Skip to main content

Advertisement

Log in

Expression of angiogenic and fibrogenic factors in proliferative vitreoretinal disorders

  • Original paper
  • Published:
International Ophthalmology Aims and scope Submit manuscript

Abstract

Purpose

To investigate the expression of connective tissue growth factor (CTGF) in the retina of human subjects with diabetes mellitus, and CTGF, CD105, and gelatinase B in proliferative diabetic retinopathy (PDR) and proliferative vitreoretinopathy (PVR) epiretinal membranes.

Methods

Twelve donor eyes from six subjects with diabetes mellitus, 10 eyes from five nondiabetic subjects, 14 PDR membranes, and five PVR membranes were studied by immunohistochemical techniques. In situ zymography was used to examine gelatinolytic activity in four PDR membranes.

Results

In nondiabetic retinas, there was no immunoreactivity for CTGF. Diabetic retinas showed immunoreactivity for CTGF in ganglion cells and microglia. Vascular endothelial cells in PDR membranes expressed CTGF, CD105, and gelatinase B in 10 (71.4%), 11 (78.6%), and 5 (35.7%) membranes, respectively. Myofibroblasts in PDR membranes expressed CTGF, and gelatinase B in 14 (100%), and 6 (42.9%) membranes, respectively. There was a significant correlation between the number of blood vessels expressing the panendothelial marker CD34 and the number of blood vessels expressing CTGF (r = 0.7884; P = 0.0008), and CD105 (r = 0.6901; P = 0.0063), and the number of myofibroblasts expressing CTGF (r = 0.5922; P = 0.0257). There was a significant correlation between the number of myofibroblasts expressing α-smooth muscle actin and the number of myofibroblaasts expressing CTGF (r = 0.8393; P = 0.0002). In situ zymography showed the presence of gelatinolytic activity in vascular endothelial cells in PDR membranes. Myofibroblasts in PVR membranes expressed CTGF, and gelatinase B.

Conclusions

These results suggest a possible role of CTGF, CD105, and gelatinase B in the pathogenesis of proliferative vitreoretinal disorders.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Blom IE, Goldschmeding R, Leask A (2002) Gene regulation of connective tissue growth factor: new targets for antifibrotic therapy? Matrix Biol 21:473–482

    Article  PubMed  CAS  Google Scholar 

  2. Twigg SM, Joly AH, Chen MM, Tsubaki J, Kim H-S, Hwa V et al (2002) Connective tissue growth factor/IGF-binding protein-related protein-2 is a mediator in the induction of fibronectin by advanced glycosylation end-products in human dermal fibroblasts. Endocrinology 143:1260–1269

    Article  PubMed  CAS  Google Scholar 

  3. Wang JF, Olson ME, Ball DK, Brigstock DR, Hart DA (2003) Recombinant connective tissue growth factor modulates porcine skin fibroblast gene expression. Wound Rep Reg 11:220–229

    Article  Google Scholar 

  4. Shimo T, Nakanishi T, Nishida T, Asano M, Kanyama M, Kuboki T et al (1999) Connective tissue growth factor induces the proliferation, migration, and tube formation of vascular endothelial cells in vitro, and angiogenesis in vivo. J Biochem 126:137–145

    PubMed  CAS  Google Scholar 

  5. Duff SE, Li C, Garland JM, Kumar S (2003) CD105 is important for angiogenesis: evidence and potential applications. FASEB J 17:984–992

    Article  PubMed  CAS  Google Scholar 

  6. Nguyen M, Arkell J, Jackson CJ (2001) Human endothelial gelatinase and angiogenesis. Int J Biochem Cell Biol 33:960–970

    Article  PubMed  CAS  Google Scholar 

  7. Matrisian L (1990) Matrix metalloproteinases and their inhibitors in matrix remodeling. Trends Genet 6:121–125

    Article  PubMed  CAS  Google Scholar 

  8. Paemen L, Martens E, Masure S, Opdenakker G (1995) Monoclonal antibodies specific for natural human neutrophil gelatinase B used for affinity purification, quantitation by two-site ELISA and inhibition of enzymatic activity. Eur J Biochem 234:759–765

    Article  PubMed  CAS  Google Scholar 

  9. Pagenstecher A, Stalder AK, Kincaid CL, Volk B, Campbell IL (2000) Regulation of matrix metalloproteinases and their inhibitor genes in lipopolysaccharide-induced endotoxemia in mice. Am J Pathol 157:197–210

    PubMed  CAS  Google Scholar 

  10. Oh LY, Larsen PH, Krekoski CA, Edwards DR, Donovan F, Werb Z et al (1999) Matrix metalloproteinase-9/gelatinase B is required for process outgrowth by oligodendrocytes. J Neurosci 19:8464–8475

    PubMed  CAS  Google Scholar 

  11. Miller JW, Adamis AP, Aiello P (1997) Vascular endothelial growth factor in ocular neovascularization and proliferative retinopathy. Diabetes Metab Rev 13:37–50

    Article  PubMed  CAS  Google Scholar 

  12. Riser BL, Denichilo M, Cortes P, Baker C, Grondin JM, Yee J et al (2000) Regulation of connective tissue growth factor activity in cultured rat mesangial cells and its expression in experimental diabetic glomerulosclerosis. J Am Soc Nephrol 11:25–38

    Article  PubMed  CAS  Google Scholar 

  13. Twigg SM, Cao Z, McLennan SV, Burns WC, Brammar G, Forbes JM et al (2002) Renal connective tissue growth factor induction in experimental diabetes is prevented by aminoguanidine. Endocrinology 143:4907–4915

    Article  PubMed  CAS  Google Scholar 

  14. Zhou G, Li C, Cai L (2004) Advanced glycation end-products induce connective tissue growth factor-mediated renal fibrosis predominantly through transforming growth factor (-independent pathway. Am J Pathol 165:2033–2043

    PubMed  CAS  Google Scholar 

  15. Ito Y, Aten J, Bende RJ, Oemar BS, Rabelink TJ, Weening JJ et al (1998) Expression of connective tissue growth factor in human renal fibrosis. Kidney Int 53:853–861

    Article  PubMed  CAS  Google Scholar 

  16. Tikellis C, Cooper ME, Twigg SM, Burns WC, Tolcos M (2004) Connective tissue growth factor is up-regulated in the diabetic retina: amelioration by angiotensin-converting enzyme inhibition. Endocrinology 145:860–866

    Article  PubMed  CAS  Google Scholar 

  17. Kuiper EJ, Witmer AN, Klaassen I, Oliver N, Goldschmeding R, Schlingemann RO (2004) Differential expression of connective tissue growth factor in microglia and pericytes in the human diabetic retina. Br J Ophthalmol 88:1082–1087

    Article  PubMed  CAS  Google Scholar 

  18. Igarashi A, Nashiro K, Kikuchi K, Sato S, Ihn H, Fujimoto M et al (1996) Connective tissue growth factor gene expression in tissue sections from localized scleroderma, keloid, and other fibrotic skin disorders. J Invest Dermatol 106:729–733

    Article  PubMed  CAS  Google Scholar 

  19. Rachfal AW, Brigstock DR (2003) Connective tissue growth factor (CTGF/CCN2) in hepatic fibrosis. Hepatol Res 26:1–9

    Article  PubMed  CAS  Google Scholar 

  20. Meyer P, Wunderlich K, Klain HL, Prünte C, Flammer J (2002) Human connective tissue growth factor mRNA expression of epiretinal and subretinal fibrovascular membranes: a report of three cases. Ophthalmologica 21:284–291

    Article  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  23. Hinton DR, Spee C, He S, Wetz S, Usinger W, LaBree L et al (2004) Accumulation of NH2-terminal fragment of connective tissue growth factor in the vitreous of patients with proliferative diabetic retinopathy. Diabetes Care 27:758–764

    Article  PubMed  CAS  Google Scholar 

  24. Kuiper EJ, de Smet MD, van Meurs JC, Tan HS, Tanck MWT, Oliver N et al (2006) Association of connective tissue growth factor with fibrosis in vitreoretinal disorders in the human eye. Arch Ophthalmol 124:1457–1462

    Article  PubMed  CAS  Google Scholar 

  25. Park SK, Kim J, Seomun Y, Choi J, Kim DH, Han IO et al (2001) Hydrogen peroxide is a novel inducer of connective tissue growth factor. Biochem Biophys Res Commun 284:966–971

    Article  PubMed  CAS  Google Scholar 

  26. Kondo S, Kubota S, Shimo T, Nishida T, Yosimichi G, Eguchi T et al (2002) Connective tissue growth factor increased by hypoxia may initiate angiogenesis in collaboration with matrix metalloproteinases. Carcinogenesis 23:769–776

    Article  PubMed  CAS  Google Scholar 

  27. Suzuma K, Naruse K, Suzuma I, Takahara N, Ueki K, Aiello LP et al (2000) Vascular endothelial growth factor induces expression of connective tissue growth factor via KDR, Fit1, and phosphatidylinositol 3-kinase-Akt-dependent pathways in retinal vascular cells. J Biol Chem 275:40725–40731

    Article  PubMed  CAS  Google Scholar 

  28. Torsney E, Charton R, Parums D, Collis M, Arthur HM (2002) Inducible expression of human endoglin during inflammation and wound healing in vivo. Inflamm Res 51:464–470

    Article  PubMed  CAS  Google Scholar 

  29. Dales JP, Garcia S, Bonnier P, Duffaud F, Andrac-Meyer L, Ramuz O et al (2003) CD105 expression is a marker of high metastatic risk and poor outcome in breast carcinomas. Correlation between immunohistochemical analysis and long-term follow-up in a series of 929 patients. Am J Clin Pathol 119:374–380

    Article  PubMed  Google Scholar 

  30. Saad RS, Liu YL, Nathan G, Gelebrezze J, Medich D, Silverman JF (2004) Endoglin (CD105) and vascular endothelial growth factor as prognostic markers in colorectal cancer. Mod Pathol 17:197–203

    Article  PubMed  CAS  Google Scholar 

  31. Gillard JA, Reed MW, Buttle D, Cross SS, Brown NJ (2004) Matrix metalloproteinase activity and immunohistochemical profile of matrix metalloproteinase-2 and -9 and tissue inhibitor of metalloproteinase-1 during human dermal wound healing. Wound Repair Regen 12:295–304

    Article  PubMed  Google Scholar 

  32. Ramos C, Montaño M, Garcia-Alvarez J, Ruiz V, Uhal BD, Selman M et al (2001) Fibroblasts from idiopathic pulmonary fibrosis and normal lungs differ in growth rate, apoptosis, and tissue inhibitor of metalloproteinases expression. Am J Respir Cell Mol Biol 24:591–598

    PubMed  CAS  Google Scholar 

  33. Majka S, McGuire PG, Das A (2002) Regulation of matrix metalloproteinase expression by tumor necrosis factor in a murine model of retinal neovascularization. Invest Ophthalmol Vis Sci 43:260–266

    PubMed  Google Scholar 

  34. Behzadian MA, Wang X-L, Windsor LJ, Ghaly N, Caldwell RB (2001) TGF-β increases retinal endothelial cell permeability by increasing MMP-9: possible role of glial cells in endothelial barrier function. Invest Ophthalmol Vis Sci 42:853–859

    PubMed  CAS  Google Scholar 

  35. Das A, Fanslow W, Cerretti D, Warren E, Talarico N, McGuire P (2003) Angiopoietin/Tek interactions regulate MMP-9 expression and retinal neovascularization. Lab Invest 83:1637–1645

    Article  PubMed  CAS  Google Scholar 

  36. Giebel SJ, Menicucci G, McGuire PG, Das A (2005) Matrix metalloproteinases in early diabetic retinopathy and their role in alteration of the blood–retinal barrier. Lab Invest 85:597–607

    Article  PubMed  CAS  Google Scholar 

  37. Taraboletti G, D’Ascenzo S, Borsotti P, Giavazzi R, Pavan A, Dolo V (2002) Shedding of the matrix metalloproteinases MMP-2, MMP-9, and MT1-MMP as membrane vesicle-associated components by endothelial cells. Am J Pathol 160:673–680

    PubMed  CAS  Google Scholar 

  38. Das A, McGuire PG, Eriqat C, Ober RR, De Juan E Jr, Williams GA et al (1999) Human diabetic neovascular membranes contain high levels of urokinase and metalloproteinase enzymes. Invest Ophthalmol Vis Sci 40:809–813

    PubMed  CAS  Google Scholar 

  39. Noda K, Ishida S, Inoue M, Obata K, Oguchi Y, Okada Y et al (2003) Production and activation of matrix metalloproteinase-2 in proliferative diabetic retinopathy. Invest Ophthalmol Vis Sci 44:2163–2170

    Article  PubMed  Google Scholar 

  40. Abu El-Asrar AM, Dralands L, Veckeneer M, Geboes K, Missotten L, Van Aelst I et al (1998) Gelatinase B in proliferative vitreoretinal disorders. Am J Ophthalmol 125:844–851

    Article  PubMed  CAS  Google Scholar 

  41. Johnson C, Sung HJ, Lessner SM, Fini ME, Galis ZS (2004) Matrix metalloproteinase-9 is required for adequate angiogenic revascularization of ischemic tissues: potential role in capillary branching. Circ Res 94:262–268

    Article  PubMed  CAS  Google Scholar 

  42. Das A, McLamore A, Song W, McGuire P (1999) Retinal neovascularization is suppressed with a MMP inhibitor. Arch Ophthalmol 117:498–503

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors thank Mr. Dustan Kangave, MSc for statistical assistance, Mr. Johan Van Even and Ms. Christel Van den Broeck for technical assistance, and Ms. Connie B. Unisa-Marfil for secretarial work. This work was supported by the College of Medicine Research Center, King Saud University, Riyadh, Saudi Arabia.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Ahmed M. Abu El-Asrar.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Abu El-Asrar, A.M., Van den Steen, P.E., Al-Amro, S.A. et al. Expression of angiogenic and fibrogenic factors in proliferative vitreoretinal disorders. Int Ophthalmol 27, 11–22 (2007). https://doi.org/10.1007/s10792-007-9053-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10792-007-9053-x

Keywords

Navigation