Anterior Segment, Corneal and External Disorders
Read Time: 7 mins

Possible Role of Pigment-epithelium-derived Factor in Corneal Angiogenesis

Copy Link
Published Online: Mar 2nd 2011 European Ophthalmic Review, 2009,3(1):64-7 DOI:
Authors: Gysbert Van Setten, Oran Abdiu
Quick Links:
Article Information

The detection of pigment-epithelium-derived factor (PEDF) in corneal tissue has allowed greater understanding of the avascularity of corneal tissue. The ability of the cornea to maintain the avascular nature of this tissue, also referred to as the angiogenic privilege of the cornea, could be partly attributed to the presence of this factor. This privilege is severely impaired by various diseases of the ocular surface associated with inflammation and infection that are often followed by neovascularisation, which compromises the transparency of the cornea and results in visual impairment. The rapidly increasing insights into the basic mechanisms controlling neovascularisation, i.e. balance of growth factor activation and enzymatic activity, has most recently led to the development of large-scale use of specific antiangiogenic agents in the treatment of neovascular age-related macular degeneration (AMD). Focusing on the effects of vascular endothelial growth factor (VEGF), the use of such agents, including bevacizumab (Avastin®), a humanised anti-VEGF monoclonal antibody originally used in the treatment of metastatic colorectal cancer, has been investigated in corneal angiogenesis. PEDF is only one of the many factors involved in ocular angiogenesis. However, although it is only a small protein, it has strong antiangiogenic actions that are expressed in the retinal pigment epithelial (RPE) layer, as well as in other parts of the eye. There are specific characteristics that could designate a special role for PEDF in the regulation of avascularity in the eye. In this article, we focus on corneal angiogenesis and highlight the special features of this somewhat unexplored cytokine, outlining the current knowledge and possible role of PEDF in corneal neovascularisation.


Angiogenesis, corneal neovascularisation, pigment-epithelium-derived factor (PEDF), growth factors


Pigment-epithelial-derived factor (PEDF) is an extracellular 50kDa secreted glycoprotein of the serpin family. In contrast to most other serpins, which are protease inhibitors, PEDF does not seem to exert inhibitory actions against any known proteases.1,2 Only very few other serpins are considered to be non-inhibitory, including ovalalbumin and angiotensinogen. Interestingly, one product of angiotensinogen, angiotensin II, cross-talks with the endothelial growth factor receptors (EGFRs), consequently shedding new light on tumour cell proliferation.3

Furthermore, PEDF has antitumour actions as well,4 but the detailed mechanisms of these actions are not yet clarified. However, PEDF most likely binds to receptors on the cell surface, leading to intracellular activity and altered transcription. In the search for PEDF receptors, the data suggested that PEDF has a 44-mer peptide cellsurface receptor responsible for its binding to retinoblastoma Y-79 cells.5 The crystal structure of PEDF has been determined, showing a striking asymmetrical molecular charge distribution,6 and two binding sites for PEDF to extracellular matrix components have been described: a high-affinity binding area to collagen type I and a lowaffinity binding site to heparin, with evidence for a collagen-1 binding site on the negatively charged part of PEDF.7 Different binding sites on PEDF for collagen and heparin were then located.8 Other data indicate that some RPE cells may produce heparin with binding affinity to PEDF, which could be of importance in receptor binding on the cell surface.9 Using an in vitro model, data showed that PEDF inhibits angiogenesis in microvascular endothelial cells via regulated translocation of vascular EGFR (VEGFR)-1 and phosphorylation of VEGFR-1; this in turn inhibits VEGF-2-induced angiogenesis.10 A protein with phospholipase A2 activity, PEDF receptor (PEDF-R), with high affinity for PEDF was detected in the human retinal pigment epithelia (RPE), suggesting a pathway for cell signalling at the cell surface.11 PEDF further inhibited VEGF expression in the oxygen-induced hypoxic retina of mice, and also inhibited the binding of VEGF to the VEGFR-2, the main VEGF receptor for vascular permeability and angiogenesis.12

The effect of the observed structural change of PEDF following exposure to heparin13 is not known, although an alteration of receptor kinetics should not be excluded. PEDF was first purified from human foetal (RPE) cells, where it promoted neuronal differentiation of cultured human Y-79 retinoblastoma cells.14 PEDF is present in the retina and its RPE cells, but also in other parts of the eye, including ganglion cells and the ciliar epithelium,15,16 as well as in tissues of the human body that are rich in collagen, such as bone and cartilage. The gene for PEDF has been localised to chromosome 17p13,17 the same chromosome responsible for autosomal retinitis pigmentosa18 and Leber congenital amaurosis.19

Pigment-epithelium-derived Factor as a Neuroprotective Factor
Corneal innervation and reinnervation has been shown to be of major importance in corneal wound healing. In this context, the ability of PEDF to protect spinal motor neurons using a culture model based on a specific defect in glutamate transport in amyotrophic lateral sclerosis (ALS) was shown.20 Additionally, PEDF treatment significantly increases the survival of embryonic chock spinal motor neurons in culture in a dose-dependent way, promoting neurite outgrowth of cultured motor neurons and also preventing death of axotomised motor neurons in vivo.21

The known neurotoxicity of glutamate is considered to be an important mechanism in programmed cell death, and is therefore related to different neurodegenerative disorders. PEDF inhibited glutamate-induced apoptosis in cerebellar granulae cells.22,23 This has been shown to be mediated by activation of the transcription factor NF-kappa B (NF-κB); however, PEDF did not regulate the antiapoptotic genes Bcl-2, Bcl-x and Mn-SOD.24 The earlier detected 44-mer peptide 78-121 out of 418 suggested cell-surface receptors binding to retinoblastoma cells20 was identified as the PEDF region responsible for its neuroprotective actions.25 It is not known whether PEDF has similar morphogenic effects within corneal development to those observed in the development of retinal photoreceptors.26

Pigment-epithelium-derived Factor Antiangiogenic Actions in the Eye
As outlined above, there has been significant progress in our understanding of how PEDF may exert its effects. However, the underlying mechanisms concerning the regulation and balance of PEDF and other growth factors involved in angiogenesis of the eye are still unclear.

The first presented antiangiogenic actions of PEDF in the mammalian eye showed that PEDF angiostatin inhibited neovascularisation in the retina more efficiently than the earlier well-studied antiangiogenic factors and, furthermore, that under hypoxia VEGF secretion was high and PEDF expression low.27 Intravitreal injection of PEDF protected retinal photoreceptors from morphological and functional deterioration in light-exposed rats.28 In another model with ischaemic-induced retinopathy in rats, VEGF levels were found to increase to a greater extent than PEDF levels, with a VEGF–PEDF ratio correlating to the observed retinal neovascularisation, suggesting an impaired balance between stimulators and inhibitors of angiogenesis that may contribute to retinal neovascularisation.29 PEDF prevented retinal ischaemiainduced neovascularisation as it appeared from apoptosis of endothelial cells in a murine model,30 and PEDF expression increased in retinal epithelial cells and the retina following laserphotocoagulation, suggesting PEDF could play a role in inhibiting neovascularisation.31 PEDF is further upgraded in differentiated but not in non-differentiated RPE cells.32

The clinical importance of PEDF was emphasised by a study in which intraocular PEDF levels were found to be low in human eyes with retinal ischaemia, including proliferative diabetic retinopathy (DR), compared with controls, suggesting that the loss of antiangiogenic inhibition is of importance in mediating neovascularisation.33 In a prospective case-control study, PEDF concentrations were low in the vitreous of patients with choroidal neovascularisation (CNV) and agerelated macular degeneration (AMD) compared with age-matched control patients.34 Experimental studies with intravitreal injections in a mouse model of oxygen-induced ischaemic retinopathy prevented retinal neovascularisation and suppressed VEGF-induced retinal microvascular endothelial cell proliferation.35 PEDF was found in different tissues of the rat eye and expressed in areas of CNV following laser coagulation, suggesting that PEDF may modulate the process of CNV.36 Lower levels of PEDF and high expression of VEGF were found in the vitreous of patients with DR compared with high levels of PEDF and undetectable levels of VEGF in vitreous samples from patients with idiopathic macular hole, suggesting that an inbalance of PEDF and VEGF may be related to angiogenesis in DR, which in turn can lead to active proliferative DR.37 PEDF was also seen in the subretinal fluid of retinal detachment, which indicates a role in preventing subretinal neovascularisation.38 The concentration of PEDF in tissues may be of crucial importance. Low PEDF concentrations in choroids may play a role in the development of choroidal neovascularisation, as PEDF levels were significantly lower in aged choroids with AMD compared with choroids of age-matched control patients, whereas levels of VEGF were similar in both groups.39

Vascular angiogenesis is possibly linked to lymphangiogenesis and should be considered an advanced multistep process defined as growth of new vessels from pre-existing ones40 triggered by hypoxia and inflammation. In corneal angiogenesis, the limbal region is the site of origin and neovacularisation can be seen at the surface as well as in the stromal layers, depending on the underlying cause.41 An imbalance between proangiogenic and antiangiogenic molecules seems to be of great importance,42 as are other factors, including matrix metalloproteinases. Among the current experimental study designs, the corneal pocket assay is a widely used method in angiogenesis research. Although originally developed for use in the eyes of rabbits,43 later models often use mice instead,44 where angiogenic-stimulating factors are implanted into the cornea and, as the healthy cornea is avascular, all emerging vessels are considered new vessels.45

The counteractive factors of PEDF-regulated vessel-inhibitory activity include VEGF, which is the pre-eminent growth factor promoting pathological angiogenesis. VEGF expression in the cornea was first described in the basal layer of the epithelium46 and its receptors were expressed with increased intensity in inflamed and vascularised human corneal buttons compared with normal corneas, which suggests that VEGF may be involved in corneal vascularisation.47 VEGF, transforming growth factor (TGF)-α and TGF-β expression were localised in human corneas with neovascularisation.48 In corneas of Pax6± mice, bound VEGF-A and expression of soluble VEGFR-1 (also known as sflt-1) were found.49

Based on this knowledge, current antiangiogenic strategies in the cornea focus on the use of modified antibodies against VEGF. Promising results have been achieved by subconjunctival injections with bevacizumab (Avastin®) in patients with superficial and deep corneal neovascularisation; neovascularisation was reduced but no significant change of the centricity of vessels was seen.50 Corneal angiogenesis in animal rabbit models could be inhibited by using subconjunctival injections of bevacizumab.51,52 However, there was no short-term regression of corneal vessels in recurrent pterygium disease after subconjunctival bevacizumab injection.53 More similar studies54–57 will further outline the effects of anti-VEGF treatment in the anterior segment.

Pigment-epithelium-derived Factor in the Cornea and Tear Fluid
Only a few studies have been conducted so far regarding PEDF in the anterior segment of the eye. PEDF was detected in the tear fluid of some healthy volunteers, suggesting that PEDF may play a role in the regulation of neovascularisation at the ocular surface.58

In normal samples, high levels of PEDF were seen in human corneas with less expression in the conjunctiva, but in patients with pterygia, only very few samples showed faint PEDF staining, and in the remaining samples PEDF was not detectable at all.59 In the same samples, highly elevated levels of VEGF were seen in the pterygial samples and detectable levels were seen in the conjunctiva, but not in the cornea.

From clinical experience, it is well-known that with the use of amniotic membranes on the ocular surface, less corneal neovascularisation is seen. By investigating human amniotic membranes, PEDF expression was detected, suggesting that PEDF may contribute to the suppression of corneal angiogenesis.60

Matrix Metalloproteinases
The processing and downregulation of PEDF most likely involve major enzymatic factors of wound-healing events, such as matrix metalloproteinases (MMP). MMPs are of importance in angiogenesis as they dissolve basement membranes and extracellular matrix components, which in turn allow endothelial cells to proliferate, emphasising their possible role in pterygial disease. Pterygia is characterised by a proliferative and inflammatory growth of limbal cell origin that invades the cornea, causing dissolution of the Bowman’s layer and leading to the loss of the natural collagenous barrier separating the epithelium from the stroma. The altered MMP expression in altered basal limbal epithelial cells compared with normal tissue suggests these cells play an important role in the formation and migration of a pterygium.61 The expression of MMPs and their inhibitors at the pterygial head has also been identified.62

The positive feedback between MMP-9 and VEGF in human hypoxic RPE cells emphasises the importance of the enzymatic system in the regulation of VEGF. Raised levels of VEGF increased MMP-9 and exogenous administration of MMP-9 increased VEGF levels.63 Increased expression of MMP-2, messenger RNA (mRNA) and VEGF was first presented in rat corneas following retinal photocoagulation,64 and PEDF levels decreased in hypoxia in a mouse ROP model, most likely as an effect of increased proteolytic actions by MMP-2 and MMP-9.65

The underlying mechanisms of corneal angiogenesis are complex and include different growth factors. PEDF is not as well investigated in neovascularisation in the anterior segment of the eye as in the retina, and current studies so far mostly address the potential role of VEGF and the effects of anti-VEGF therapies. Furthermore, many studies in this area use in vitro or animal models with limitations. However, the balance between expression of PEDF and VEGF observed here, as well as in other parts of the eye, and the possible link via mediators such as MMPs described above suggest that PEDF may play an important role in corneal angiogenesis and wound healing. The tear fluid plays an important role in maintaining corneal homeostasis, and the fact that PEDF was found in detectable amounts in human tears in some samples may be of importance in the regulation of neovascularisation at the ocular surface, but the origin and mechanism of PEDF here are still unclear. Further research in the cornea and tear fluid is required to establish its role and the pathways in which it exerts its actions. Most interestingly, however, PEDF, as an antiangiogenic protein, has different biochemical characteristics from other vascular-inhibitory substances. Better understanding of this system may open the door to new therapeutic strategies in order to maintain or re-establish corneal transparency and vision.

Article Information:

The authors have no conflicts of interest to declare.


Oran Abdiu, St Erik’s Eye Hospital, Polhemsgatan 50, 112 82 Stockholm, Sweden. E:




  1. Steele FR, Chader GJ, Johnson LV, et al., Pigment epithelium-derived factor: neurotrophic activity and identification as a member of the serine protease inbhibitor gene family, Proc Natl Acad Sci U S A, 1993; 90:1526–30.
  2. Becerra SP, Sagasti A, Spinela P, et al., Pigment epithelium-derived factor acts as a noninhibitory serpin. Neurotrophic activity does not require the serpin reactive loop, J Biol Chem, 1995;270:25992–9.
  3. Itabashi H, Maesawa C, Oikawa H, et al., Angiotensin II and epidermal growth factor receptor cross-talk mediated by a disintegrin and metalloprotease accelerates tumor cell proliferation of hepatocellular carcinoma cell lines, Hepatol Res, 2008;38(6):601–13.
  4. Fernandez-Garcia NI, Volpert OV, Jimenez B, Pigment epithelium-derived factor as a multifunctional antitumor factor, J Mol Med, 2007;85(1):15–22.
  5. Alberdi EM, Aymerich MS, Becerra SP, Binding of pigment epithelium-derived factor (PEDF) to retinoblastoma cells and cerebellar granule neurons. Evidence for a PEDF receptor, J Biol Chem, 1999;274:31605–12.
  6. Simonovic M, Gettins PGW, Volz K, Crystal structure of human PEDF, a potent antiangiogenic and neurite growth-promoting factor, Proc Natl Acad Sci U S A, 2001;98(20):11131–5.
  7. Meyer C, Notari L, Becerra SP, Mapping the type I collagen-binding site on pigment epithelium-derived factor. Implications for its antiangiogenic activity, J Biol Chem, 2002;277(47):45400–454007.
  8. Yasui N, Mori T, Morito D, et al., Dual-site recognition of different extracellular matrix components by antiangiogenic/neurotrophic serpin, PEDF, Biochemistry, 2003;42(11):3160–67.
  9. Alberdi EM, Glycosaminoglycans in human retinoblastoma cells: heparan sulfate, a modulator of the pigment epithelium-derived factor-receptor interactions, BMC Biochemistry, 2003;4:1.
  10. Cai J, Jiang WG, Grant MB, et al., Pigment epitheliumderived factor inhibits angiogenesis via regulated intracellular proteolysis of vascular endothelial growth factor receptor 1, J Biol Chem, 2006;281(6):3604–13.
  11. Notari, L, Baladron V, Aroca-Aguilar JD, et al., Identification of a lipase-linked cell membrane receptor for pigment epithelium-derived factor, J Biol Chem, 2006;281(49):38022–37.
  12. Zhang SX, Wang JJ, Gao G, et al., Pigment epitheliumderived growth factor downregulates vascular endothelial growth factor (VEGF) expression and inhibits VEGF-VEGF receptor 2 binding in diabetic retinopathy, J Mol Endocrin, 2006;37(1):1–12.
  13. Valnickova Z, Petersen SV, Nielsen SB, et al., Heparin binding induces a conformational change in pigment epithelium-derived factor, J Biol Chem, 2007;282(9):6661–7.
  14. Tombran-Tink J, Johnson L, Neuronal differentiation of retinoblastoma cells induced by medium conditioned by human RPE cells, Invest Ophthalmol Vis Sci, 1989;30:1700–7.
  15. Karakousis P, John SK, Kathryn C, et al., Localization of pigment epithelium-derived factor (PEDF) in developing and adult human ocular tissues, Mol Vis, 2001;7:154–63.
  16. Ortego J, Escribano J, Becerra SP, et al., Gene expression of the neurotrophic PEDF in the human ciliary epithelium, Invest Ophthalmol Vis Sci, 1996;37:2759–67.
  17. Tombran-Tink J, Pawar H, Swaroop A, et al., Localization of the gene for pigment epithelium-derived factor (PEDF) to chromosom17p13.1 and expression in cultured human retinoblastoma cells, Genomics, 1994;19:266–72.
  18. Goliath R, Shugart Y, Janssens P, et al., Fine localization of the gene for autosomal Retinitis pigmentosa on chromosome 17p, Am J Hum Genet, 1995;57:962–5.
  19. Koenekoop R, Pina AL, Loyer M, et al., Four polymorphic variations in the PEDF gene identified in the screening of patients with Leber congenital amaurosis, Mol Vis, 1999;5:10.
  20. Bilak MM, Corse AM, Bilak SR, et al., Pigment epithelium-derived factor (PEDF) protects motor neurons from chronic glutamate-mediated neurodegeneration, J Neuropathol Exp Neurol, 1999;58:719–28.
  21. Houenou LJ, D´Costa AP, Li L, et al., Pigment epitheliumderived factor promotes the survival and differentiation of developing spinal motor neurons, J Comp Neurol, 1999;412:506–14.
  22. Taniwaki T, Hirashima N, Becerra SP, et al., Pigment epithelium-derived factor protects cultured cerebellar granule cells against glutamate-induced neurotoxicity, J Neurochem, 1997;68(1):26–32.
  23. Araki T, Taniwaki T, Becerra SP et al., Pigment epithelium-derived factor (PEDF) differentially protects immature but not mature cerebellar granule cells against apoptotic cell death, J Neurosci Res, 1998;53:7–15.
  24. Yabe T, Wilson D, Schwartz JP, NFkappaB activation is required for the neuroprotective effects of pigment epithelium-derived factor (PEDF) on cerebellar granule neurons, J Biol Chem, 2001;276(46):43313–19.
  25. Bilak MM, Becerra SP, Vincent AM, et al., Identification of the neuroprotective molecular region of pigment epithelium-derived factor and its binding sites on motor neurons, J Neurosci, 2002;22(21):9378–86.
  26. Jablonski M, Tombran-Tink J, Mrazek DA, et al., Pigment epithelium-derived factor supports normal development of photoreceptor neurons and opsin expression after retinal pigment epithelium removal, J Neurosci, 2000;20: 7149–57.
  27. Dawson DW, Volpert OV, Gillis P, et al., Pigment epithelial-derived factor; a potent inhibitor of angiogenesis, Science, 1999;285:245–8.
  28. Cao W, Tombran-Tink J, Elias R, et al., In vivo protection of photoreceptors from light damage by pigment epithelium-derived factor, Invest Ophthalmol Vis Sci, 2001;42:1646–52.
  29. Gao GQ, Li Y, Zhang DC, et al., Unbalanced expression of VEGF and PEDF in ischemia-induced retinal neovascularization, FEBS Lett, 2001;489:270–76.
  30. Stellmach VV, Crafoord SE, Zhou W, et al., Prevention of ischemia-induced retinopathy by the natural ocular antiangiogenic agent pigment epithelium-derived factor, Proc Natl Acad Sci U S A, 2001;98:2593–7.
  31. Ogata N, Tombran-Tink J, Jo N, et al., Upregulation of pigment epithelium-derived factor after laser photocoagulation, Am J Ophthalmol, 2001;132:427–9.
  32. Ohno-Matsui K, Morita I, Tombran-Tink J, et al., Novel mechanism for age-related macular degeneration: an equilibrium shift between the angiogenesis factors VEGF and PEDF, J Cell Phys, 2001;189:323–33.
  33. Spranger J, Osterhoff M, Reinmann M, et al., Loss of antiangiogenic pigment epithelium-derived factor in patients with angiogenic eye disease, Diabetes, 2001; 50(12):2641–5.
  34. Holekamp NM, Bouck N, Volpert O, Pigment epitheliumderived factor is deficient in the vitreous of patients with choroidal neovascularization due to age-related macular degeneration, Am J Ophthalmol, 2002;134:220–27.
  35. Duh E, Yang HS, Suzuma I, et al., Pigment epitheliumderived factor suppresses ischemia-induced retinal vascularization and VEGF-induced migration and growth, Invest Ophthalmol Vis Sci, 2002;43(3):821–9.
  36. Ogata N, Wada M, Tsuyoshi O, et al., Expression of pigment epithelium-derived factor in normal adult rat eye and experimental choroidal neovascularisation, Invest Ophthalmol Vis Sci, 2002;43(4):1168–75.
  37. Ogata N, Nishikawa M, Nishimura T, et al., Unbalanced vitreous levels of pigment epithelium-derived factor and vascular endothelial growth factor in diabetic retinopathy, Am J Ophthalmol, 2002;134:348–53.
  38. Abdiu O, Van Setten G, Detection of PEDF in subretinal fluid of retinal detachment: possible role in prevention of subretinal neovascularization: preliminary results, Ophthalmic Res, 2006;38(4):189–92.
  39. Bhutto IA, McLeod DS, Hasegawa T, et al., Pigment epithelium-derived factor (PEDF) and vascular endothelial growth factor (VEGF) in aged human choroid and eyes with age-related macular degeneration, Exp Eye Res, 2006;82(1):99–110.
  40. Carmeliet P, Angiogenesis in health and disease, Nat Med, 2003;6:653–60.
  41. Cursifien C, Kuchle M, Naumann GO, et al., Angiogenesis in corneal diseases; histopathologic evaluation of 254 human corneal buttons with neovascularisation, Cornea, 1998;17:611–13.
  42. Chang J-H, Gabison E, Kato T, et al., Corneal neovascularisation, Curr Opin Ophthalmol, 2001;12(4):242–9.
  43. Gimbrone MA, Cotran RS, Leapman SB, et al., Tumor growth and neovascularisation: an experimental model using the rabbit cornea, J Natl Cancer Inst, 1974;52(2): 413–27.
  44. Kenyon BM, Voegt EE, Chen CC, et al., A model of angiogenesis in the mouse cornea, Invest Ophthalmol Vis Sci, 1996;37:1625–32.
  45. Auerbach R, Lewis R, Shinners B, et al., Angiogenesis Assays; A critical overview, Clinical Chemistry, 2003;49:1: 32–40.
  46. Van Setten G, Vascular endothelial growth factor (VEGF) in normal human corneal epithelium; detection and physiological importance, Acta Ophthalmol Scand, 1997;75(6):649–52.
  47. 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;41:2514–22.
  48. Cursifien C, Rummelt C, Kuchle M, Immunohistochemical localization of vascular endothelial growth factor, transforming growth factor alpha, and transforming growth factor beta1 in human corneas with vascularization, Cornea, 2000;19:526–33.
  49. Ambati B, Nozaki M, Singh N, et al., Corneal vascularity is due to soluble VEGF receptor-1, Nature, 2006;443:993–7.
  50. Bahar I, Kaiserman I, McAllum P, et al., Subconjunctival bevacizumab injection for corneal neovascularization, Cornea, 2008;27(2):142–7.
  51. Kim T, Kim SW, Kim S, et al., Inhibition of experimental corneal vascularisation by using subconjunctival injection of bevacizumab (Avastin), Cornea, 2008;27(3):349–52.
  52. Papathanassiou M, Thedossiadis P, Liarakos V, et al., Inhibition of corneal neovascularisation by subconjunctival bevacizumab in an animal model, Am J Ophthalmol, 2008;145(3):424–31.
  53. Bahar I, Kaiserman I, McAllum P, et al., Subconjunctival bevacizumab injection for corneal neovascularization in recurrent pterygium, Current Eye Res, 2008;33:23–8.
  54. Chen WL, Lin CT, Chen MY, et al., Successful inhibition of corneal neovascularisation formation by subconjunctival injection of bevacizumab (Avastin) in various animal models, ARVO abstract, 2008, program number/poster board number 1471/D1019.
  55. Rosner M, Habot-Wilner Z, Ivanir Y, et al., The inhibitory effect of different concentrations of topical bevacizumab on corneal neovascularisation, ARVO abstract, 2008, program number/poster board number 1473/D1021.
  56. Avisar I, Dratviman O, Kremer I, et al., Therapeutic effect of subconjunctival and intraocular bevacizumab (Avastin) injections in a mouse model of corneal neovascularisation, ARVO abstract, 2008, program number/poster board number 3745.
  57. Moriyama AS, Moraes Filho MN, Furlani B, et al., Effect of topical bevacizumab on corneal angiogenesis in the rabbit model, ARVO abstract, 2008, program number/poster board number 3744.
  58. Abdiu O, Van Setten G, Antiangiogenic activity in tears: presence of pigment-epithelium-derived factor. New insights and preliminary results, Ophthalmic Res, 2008; 40(1):16–18.
  59. Jin J, Guan M, Sima J, et al., Decreased pigment epithelium-derived factor and increased vascular endothelial growth factor levels in pterygia, Cornea, 2003;22(5):473–7.
  60. Shao C, Sima J, Zhang S, et al., Suppression of corneal neovascularisation by PEDF release from human amniotic membranes, Invest Ophthalmol Vis Sci, 2004;45:1758–62.
  61. Dushku N, John M, Schultz GS, et al., Pterygia pathogenesis: corneal invasion by matrix metalloproteinase (MMP) expressing altered limbsl basal stem cells and activation of fibroblasts, ARVO abstract, Invest Ophthalmol Vis Sci, 2000;41(4):S451, abstract 2388.
  62. Di Girolamo N, Wakefield D, Coroneo MT, Differential expression of matrix metalloproteinases and their tissue inhibitors at the advancing pterygium head, Invest Ophthalmol Vis Sci, 2000;41(13):4142–9.
  63. Hollborn M, Stathopoulos C, Steffen A, et al., Positive feedback regulation between MMP-9 and VEGF in human RPE cells, Invest Ophthalmol Vis Sci, 2007;48(9): 4360–67.
  64. Kvanta A, Sarman S, Fagerholm P, et al., Expression of matrix metalloproteinase-2 (MMP-2) and vascular endothelial growth factor (VEGF) in inflammationassociated corneal neovascularization, Exp Eye Res, 2000;70:419–28.
  65. Notari L, Miller A, Martinez A, et al., Pigment epitheliumderived growth factor is a substrate for matrix metalloproteinase type 2 and type 9: implications for downregulation in hypoxia, Invest Ophthalmol Vis Sci, 2005;46(8):2736–47.

Further Resources

Share this Article
Related Content In Corneal and External Disorders
  • Copied to clipboard!
    accredited arrow-down-editablearrow-downarrow_leftarrow-right-bluearrow-right-dark-bluearrow-right-greenarrow-right-greyarrow-right-orangearrow-right-whitearrow-right-bluearrow-up-orangeavatarcalendarchevron-down consultant-pathologist-nurseconsultant-pathologistcrosscrossdownloademailexclaimationfeedbackfiltergraph-arrowinterviewslinkmdt_iconmenumore_dots nurse-consultantpadlock patient-advocate-pathologistpatient-consultantpatientperson pharmacist-nurseplay_buttonplay-colour-tmcplay-colourAsset 1podcastprinter scenerysearch share single-doctor social_facebooksocial_googleplussocial_instagramsocial_linkedin_altsocial_linkedin_altsocial_pinterestlogo-twitter-glyph-32social_youtubeshape-star (1)tick-bluetick-orangetick-red tick-whiteticktimetranscriptup-arrowwebinar Sponsored Department Location NEW TMM Corporate Services Icons-07NEW TMM Corporate Services Icons-08NEW TMM Corporate Services Icons-09NEW TMM Corporate Services Icons-10NEW TMM Corporate Services Icons-11NEW TMM Corporate Services Icons-12Salary £ TMM-Corp-Site-Icons-01TMM-Corp-Site-Icons-02TMM-Corp-Site-Icons-03TMM-Corp-Site-Icons-04TMM-Corp-Site-Icons-05TMM-Corp-Site-Icons-06TMM-Corp-Site-Icons-07TMM-Corp-Site-Icons-08TMM-Corp-Site-Icons-09TMM-Corp-Site-Icons-10TMM-Corp-Site-Icons-11TMM-Corp-Site-Icons-12TMM-Corp-Site-Icons-13TMM-Corp-Site-Icons-14TMM-Corp-Site-Icons-15TMM-Corp-Site-Icons-16TMM-Corp-Site-Icons-17TMM-Corp-Site-Icons-18TMM-Corp-Site-Icons-19TMM-Corp-Site-Icons-20TMM-Corp-Site-Icons-21TMM-Corp-Site-Icons-22TMM-Corp-Site-Icons-23TMM-Corp-Site-Icons-24TMM-Corp-Site-Icons-25TMM-Corp-Site-Icons-26TMM-Corp-Site-Icons-27TMM-Corp-Site-Icons-28TMM-Corp-Site-Icons-29TMM-Corp-Site-Icons-30TMM-Corp-Site-Icons-31TMM-Corp-Site-Icons-32TMM-Corp-Site-Icons-33TMM-Corp-Site-Icons-34TMM-Corp-Site-Icons-35TMM-Corp-Site-Icons-36TMM-Corp-Site-Icons-37TMM-Corp-Site-Icons-38TMM-Corp-Site-Icons-39TMM-Corp-Site-Icons-40TMM-Corp-Site-Icons-41TMM-Corp-Site-Icons-42TMM-Corp-Site-Icons-43TMM-Corp-Site-Icons-44TMM-Corp-Site-Icons-45TMM-Corp-Site-Icons-46TMM-Corp-Site-Icons-47TMM-Corp-Site-Icons-48TMM-Corp-Site-Icons-49TMM-Corp-Site-Icons-50TMM-Corp-Site-Icons-51TMM-Corp-Site-Icons-52TMM-Corp-Site-Icons-53TMM-Corp-Site-Icons-54TMM-Corp-Site-Icons-55TMM-Corp-Site-Icons-56TMM-Corp-Site-Icons-57TMM-Corp-Site-Icons-58TMM-Corp-Site-Icons-59TMM-Corp-Site-Icons-60TMM-Corp-Site-Icons-61TMM-Corp-Site-Icons-62TMM-Corp-Site-Icons-63TMM-Corp-Site-Icons-64TMM-Corp-Site-Icons-65TMM-Corp-Site-Icons-66TMM-Corp-Site-Icons-67TMM-Corp-Site-Icons-68TMM-Corp-Site-Icons-69TMM-Corp-Site-Icons-70TMM-Corp-Site-Icons-71TMM-Corp-Site-Icons-72