating condition.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. Gipson IK. Age-related changes and diseases of the ocular surface and corneadiseases of the ocular surface and cornea. Invest Ophthalmol Vis Sci. 2013;54(14):ORSF48–53. https://doi.org/10.1167/iovs.13-12840.

    Article  PubMed  Google Scholar 

  2. Roshandel D, Eslani M, Baradaran-Rafii A, Cheung AY, Kurji K, Jabbehdari S, et al. Current and emerging therapies for corneal neovascularization. The ocular surface. 2018;16(4):398–414. https://doi.org/10.1016/j.jtos.2018.06.004.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Richardson A, Wakefield D, Di Girolamo N. Fate mapping mammalian corneal epithelia. The ocular surface. 2016;14(2):82–99. https://doi.org/10.1016/j.jtos.2015.11.007.

    Article  PubMed  Google Scholar 

  4. Meek KM, Knupp C. Corneal structure and transparency. Prog Retin Eye Res. 2015;49:1–16. https://doi.org/10.1016/j.preteyeres.2015.07.001.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Azar DT. Corneal angiogenic privilege: angiogenic and antiangiogenic factors in corneal avascularity, vasculogenesis, and wound healing (an American Ophthalmological Society thesis). Trans Am Ophthalmol Soc. 2006;104:264–302.

    PubMed  PubMed Central  Google Scholar 

  6. Ellenberg D, Azar DT, Hallak JA, Tobaigy F, Han KY, Jain S, et al. Novel aspects of corneal angiogenic and lymphangiogenic privilege. Prog Retin Eye Res. 2010;29(3):208–48. https://doi.org/10.1016/j.preteyeres.2010.01.002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Streilein JW. Anterior chamber associated immune deviation: the privilege of immunity in the eye. Surv Ophthalmol. 1990;35(1):67–73.

    Article  CAS  Google Scholar 

  8. Cursiefen C. Immune privilege and angiogenic privilege of the cornea. Chemical immunology and allergy. 2007;92:50–7. https://doi.org/10.1159/000099253.

    Article  CAS  PubMed  Google Scholar 

  9. Hamrah P, Huq SO, Liu Y, Zhang Q, Dana MR. Corneal immunity is mediated by heterogeneous population of antigen-presenting cells. J Leukoc Biol. 2003;74(2):172–8. https://doi.org/10.1189/jlb.1102544.

    Article  CAS  PubMed  Google Scholar 

  10. Holmes DI, Zachary I. The vascular endothelial growth factor (VEGF) family: angiogenic factors in health and disease. Genome Biol. 2005;6(2):209. https://doi.org/10.1186/gb-2005-6-2-209.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Risau W. Mechanisms of angiogenesis. Nature. 1997;386(6626):671–4. https://doi.org/10.1038/386671a0.

    Article  CAS  PubMed  Google Scholar 

  12. Folkman J, Klagsbrun M. Angiogenic factors. Science (New York, NY). 1987;235(4787):442–7. https://doi.org/10.1126/science.2432664.

    Article  CAS  Google Scholar 

  13. Harper SJ, Bates DO. VEGF-A splicing: the key to anti-angiogenic therapeutics? Nat Rev Cancer. 2008;8(11):880–7. https://doi.org/10.1038/nrc2505.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Cursiefen C, Chen L, Borges LP, Jackson D, Cao J, Radziejewski C, et al. VEGF-A stimulates lymphangiogenesis and hemangiogenesis in inflammatory neovascularization via macrophage recruitment. J Clin Invest. 2004;113(7):1040–50. https://doi.org/10.1172/jci20465.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Beenken A, Mohammadi M. The FGF family: biology, pathophysiology and therapy. Nat Rev Drug Discov. 2009;8(3):235–53. https://doi.org/10.1038/nrd2792.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Hoch RV, Soriano P. Roles of PDGF in animal development. Development (Cambridge, England). 2003;130(20):4769–84. https://doi.org/10.1242/dev.00721.

    Article  CAS  Google Scholar 

  17. Hoppenreijs VP, Pels E, Vrensen GF, Felten PC, Treffers WF. Platelet-derived growth factor: receptor expression in corneas and effects on corneal cells. Invest Ophthalmol Vis Sci. 1993;34(3):637–49.

    CAS  PubMed  Google Scholar 

  18. 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. https://doi.org/10.1161/01.res.83.3.233.

    Article  CAS  PubMed  Google Scholar 

  19. Ghajar CM, George SC, Putnam AJ. Matrix metalloproteinase control of capillary morphogenesis. Crit Rev Eukaryot Gene Expr. 2008;18(3):251–78.

    Article  CAS  Google Scholar 

  20. Unemori EN, Bouhana KS, Werb Z. Vectorial secretion of extracellular matrix proteins, matrix-degrading proteinases, and tissue inhibitor of metalloproteinases by endothelial cells. J Biol Chem. 1990;265(1):445–51.

    CAS  PubMed  Google Scholar 

  21. Mimura T, Han KY, Onguchi T, Chang JH, Kim TI, Kojima T, et al. MT1-MMP-mediated cleavage of decorin in corneal angiogenesis. J Vasc Res. 2009;46(6):541–50. https://doi.org/10.1159/000226222.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Li A, Dubey S, Varney ML, Dave BJ, Singh RK. IL-8 directly enhanced endothelial cell survival, proliferation, and matrix metalloproteinases production and regulated angiogenesis. J Immunol (Baltimore, Md : 1950). 2003;170(6):3369–76. https://doi.org/10.4049/jimmunol.170.6.3369.

    Article  CAS  Google Scholar 

  23. Chen L, Huq S, Gardner H, de Fougerolles AR, Barabino S, Dana MR. Very late antigen 1 blockade markedly promotes survival of corneal allografts. Archiv ophthalmol (Chicago, Ill : 1960). 2007;125(6):783–8. https://doi.org/10.1001/archopht.125.6.783.

    Article  CAS  Google Scholar 

  24. Senger DR, Perruzzi CA, Streit M, Koteliansky VE, de Fougerolles AR, Detmar M. The alpha(1)beta(1) and alpha(2)beta(1) integrins provide critical support for vascular endothelial growth factor signaling, endothelial cell migration, and tumor angiogenesis. Am J Pathol. 2002;160(1):195–204. https://doi.org/10.1016/s0002-9440(10)64363-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Nakao S, Hata Y, Miura M, Noda K, Kimura YN, Kawahara S, et al. Dexamethasone inhibits interleukin-1beta-induced corneal neovascularization: role of nuclear factor-kappaB-activated stromal cells in inflammatory angiogenesis. Am J Pathol. 2007;171(3):1058–65. https://doi.org/10.2353/ajpath.2007.070172.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kendall RL, Wang G, Thomas KA. Identification of a natural soluble form of the vascular endothelial growth factor receptor, FLT-1, and its heterodimerization with KDR. Biochem Biophys Res Commun. 1996;226(2):324–8. https://doi.org/10.1006/bbrc.1996.1355.

    Article  CAS  PubMed  Google Scholar 

  27. Cursiefen C, Chen L, Saint-Geniez M, Hamrah P, Jin Y, Rashid S, et al. Nonvascular VEGF receptor 3 expression by corneal epithelium maintains avascularity and vision. Proc Natl Acad Sci U S A. 2006;103(30):11405–10. https://doi.org/10.1073/pnas.0506112103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Albuquerque RJ, Hayashi T, Cho WG, Kleinman ME, Dridi S, Takeda A, et al. Alternatively spliced vascular endothelial growth factor receptor-2 is an essential endogenous inhibitor of lymphatic vessel growth. Nat Med. 2009;15(9):1023–30. https://doi.org/10.1038/nm.2018.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Filleur S, Nelius T, de Riese W, Kennedy RC. Characterization of PEDF: a multi-functional serpin family protein. J Cell Biochem. 2009;106(5):769–75. https://doi.org/10.1002/jcb.22072.

    Article  CAS  PubMed  Google Scholar 

  30. Karakousis PC, John SK, Behling KC, Surace EM, Smith JE, Hendrickson A, et al. Localization of pigment epithelium derived factor (PEDF) in developing and adult human ocular tissues. Mol Vis. 2001;7:154–63.

    CAS  PubMed  Google Scholar 

  31. O’Reilly MS, Boehm T, Shing Y, Fukai N, Vasios G, Lane WS, et al. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell. 1997;88(2):277–85. https://doi.org/10.1016/s0092-8674(00)81848-6.

    Article  PubMed  Google Scholar 

  32. Al-Torbak AA. Photodynamic therapy with verteporfin for corneal neovascularization. Middle East Afr J Ophthalmol. 2012;19(2):185–9. https://doi.org/10.4103/0974-9233.95246.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Al-Abdullah AA, Al-Assiri A. Resolution of bilateral corneal neovascularization and lipid keratopathy after photodynamic therapy with verteporfin. Optometry (St Louis, Mo). 2011;82(4):212–4. https://doi.org/10.1016/j.optm.2010.09.012.

    Article  Google Scholar 

  34. Kumar J, Gehra A, Sirohi N. Role of frequency doubled Nd: Yag laser in treatment of corneal neovascularisation. J Clin Diagn Res. 2016;10(4):NC01–NC4. https://doi.org/10.7860/JCDR/2016/17502.7543.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Gordon YJ, Mann RK, Mah TS, Gorin MB. Fluorescein-potentiated argon laser therapy improves symptoms and appearance of corneal neovascularization. Cornea. 2002;21(8):770–3.

    Article  Google Scholar 

  36. Krasnick NM, Spigelman AV. Comparison of yellow dye, continuous wave Nd:YAG, and argon green laser on experimentally induced corneal neovascularization. J Refract Surg (Thorofare, NJ : 1995). 1995;11(1):45–9.

    Article  CAS  Google Scholar 

  37. Faraj LA, Elalfy MS, Said DG, Dua HS. Fine needle diathermy occlusion of corneal vessels. Br J Ophthalmol. 2014;98(9):1287–90. https://doi.org/10.1136/bjophthalmol-2014-304891.

    Article  PubMed  Google Scholar 

  38. Trikha S, Parikh S, Osmond C, Anderson DF, Hossain PN. Long-term outcomes of fine needle diathermy for established corneal neovascularisation. Br J Ophthalmol. 2014;98(4):454–8. https://doi.org/10.1136/bjophthalmol-2013-303729.

    Article  CAS  PubMed  Google Scholar 

  39. Kheirkhah A, Johnson DA, Paranjpe DR, Raju VK, Casas V, Tseng SCG. Temporary sutureless amniotic membrane patch for acute alkaline burns. JAMA Ophthalmol. 2008;126(8):1059–66. https://doi.org/10.1001/archopht.126.8.1059.

    Article  Google Scholar 

  40. Lee HS, Lee JH, Kim CE, Yang JW. Anti-neovascular effect of chondrocyte-derived extracellular matrix on corneal alkaline burns in rabbits. Graefes Arch Clin Exp Ophthalmol. 2014;252(6):951–61. https://doi.org/10.1007/s00417-014-2633-3.

    Article  CAS  PubMed  Google Scholar 

  41. McNATT LG, WEIMER L, YANNI J, CLARK AF. Angiostatic activity of steroids in the chick embryo CAM and rabbit cornea models of neovascularization. J Ocul Pharmacol Ther. 1999;15(5):413–23. https://doi.org/10.1089/jop.1999.15.413.

    Article  CAS  PubMed  Google Scholar 

  42. Carnahan MC, Goldstein DA. Ocular complications of topical, peri-ocular, and systemic corticosteroids. Curr Opin Ophthalmol. 2000;11(6):478–83.

    Article  CAS  Google Scholar 

  43. Pakneshan P, Birsner AE, Adini I, Becker CM, D’Amato RJ. Differential suppression of vascular permeability and corneal angiogenesis by nonsteroidal anti-inflammatory drugs. Invest Ophthalmol Vis Sci. 2008;49(9):3909–13. https://doi.org/10.1167/iovs.07-1527.

    Article  PubMed  Google Scholar 

  44. Baroja-Mazo A, Revilla-Nuin B, Ramirez P, Pons JA. Immunosuppressive potency of mechanistic target of rapamycin inhibitors in solid-organ transplantation. World J Transplant. 2016;6(1):183–92. https://doi.org/10.5500/wjt.v6.i1.183.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Bock F, Matthaei M, Reinhard T, Bohringer D, Christoph J, Ganslandt T, et al. High-dose subconjunctival cyclosporine a implants do not affect corneal neovascularization after high-risk keratoplasty. Ophthalmology. 2014;121(9):1677–82. https://doi.org/10.1016/j.ophtha.2014.03.016.

    Article  PubMed  Google Scholar 

  46. Bucak YY, Erdurmus M, Terzi EH, Kukner A, Celebi S. Inhibitory effects of topical cyclosporine A 0.05% on immune-mediated corneal neovascularization in rabbits. Graefes Arch Clin Exp Ophthalmol. 2013;251(11):2555–61. https://doi.org/10.1007/s00417-013-2467-4.

    Article  CAS  PubMed  Google Scholar 

  47. Yoo AR, Chung SK. Effects of subconjunctival tocilizumab versus bevacizumab in treatment of corneal neovascularization in rabbits. Cornea. 2014;33(10):1088–94. https://doi.org/10.1097/ico.0000000000000220.

    Article  PubMed  Google Scholar 

  48. Sloper CM, Powell RJ, Dua HS. Tacrolimus (FK506) in the management of high-risk corneal and limbal grafts. Ophthalmology. 2001;108(10):1838–44.

    Article  CAS  Google Scholar 

  49. Ferrari G, Bignami F, Giacomini C, Franchini S, Rama P. Safety and efficacy of topical infliximab in a mouse model of ocular surface scarring Safety and efficacy of topical infliximab. Invest Ophthalmol Vis Sci. 2013;54(3):1680–8. https://doi.org/10.1167/iovs.12-10782.

    Article  CAS  PubMed  Google Scholar 

  50. Kim JW, Chung SK. The effect of topical infliximab on corneal neovascularization in rabbits. Cornea. 2013;32(2):185–90. https://doi.org/10.1097/ICO.0b013e318271cc2a.

    Article  PubMed  Google Scholar 

  51. Ozdemir O, Altintas O, Altintas L, Yildiz DK, Sener E, Caglar Y. Effects of subconjunctivally injected bevacizumab, etanercept, and the combination of both drugs on experimental corneal neovascularization. Can J Ophthalmol. 2013;48(2):115–20. https://doi.org/10.1016/j.jcjo.2012.12.003.

    Article  PubMed  Google Scholar 

  52. Oguido APMT, Hohmann MSN, Pinho-Ribeiro FA, Crespigio J, Domiciano TP, Verri WA, Jr et al. Naringenin eye drops inhibit corneal neovascularization by anti-inflammatory and antioxidant mechanisms Naringenin inhibits corneal neovascularization. Invest Ophthalmol Vis Sci 2017;58(13):5764–5776. doi:https://doi.org/10.1167/iovs.16-19702.

    Article  CAS  Google Scholar 

  53. Rodrigues EB, Farah ME, Maia M, Penha FM, Regatieri C, Melo GB, et al. Therapeutic monoclonal antibodies in ophthalmology. Prog Retin Eye Res. 2009;28(2):117–44. https://doi.org/10.1016/j.preteyeres.2008.11.005.

    Article  CAS  PubMed  Google Scholar 

  54. Koenig Y, Bock F, Horn F, Kruse F, Straub K, Cursiefen C. Short- and long-term safety profile and efficacy of topical bevacizumab (Avastin) eye drops against corneal neovascularization. Graefes Arch Clin Exp Ophthalmol. 2009;247(10):1375–82. https://doi.org/10.1007/s00417-009-1099-1.

    Article  CAS  PubMed  Google Scholar 

  55. Oner V, Kucukerdonmez C, Akova YA, Colak A, Karalezli A. Topical and subconjunctival bevacizumab for corneal neovascularization in an experimental rat model. Ophthalmic Res. 2012;48(3):118–23. https://doi.org/10.1159/000337139.

    Article  CAS  PubMed  Google Scholar 

  56. Ferrari G, Dastjerdi MH, Okanobo A, Cheng SF, Amparo F, Nallasamy N, et al. Topical ranibizumab as a treatment of corneal neovascularization. Cornea. 2013;32(7):992–7. https://doi.org/10.1097/ICO.0b013e3182775f8d.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Ahn YJ, Hwang HB, Chung SK. Ranibizumab injection for corneal neovascularization refractory to bevacizumab treatment. Korean J Ophthalmol. 2014;28(2):177–80. https://doi.org/10.3341/kjo.2014.28.2.177.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Kim JH, Seo HW, Han HC, Lee JH, Choi SK, Lee D. The effect of bevacizumab versus ranibizumab in the treatment of corneal neovascularization: a preliminary study. Korean J Ophthalmol. 2013;27(4):235–42. https://doi.org/10.3341/kjo.2013.27.4.235.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Wang Q, Yang J, Tang K, Luo L, Wang L, Tian L, et al. Pharmacological characteristics and efficacy of a novel anti-angiogenic antibody FD006 in corneal neovascularization. BMC Biotechnol. 2014;14:17. https://doi.org/10.1186/1472-6750-14-17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Akar EE, Oner V, Kucukerdonmez C, Aydin AY. Comparison of subconjunctivally injected bevacizumab, ranibizumab, and pegaptanib for inhibition of corneal neovascularization in a rat model. Int J Ophthalmol. 2013;6(2):136–40. https://doi.org/10.3980/j.issn.2222-3959.2013.02.05.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Oliveira HB, Sakimoto T, Javier JA, Azar DT, Wiegand SJ, Jain S, et al. VEGF Trap(R1R2) suppresses experimental corneal angiogenesis. Eur J Ophthalmol. 2010;20(1):48–54.

    Article  Google Scholar 

  62. Park YR, Chung SK. Inhibitory effect of topical aflibercept on corneal neovascularization in rabbits. Cornea. 2015;34(10):1303–7. https://doi.org/10.1097/ico.0000000000000507.

    Article  PubMed  Google Scholar 

  63. Dohlman TH, Omoto M, Hua J, Stevenson W, Lee SM, Chauhan SK, et al. VEGF-trap aflibercept significantly improves long-term graft survival in high-risk corneal transplantation. Transplantation. 2015;99(4):678–86. https://doi.org/10.1097/tp.0000000000000512.

    Article  CAS  PubMed  Google Scholar 

  64. Berdugo M, Andrieu-Soler C, Doat M, Courtois Y, BenEzra D, Behar-Cohen F. Downregulation of IRS-1 expression causes inhibition of corneal angiogenesis. Invest Ophthalmol Vis Sci. 2005;46(11):4072–8. https://doi.org/10.1167/iovs.05-0105.

    Article  PubMed  Google Scholar 

  65. Cursiefen C, Viaud E, Bock F, Geudelin B, Ferry A, Kadlecova P, et al. Aganirsen antisense oligonucleotide eye drops inhibit keratitis-induced corneal neovascularization and reduce need for transplantation: the I-CAN study. Ophthalmology. 2014;121(9):1683–92. https://doi.org/10.1016/j.ophtha.2014.03.038.

    Article  PubMed  Google Scholar 

  66. Eisen T, Joensuu H, Nathan PD, Harper PG, Wojtukiewicz MZ, Nicholson S, et al. Regorafenib for patients with previously untreated metastatic or unresectable renal-cell carcinoma: a single-group phase 2 trial. Lancet Oncol. 2012;13(10):1055–62. https://doi.org/10.1016/s1470-2045(12)70364-9.

    Article  CAS  PubMed  Google Scholar 

  67. Detry B, Blacher S, Erpicum C, Paupert J, Maertens L, Maillard C, et al. Sunitinib inhibits inflammatory corneal lymphangiogenesis. Invest Ophthalmol Vis Sci. 2013;54(5):3082–93. https://doi.org/10.1167/iovs.12-10856.

    Article  CAS  PubMed  Google Scholar 

  68. Kaya MK, Demir T, Bulut H, Akpolat N, Turgut B. Effects of lapatinib and trastuzumab on vascular endothelial growth factor in experimental corneal neovascularization. Clin Exp Ophthalmol. 2015;43(5):449–57. https://doi.org/10.1111/ceo.12500.

    Article  PubMed  Google Scholar 

  69. Seo JW, Chung SH, Choi JS, Joo CK. Inhibition of corneal neovascularization in rats by systemic administration of sorafenib. Cornea. 2012;31(8):907–12. https://doi.org/10.1097/ICO.0b013e31823f8b9c.

    Article  PubMed  Google Scholar 

  70. Doukas J, Mahesh S, Umeda N, Kachi S, Akiyama H, Yokoi K, et al. Topical administration of a multi-targeted kinase inhibitor suppresses choroidal neovascularization and retinal edema. J Cell Physiol. 2008;216(1):29–37. https://doi.org/10.1002/jcp.21426.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Amparo F, Sadrai Z, Jin Y, Alfonso-Bartolozzi B, Wang H, Shikari H, et al. Safety and efficacy of the multitargeted receptor kinase inhibitor pazopanib in the treatment of corneal neovascularization. Invest Ophthalmol Vis Sci. 2013;54(1):537–44. https://doi.org/10.1167/iovs.12-11032.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Onder HI, Erdurmus M, Bucak YY, Simavli H, Oktay M, Kukner AS. Inhibitory effects of regorafenib, a multiple tyrosine kinase inhibitor, on corneal neovascularization. Int J Ophthalmol. 2014;7(2):220–5. https://doi.org/10.3980/j.issn.2222-3959.2014.02.06.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Su W, Li Z, Li Y, Lin M, Yao L, Liu Y, et al. Doxycycline enhances the inhibitory effects of bevacizumab on corneal neovascularization and prevents its side effects. Invest Ophthalmol Vis Sci. 2011;52(12):9108–15. https://doi.org/10.1167/iovs.11-7255.

    Article  PubMed  Google Scholar 

  74. Xiao O, Xie ZL, Lin BW, Yin XF, Pi RB, Zhou SY. Minocycline inhibits alkali burn-induced corneal neovascularization in mice. PLoS One. 2012;7(7):e41858. https://doi.org/10.1371/journal.pone.0041858.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Goktas S, Erdogan E, Sakarya R, Sakarya Y, Yılmaz M, Ozcimen M, et al. Inhibition of corneal neovascularization by topical and subconjunctival tigecycline. J Ophthalmol. 2014;2014:452685. https://doi.org/10.1155/2014/452685.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. • Liu S, Romano V, Steger B, Kaye SB, Hamill KJ, Willoughby CE. Gene-based antiangiogenic applications for corneal neovascularization. Surv Ophthalmol. 2018;63(2):193–213. https://doi.org/10.1016/j.survophthal.2017.10.006A recent review on applications of gene therapy in corneal neovascularization.

    Article  PubMed  Google Scholar 

  77. Iriyama A, Usui T, Yanagi Y, Amano S, Oba M, Miyata K, et al. Gene transfer using micellar nanovectors inhibits corneal neovascularization in vivo. Cornea. 2011;30(12):1423–7. https://doi.org/10.1097/ICO.0b013e318206c893.

    Article  PubMed  Google Scholar 

  78. Lai CM, Brankov M, Zaknich T, Lai YK, Shen WY, Constable IJ, et al. Inhibition of angiogenesis by adenovirus-mediated sFlt-1 expression in a rat model of corneal neovascularization. Hum Gene Ther. 2001;12(10):1299–310. https://doi.org/10.1089/104303401750270959.

    Article  CAS  PubMed  Google Scholar 

  79. Cho YK, Zhang X, Uehara H, Young JR, Archer B, Ambati B. Vascular endothelial growth factor receptor 1 morpholino increases graft survival in a murine penetrating keratoplasty model. Invest Ophthalmol Vis Sci. 2012;53(13):8458–71. https://doi.org/10.1167/iovs.12-10408.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Hayashi T, Usui T, Yamagami S. Suppression of allograft rejection with soluble VEGF receptor 2 chimeric protein in a mouse model of corneal transplantation. Tohoku J Exp Med. 2016;239(1):81–8. https://doi.org/10.1620/tjem.239.81.

    Article  CAS  PubMed  Google Scholar 

  81. Zuo L, Fan Y, Wang F, Gu Q, Xu X. A siRNA targeting vascular endothelial growth factor-A inhibiting experimental corneal neovascularization. Curr Eye Res. 2010;35(5):375–84. https://doi.org/10.3109/02713681003597230.

    Article  CAS  PubMed  Google Scholar 

  82. Qazi Y, Stagg B, Singh N, Singh S, Zhang X, Luo L, et al. Nanoparticle-mediated delivery of shRNA. VEGF-a plasmids regresses corneal neovascularization. Invest Ophthalmol Vis Sci. 2012;53(6):2837–44. https://doi.org/10.1167/iovs.11-9139.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Zhou SY, Xie ZL, Xiao O, Yang XR, Heng BC, Sato Y. Inhibition of mouse alkali burn induced-corneal neovascularization by recombinant adenovirus encoding human vasohibin-1. Mol Vis. 2010;16:1389–98.

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Ge HY, Xiao N, Yin XL, Fu SB, Ge JY, Shi Y, et al. Comparison of the antiangiogenic activity of modified RGDRGD-endostatin to endostatin delivered by gene transfer in vivo rabbit neovascularization model. Mol Vis. 2011;17:1918–28.

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Saika S, Yamanaka O, Okada Y, Miyamoto T, Kitano A, Flanders KC, et al. Effect of overexpression of PPARgamma on the healing process of corneal alkali burn in mice. Am J Phys Cell Phys. 2007;293(1):C75–86. https://doi.org/10.1152/ajpcell.00332.2006.

    Article  CAS  Google Scholar 

  86. Mohan RR, Tovey JC, Sharma A, Schultz GS, Cowden JW, Tandon A. Targeted decorin gene therapy delivered with adeno-associated virus effectively retards corneal neovascularization in vivo. PLoS One. 2011;6(10):e26432. https://doi.org/10.1371/journal.pone.0026432.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Yoon KC, Ahn KY, Lee JH, Chun BJ, Park SW, Seo MS, et al. Lipid-mediated delivery of brain-specific angiogenesis inhibitor 1 gene reduces corneal neovascularization in an in vivo rabbit model. Gene Ther. 2005;12(7):617–24. https://doi.org/10.1038/sj.gt.3302442.

    Article  CAS  PubMed  Google Scholar 

  88. Seta F, Patil K, Bellner L, Mezentsev A, Kemp R, Dunn MW, et al. Inhibition of VEGF expression and corneal neovascularization by siRNA targeting cytochrome P450 4B1. Prostaglandins & other lipid mediators. 2007;84(3–4):116–27. https://doi.org/10.1016/j.prostaglandins.2007.05.001.

    Article  CAS  Google Scholar 

  89. Yoon KC, Bae JA, Park HJ, Im SK, Oh HJ, Lin XH, et al. Subconjunctival gene delivery of the transcription factor GA-binding protein delays corneal neovascularization in a mouse model. Gene Ther. 2009;16(8):973–81. https://doi.org/10.1038/gt.2009.50.

    Article  CAS  PubMed  Google Scholar 

  90. Kuo CN, Yang LC, Yang CT, Lai CH, Chen MF, Chen CY, et al. Inhibition of corneal neovascularization with plasmid pigment epithelium-derived factor (p-PEDF) delivered by synthetic amphiphile INTeraction-18 (SAINT-18) vector in an experimental model of rat corneal angiogenesis. Exp Eye Res. 2009;89(5):678–85. https://doi.org/10.1016/j.exer.2009.06.021.

    Article  CAS  PubMed  Google Scholar 

  91. • Mukwaya A, Jensen L, Peebo B, Lagali N. MicroRNAs in the cornea: role and implications for treatment of corneal neovascularization. The ocular surface. 2019. https://doi.org/10.1016/j.jtos.2019.04.002A very good review on miRNA therapy for corneal angiogenesis.

    Article  Google Scholar 

  92. Bhela S, Mulik S, Gimenez F, Reddy PB, Richardson RL, Varanasi SK, et al. Role of miR-155 in the pathogenesis of herpetic stromal keratitis. Am J Pathol. 2015;185(4):1073–84. https://doi.org/10.1016/j.ajpath.2014.12.021.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Mulik S, Xu J, Jagadeesh Reddy PB, Rajasagi N, Gimenez F, Sharma S et al. Role of miR-132 in angiogenesis after ocular infection with herpes simplex virus. 2012.

  94. Mulik S, Xu J, Reddy PBJ, Rajasagi NK, Gimenez F, Sharma S, et al. Role of miR-132 in angiogenesis after ocular infection with herpes simplex virus. Am J Pathol. 2012;181(2):525–34. https://doi.org/10.1016/j.ajpath.2012.04.014.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Li X, Zhou H, Tang W, Guo Q, Zhang Y. Transient downregulation of microRNA-206 protects alkali burn injury in mouse cornea by regulating connexin 43. Int J Clin Exp Pathol. 2015;8(3):2719–27.

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Zong R, Zhou T, Lin Z, Bao X, Xiu Y, Chen Y, et al. Down-regulation of MicroRNA-184 is associated with corneal neovascularization MicroRNA-184 and corneal neovascularization. Invest Ophthalmol Vis Sci. 2016;57(3):1398–407. https://doi.org/10.1167/iovs.15-17417.

    Article  CAS  PubMed  Google Scholar 

  97. Grimaldo S, Yuen D, Theis J, Ng M, Ecoiffier T, Chen L. MicroRNA-184 regulates corneal lymphangiogenesis. Invest Ophthalmol Vis Sci. 2015;56(12):7209–13. https://doi.org/10.1167/iovs.15-17733.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Dews M, Homayouni A, Yu D, Murphy D, Sevignani C, Wentzel E, et al. Augmentation of tumor angiogenesis by a Myc-activated microRNA cluster. Nat Genet. 2006;38(9):1060–5. https://doi.org/10.1038/ng1855.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Bolisetty MT, Dy G, Tam W, Beemon KL. Reticuloendotheliosis virus strain T induces miR-155, which targets JARID2 and promotes cell survival. J Virol. 2009;83(23):12009–17. https://doi.org/10.1128/jvi.01182-09.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Yu H, Lu Y, Li Z, Wang Q. microRNA-133: expression, function and therapeutic potential in muscle diseases and cancer. Curr Drug Targets. 2014;15(9):817–28.

    Article  CAS  Google Scholar 

  101. Wang Y, Huang C, Reddy Chintagari N, Bhaskaran M, Weng T, Guo Y, et al. miR-375 regulates rat alveolar epithelial cell trans-differentiation by inhibiting Wnt/β-catenin pathway. Nucleic Acids Res. 2013;41(6):3833–44. https://doi.org/10.1093/nar/gks1460.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Lee SK, Teng Y, Wong HK, Ng TK, Huang L, Lei P, et al. MicroRNA-145 regulates human corneal epithelial differentiation. PLoS One. 2011;6(6):e21249. https://doi.org/10.1371/journal.pone.0021249.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Wu Y, Crawford M, Mao Y, Lee RJ, Davis IC, Elton TS, et al. Therapeutic delivery of MicroRNA-29b by cationic lipoplexes for lung cancer. Molecular therapy Nucleic acids. 2013;2:e84. https://doi.org/10.1038/mtna.2013.14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Ibrahim AF, Weirauch U, Thomas M, Grunweller A, Hartmann RK, Aigner A. MicroRNA replacement therapy for miR-145 and miR-33a is efficacious in a model of colon carcinoma. Cancer Res. 2011;71(15):5214–24. https://doi.org/10.1158/0008-5472.Can-10-4645.

    Article  CAS  PubMed  Google Scholar 

  105. Schade A, Delyagina E, Scharfenberg D, Skorska A, Lux C, David R, et al. Innovative strategy for microRNA delivery in human mesenchymal stem cells via magnetic nanoparticles. Int J Mol Sci. 2013;14(6):10710–26.

    Article  Google Scholar 

  106. Dua HS, Azuara-Blanco A. Limbal stem cells of the corneal epithelium. Surv Ophthalmol. 2000;44(5):415–25.

    Article  CAS  Google Scholar 

  107. Holland EJ, Schwartz GS. The Paton lecture: ocular surface transplantation: 10 years’ experience. Cornea. 2004;23(5):425–31.

    Article  Google Scholar 

  108. Özdemir Ö, Tekeli O, Örnek K, Arslanpençe A, Yalçιndağ NF. Limbal autograft and allograft transplantations in patients with corneal burns. Eye. 2004;18(3):241–8. https://doi.org/10.1038/sj.eye.6700640.

    Article  PubMed  Google Scholar 

  109. Cheung AY, Sarnicola E, Holland EJ. Long-term ocular surface stability in conjunctival limbal autograft donor eyes. Cornea. 2017;36(9):1031–5. https://doi.org/10.1097/ico.0000000000001260.

    Article  PubMed  Google Scholar 

  110. Yao L, Li ZR, Su WR, Li YP, Lin ML, Zhang WX, et al. Role of mesenchymal stem cells on cornea wound healing induced by acute alkali burn. PLoS One. 2012;7(2):e30842. https://doi.org/10.1371/journal.pone.0030842.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Jiang TS, Cai L, Ji WY, Hui YN, Wang YS, Hu D, et al. Reconstruction of the corneal epithelium with induced marrow mesenchymal stem cells in rats. Mol Vis. 2010;16:1304–16.

    PubMed  PubMed Central  Google Scholar 

  112. Murphy N, Lynch K, Lohan P, Treacy O, Ritter T. Mesenchymal stem cell therapy to promote corneal allograft survival: current status and pathway to clinical translation. Cur Opinion Organ Transplant. 2016;21(6):559–67. https://doi.org/10.1097/mot.0000000000000360.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. The Vascular Biology Program and Department of Surgery, Boston Children’s Hospital, Boston, Karp Research Building, 1 Blackfan Street, Karp 11.006F, Boston, MA, 02115, USA

    Sumana R. Chintalapudi

  2. Department of Ophthalmology, Harvard Medical School, Boston, MA, USA

    Sumana R. Chintalapudi

Authors
  1. Sumana R. Chintalapudi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sumana R. Chintalapudi.

Ethics declarations

Conflict of Interest

No potential conflicts of interest relevant to this article were reported.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Wound Healing and Tissue Repair.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chintalapudi, S.R. Therapeutic Strategies for Corneal Wound Angiogenesis. Curr Pathobiol Rep 8, 15–24 (2020). https://doi.org/10.1007/s40139-020-00206-w

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40139-020-00206-w

Keywords

Search

Navigation