Top

Graefe's Archive for Clinical and Experimental Ophthalmology

Published in:

01-01-2004 | Review

Role of growth factors and the wound healing response in age-related macular degeneration

Author: Reinier O. Schlingemann

Published in: Graefe's Archive for Clinical and Experimental Ophthalmology | Issue 1/2004

Abstract

Growth factors (GF) are important in several stages of the pathogenesis of age-related macular disease (AMD). In choroidal neovascularization (CNV) in exudative AMD, the GF involved are similar to those involved in wound healing of the skin. Like granulation tissue of skin, CNV is characterized by clotting, inflammation, angiogenesis and fibrosis, and like in skin wounds, members of the VEGF, angiopoietin, PDGF and TGF-β families of GF are expressed. However, several of these GF may also serve physiological functions in the normal eye, where the retinal pigment epithelium (RPE) employs them to provide trophic support to the neuroretina and choriocapillaris, in addition to maintaining an anti-angiogenic state. Derangement of these physiological functions may underlie the initiation of CNV in AMD. Basolateral secretion of VEGF-A by the RPE maintains the choriocapillaris, and is enhanced by hypoxia. Age-related changes in Bruch’s membrane lead to impairment of this trophic function and choriocapillaris atrophy, as well as to decreased diffusion of oxygen towards the neuroretina. The resulting outer retina hypoxia may be an important driving force of CNV formation, by stimulating VEGF overexpression by the RPE, in addition to the effects of increased oxidative stress and low-grade inflammation. RPE senescence and hypoxia may also decrease expression of angiogenesis inhibitors such as PEDF, further shifting the balance to a pro-angiogenic state in the aging eye.

Abe R, Donnelly SC, Peng T, Bucala R, Metz CN (2001) Peripheral blood fibrocytes: differentiation pathway and migration to wound sites. J Immunol 166:7556–7562PubMed

Aiello LP, Northrup JM, Keyt BA, Takagi H, Iwamoto MA (1995) Hypoxic regulation of vascular endothelial growth factor in retinal cells. Arch Ophthalmol 113:1538–1544PubMed

Alon T, Hemo I, Itin A, Pe’er J, Stone J, Keshet E (1995) Vascular endothelial growth factor acts as a survival factor for newly formed retinal vessels and has implications for retinopathy of prematurity. Nat Med 1:1024–1028PubMed

Ambati J, Anand A, Fernandez S, Sakurai E, Lynn BC, Kuziel WA, Rollins BJ, Ambati BK (2003) An animal model of age-related macular degeneration in senescent Ccl-2- or Ccr-2-deficient mice. Nat Med 9:1390–1397CrossRefPubMed

Amin R, Puklin JE, Frank RN (1994) Growth factor localization in choroidal neovascular membranes of age-related macular degeneration. Invest Ophthalmol Vis Sci 35:3178–3188PubMed

Arden GB, Wolf JE (2003) Differential effects of light and alcohol on the electro-oculographic responses of patients with age-related macular disease. Invest Ophthalmol Vis Sci 44:3226–3232CrossRefPubMed

Beatty S, Koh H, Phil M, Henson D, Boulton M (2000) The role of oxidative stress in the pathogenesis of age-related macular degeneration. Surv Ophthalmol 45:115–134CrossRefPubMed

Bird AC (2003) The Bowman lecture. Towards an understanding of age-related macular disease. Eye 17:457–466CrossRefPubMed

Blaauwgeers HG, Holtkamp GM, Rutten H, Witmer AN, Koolwijk P, Partanen TA, Alitalo K, Kroon ME, Kijlstra A, van Hinsbergh VW, Schlingemann RO (1999) Polarized vascular endothelial growth factor secretion by human retinal pigment epithelium and localization of vascular endothelial growth factor receptors on the inner choriocapillaris. Evidence for a trophic paracrine relation. Am J Pathol 155:421–428PubMed

10.

Campochiaro PA (2000) Retinal and choroidal neovascularization. J Cell Physiol 184:301–310CrossRefPubMed

11.

Carmeliet P, Storkebaum E (2002) Vascular and neuronal effects of VEGF in the nervous system: implications for neurological disorders. Semin Cell Dev Biol 13:39–53CrossRefPubMed

12.

D’Amore PA (1994) Mechanisms of retinal and choroidal neovascularization. Invest Ophthalmol Vis Sci 35:3974–3979PubMed

13.

Dawson DW, Volpert OV, Gillis P, Crawford SE, Xu H, Benedict W, Bouck NP (9–7-1999) Pigment epithelium-derived factor: a potent inhibitor of angiogenesis. Science 285:245–248CrossRef

14.

Esser S, Wolburg K, Wolburg H, Breier G, Kurzchalia T, Risau W (1998) Vascular endothelial growth factor induces endothelial fenestrations in vitro. J Cell Biol 140:947–959PubMed

15.

Folkman J (1997) Angiogenesis and angiogenesis inhibition: an overview. EXS 79:1-8PubMed

16.

Frank RN (1997) Growth factors in age-related macular degeneration: pathogenic and therapeutic implications. Ophthalmic Res 29:341–353PubMed

17.

Green WR (1991) Clinicopathologic studies of treated choroidal neovascular membranes. A review and report of two cases. Retina 11:328–356PubMed

18.

Green WR, Enger C (1993) Age-related macular degeneration histopathologic studies. The 1992 Lorenz E. Zimmerman Lecture. Ophthalmology 100:1519–1535PubMed

19.

Grossniklaus HE, Green WR (1998) Histopathologic and ultrastructural findings of surgically excised choroidal neovascularization. Submacular Surgery Trials Research Group. Arch Ophthalmol 116:745–749PubMed

20.

Grossniklaus HE, Martinez JA, Brown VB, Lambert HM, Sternberg P, Jr., Capone A, Jr., Aaberg TM, Lopez PF (1992) Immunohistochemical and histochemical properties of surgically excised subretinal neovascular membranes in age-related macular degeneration. Am J Ophthalmol 114:464–472PubMed

21.

Grossniklaus HE, Ling JX, Wallace TM, Dithmar S, Lawson DH, Cohen C, Elner VM, Elner SG, Sternberg P, Jr. (2002) Macrophage and retinal pigment epithelium expression of angiogenic cytokines in choroidal neovascularization. Mol Vis 8:119–126PubMed

22.

Hackett SF, Friedman Z, Freund J, Schoenfeld C, Curtis R, DiStefano PS, Campochiaro PA (1998) A splice variant of trkB and brain-derived neurotrophic factor are co-expressed in retinal pigmented epithelial cells and promote differentiated characteristics. Brain Res 789:201–212CrossRefPubMed

23.

Hangai M, Murata T, Miyawaki N, Spee C, Lim JI, He S, Hinton DR, Ryan SJ (2001) Angiopoietin-1 upregulation by vascular endothelial growth factor in human retinal pigment epithelial cells. Invest Ophthalmol Vis Sci 42:1617–1625PubMed

24.

He S, Jin ML, Worpel V, Hinton DR (2003) A role for connective tissue growth factor in the pathogenesis of choroidal neovascularization. Arch Ophthalmol 121:1283–1288CrossRefPubMed

25.

Hinton DR, He S, Jin ML, Barron E, Ryan SJ (2002) Novel growth factors involved in the pathogenesis of proliferative vitreoretinopathy. Eye 16:422–428CrossRefPubMed

26.

Holekamp NM, Bouck N, Volpert O (2002) Pigment epithelium-derived factor is deficient in the vitreous of patients with choroidal neovascularization due to age-related macular degeneration. Am J Ophthalmol 134:220–227

27.

Holz FG, Sheraidah G, Pauleikhoff D, Bird AC (1994) Analysis of lipid deposits extracted from human macular and peripheral Bruch’s membrane. Arch Ophthalmol 112:402–406PubMed

28.

Iruela-Arispe ML, Dvorak HF (1997) Angiogenesis: a dynamic balance of stimulators and inhibitors. [Review]. Thromb Haemost 78:672–677PubMed

29.

Ishida K, Yoshimura N, Yoshida M, Honda Y, Murase K, Hayashi K (1997) Expression of neurotrophic factors in cultured human retinal pigment epithelial cells. Curr Eye Res 16:96–101CrossRefPubMed

30.

Jablonski MM, Tombran-Tink J, Mrazek DA, Iannaccone A (2000) Pigment epithelium-derived factor supports normal development of photoreceptor neurons and opsin expression after retinal pigment epithelium removal. J Neurosci 20:7149–7157PubMed

31.

Kaplan HJ, Leibole MA, Tezel T, Ferguson TA (1999) Fas ligand (CD95 ligand) controls angiogenesis beneath the retina. Nat Med 5:292–297CrossRefPubMed

32.

Kliffen M, Sharma HS, Mooy CM, Kerkvliet S, de Jong PT (1997) Increased expression of angiogenic growth factors in age-related maculopathy. Br J Ophthalmol 81:154–162

33.

Krzystolik MG, Afshari MA, Adamis AP, Gaudreault J, Gragoudas ES, Michaud NA, Li W, Connolly E, O’Neill CA, Miller JW (2002) Prevention of experimental choroidal neovascularization with intravitreal anti-vascular endothelial growth factor antibody fragment. Arch Ophthalmol 120:338–346PubMed

34.

Kvanta A, Algvere PV, Berglin L, Seregard S (1996) Subfoveal fibrovascular membranes in age-related macular degeneration express vascular endothelial growth factor. Invest Ophthalmol Vis Sci 37:1929–1934PubMed

35.

Lafaut BA (2000) Clinicopathologic correlation of surgically removed submacular tissue. Bull Soc Belge Ophtalmol 278: 49–53PubMed

36.

Lafaut BA, Bartz-Schmidt KU, Vanden Broecke C, Aisenbrey S, De Laey JJ, Heimann K (2000) Clinicopathological correlation in exudative age related macular degeneration: histological differentiation between classic and occult choroidal neovascularisation. Br J Ophthalmol 84:239–243PubMed

37.

Li J, Zhang YP, Kirsner RS (2003) Angiogenesis in wound repair: angiogenic growth factors and the extracellular matrix. Microsc Res Tech 60:107–114CrossRefPubMed

38.

Liu X, Ye X, Yanoff M, Li W (1997) Extracellular matrix of retinal pigment epithelium regulates choriocapillaris endothelial survival in vitro. Exp Eye Res 65:117–126CrossRefPubMed

39.

Lopez PF, Sippy BD, Lambert HM, Thach AB, Hinton DR (1996) Transdifferentiated retinal pigment epithelial cells are immunoreactive for vascular endothelial growth factor in surgically excised age-related macular degeneration-related choroidal neovascular membranes. Invest Ophthalmol Vis Sci 37:855–868PubMed

40.

Luttun A, Tjwa M, Carmeliet P (2002) Placental growth factor (PlGF) and its receptor Flt-1 (VEGFR-1): novel therapeutic targets for angiogenic disorders. Ann N Y Acad Sci 979:80–93PubMed

41.

Lutty G, Grunwald J, Majji AB, Uyama M, Yoneya S (1999) Changes in choriocapillaris and retinal pigment epithelium in age-related macular degeneration. Mol Vis 5:35PubMed

42.

Mathura JR, Jr., Jafari N, Chang JT, Hackett SF, Wahlin KJ, Della NG, Okamoto N, Zack DJ, Campochiaro PA (2000) Bone morphogenetic proteins-2 and −4: negative growth regulators in adult retinal pigmented epithelium. Invest Ophthalmol Vis Sci 41:592–600PubMed

43.

Miyajima-Uchida H, Hayashi H, Beppu R, Kuroki M, Fukami M, Arakawa F, Tomita Y, Kuroki M, Oshima K (2000) Production and accumulation of thrombospondin-1 in human retinal pigment epithelial cells. Invest Ophthalmol Vis Sci 41:561–567PubMed

44.

Ogata N, Wada M, Otsuji T, Jo N, Tombran-Tink J, Matsumura M (2002) Expression of pigment epithelium-derived factor in normal adult rat eye and experimental choroidal neovascularization. Invest Ophthalmol Vis Sci 43:1168–1175PubMed

45.

Ohno-Matsui K, Morita I, Tombran-Tink J, Mrazek D, Onodera M, Uetama T, Hayano M, Murota SI, Mochizuki M (2001) Novel mechanism for age-related macular degeneration: an equilibrium shift between the angiogenesis factors VEGF and PEDF. J Cell Physiol 189:323–333CrossRefPubMed

46.

Ohno-Matsui K, Yoshida T, Uetama T, Mochizuki M, Morita I (2003) Vascular endothelial growth factor upregulates pigment epithelium-derived factor expression via VEGFR-1 in human retinal pigment epithelial cells. Biochem Biophys Res Commun 303:962–967CrossRefPubMed

47.

Otani A, Takagi H, Oh H, Koyama S, Matsumura M, Honda Y (1999) Expressions of angiopoietins and Tie2 in human choroidal neovascular membranes. Invest Ophthalmol Vis Sci 40:1912–1920PubMed

48.

Otani A, Takagi H, Oh H, Koyama S, Ogura Y, Matumura M, Honda Y (2002) Vascular endothelial growth factor family and receptor expression in human choroidal neovascular membranes. Microvasc Res 64:162–169CrossRefPubMed

49.

Penfold PL, Madigan MC, Gillies MC, Provis JM (2001) Immunological and aetiological aspects of macular degeneration. Prog Retin Eye Res 20:385–414CrossRefPubMed

50.

Rakic JM, Lambert V, Devy L, Luttun A, Carmeliet P, Claes C, Nguyen L, Foidart JM, Noel A, Munaut C (2003) Placental growth factor, a member of the VEGF family, contributes to the development of choroidal neovascularization. Invest Ophthalmol Vis Sci 44:3186–3193CrossRefPubMed

51.

Rakoczy PE, Zhang D, Robertson T, Barnett NL, Papadimitriou J, Constable IJ, Lai CM (2002) Progressive age-related changes similar to age-related macular degeneration in a transgenic mouse model. Am J Pathol 161:1515–1524PubMed

52.

Ramrattan RS, van der Schaft TL, Mooy CM, de Bruijn WC, Mulder PG, de Jong PT (1994) Morphometric analysis of Bruch’s membrane, the choriocapillaris, and the choroid in aging. Invest Ophthalmol Vis Sci 35:2857–2864PubMed

53.

Reddy VM, Zamora RL, Kaplan HJ (1995) Distribution of growth factors in subfoveal neovascular membranes in age-related macular degeneration and presumed ocular histoplasmosis syndrome. Am J Ophthalmol 120:291–301PubMed

54.

Renno RZ, Youssri AI, Michaud N, Gragoudas ES, Miller JW (2002) Expression of pigment epithelium-derived factor in experimental choroidal neovascularization. Invest Ophthalmol Vis Sci 43:1574–1580PubMed

55.

Sakurai E, Anand A, Ambati BK, van Rooijen N, Ambati J (2003) Macrophage depletion inhibits experimental choroidal neovascularization. Invest Ophthalmol Vis Sci 44:3578–3585CrossRefPubMed

56.

Schlingemann RO, Rietveld FJ, Kwaspen F, van de Kerkhof PC, et al (1991) Differential expression of markers for endothelial cells, pericytes, and basal lamina in the microvasculature of tumors and granulation tissue. Am J Pathol 138:1335–1347

57.

Schwesinger C, Yee C, Rohan RM, Joussen AM, Fernandez A, Meyer TN, Poulaki V, Ma JJ, Redmond TM, Liu S, Adamis AP, D’Amato RJ (2001) Intrachoroidal neovascularization in transgenic mice overexpressing vascular endothelial growth factor in the retinal pigment epithelium. Am J Pathol 158:1161–1172PubMed

58.

Sengupta N, Caballero S, Mames RN, Butler JM, Scott EW, Grant MB (2003) The role of adult bone marrow-derived stem cells in choroidal neovascularization. Invest Ophthalmol Vis Sci 44:4908–4913CrossRefPubMed

59.

Shih SC, Ju M, Liu N, Smith LE (2003) Selective stimulation of VEGFR-1 prevents oxygen-induced retinal vascular degeneration in retinopathy of prematurity. J Clin Invest 112:50–57CrossRefPubMed

60.

Shima DT, Adamis AP, Ferrara N, Yeo KT, Yeo TK, Allende R, Folkman J, D’Amore PA (1995) Hypoxic induction of endothelial cell growth factors in retinal cells: identification and characterization of vascular endothelial growth factor (VEGF) as the mitogen. Mol Med 1:182–193PubMed

61.

Shimo T, Nakanishi T, Nishida T, Asano M, Kanyama M, Kuboki T, Tamatani T, Tezuka K, Takemura M, Matsumura T, Takigawa M (1999) Connective tissue growth factor induces the proliferation, migration, and tube formation of vascular endothelial cells in vitro, and angiogenesis in vivo. J Biochem (Tokyo) 126:137–145

62.

Spilsbury K, Garrett KL, Shen WY, Constable IJ, Rakoczy PE (2000) Overexpression of vascular endothelial growth factor (VEGF) in the retinal pigment epithelium leads to the development of choroidal neovascularization. Am J Pathol 157:135–144PubMed

63.

The Eyetech Study Group (2003) Anti-vascular endothelial growth factor therapy for subfoveal choroidal neovascularization secondary to age-related macular degeneration: phase II study results. Ophthalmology 110:979–986CrossRefPubMed

64.

Thurston G (2003) Role of angiopoietins and Tie receptor tyrosine kinases in angiogenesis and lymphangiogenesis. Cell Tissue Res (in press)

65.

Tobe T, Takahashi K, Ohkuma H, Uyama M (1994) [Experimental choroidal neovascularization in the rat]. Nippon Ganka Gakkai Zasshi 98:837–845PubMed

66.

Uyama M (1991) [Choroidal neovascularization, experimental and clinical study]. Nippon Ganka Gakkai Zasshi 95:1145–1180PubMed

67.

van Meurs JC, Van Den Biesen PR (2003) Autologous retinal pigment epithelium and choroid translocation in patients with exudative age-related macular degeneration: short-term follow-up. Am J Ophthalmol 136:688–695CrossRefPubMed

68.

Wada M, Ogata N, Otsuji T, Uyama M (1999) Expression of vascular endothelial growth factor and its receptor (KDR/flk-1) mRNA in experimental choroidal neovascularization. Curr Eye Res 18:203–213

69.

Werner S, Grose R (2003) Regulation of wound healing by growth factors and cytokines. Physiol Rev 83:835–870PubMed

70.

Witmer AN, Vrensen GF, Van Noorden CJ, Schlingemann RO (2003) Vascular endothelial growth factors and angiogenesis in eye disease. Prog Retin Eye Res 22:1-29CrossRefPubMed

71.

Yi X, Mai LC, Uyama M, Yew DT (1998) Time-course expression of vascular endothelial growth factor as related to the development of the retinochoroidal vasculature in rats. Exp Brain Res 118:155–160CrossRefPubMed

72.

Zhao J, Song Y, Wang Y, Zhang X (2000) [Regulation effect of vascular endothelial growth factor on human fetal choroid vascularization]. Yan Ke Xue Bao 16:11–14PubMed

73.

Zhao S, Overbeek PA (2001) Regulation of choroid development by the retinal pigment epithelium. Mol Vis 7:277–282PubMed

74.

Zhao S, Rizzolo LJ, Barnstable CJ (1997) Differentiation and transdifferentiation of the retinal pigment epithelium. Int Rev Cytol 171:225–266PubMed

Title: Role of growth factors and the wound healing response in age-related macular degeneration
Author: Reinier O. Schlingemann
Publication date: 01-01-2004
Publisher: Springer-Verlag
Published in: Graefe's Archive for Clinical and Experimental Ophthalmology / Issue 1/2004
Print ISSN: 0721-832X
Electronic ISSN: 1435-702X
DOI: https://doi.org/10.1007/s00417-003-0828-0

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Role of growth factors and the wound healing response in age-related macular degeneration

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 1/2004

The many possible roles of stem cells in age-related macular degeneration

RPE cell cultivation

Measuring intraocular pressure with the Pulsair 3000 and Rebound tonometers in elderly patients without an anesthetic

EBV-induced polymorphic lymphoproliferative disorder of the iris after heart transplantation

Laser interference biometry versus ultrasound biometry in certain clinical conditions

Phakomatous choristoma of the eyelid