Skip to main content

Advertisement

Log in

Angiogenesis regulatory factors in the vitreous from patients with proliferative diabetic retinopathy

  • Original Article
  • Published:
Acta Diabetologica Aims and scope Submit manuscript

Abstract

We determined the levels of the endogenous angiogenesis inhibitors soluble vascular endothelial growth factor receptor-1 (sVEGFR-1), thrombospondin (TSP)-1 and TSP-2 in the vitreous fluid from patients with proliferative diabetic retinopathy (PDR) and correlated their levels with clinical disease activity and the levels of vascular endothelial growth factor (VEGF). Vitreous samples from 30 PDR and 25 nondiabetic patients were studied by enzyme-linked immunosorbent assay. TSP-1 was not detected. VEGF and TSP-2 levels were significantly higher in PDR with active neovascularization compared with inactive PDR and nondiabetic patients (P < 0.001 for both comparisons). VEGF, sVEGFR-1 and TSP-2 levels were significantly higher in PDR with hemorrhage compared with PDR without hemorrhage and nondiabetic patients (P = 0.0063; 0.0144; <0.001, respectively). VEGF and sVEGFR-1 levels were significantly higher in PDR without traction retinal detachment (TRD) compared with PDR with TRD and nondiabetic patients (P = 0.038; 0.022, respectively). TSP-2 levels were significantly higher in PDR with TRD compared with PDR without TRD and nondiabetic patients (P < 0.001). There was a significant correlation between levels of VEGF and sVEGFR-1 (r = 0.427, P = 0.038). Our findings suggest that upregulation of sVEGFR-1 and TSP-2 may be a protective mechanism against progression of angiogenesis associated with PDR. TSP-2 might be associated with TRD.

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.

Similar content being viewed by others

References

  1. Spranger J, Pfeiffer AP (2001) New concepts in pathogenesis and treatment of diabetic retinopathy. Exp Clin Endocrinol Diabetes 109:S438–S450

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  3. Matsunaga N, Chikaraishi Y, Izuta H, Ogata N, Shimazawa M, Matsumura M, Hara H (2008) Role of soluble vascular endothelial growth factor receptor-1 in the vitreous in proliferative diabetic retinopathy. Ophthalmology 115:1916–1922

    Article  PubMed  Google Scholar 

  4. Shibuya M (2006) Differential roles of vascular endothelial growth factor receptor-1 and receptor-2 in angiogenesis. J Biochem Mol Biol 39:469–478

    Article  PubMed  CAS  Google Scholar 

  5. Wu FTH, Stefanini MO, Gabhann FM, Kontos CD, Annex BH, Popel AS (2010) A system biology perspective on sVEGFR-1: its biological function, pathogenic role and therapeutic use. J Cell Mol Med 14:528–552

    PubMed  CAS  Google Scholar 

  6. Zhang X, Lawler J (2007) Thrombospondin-based antiangiogenic therapy. Microvasc Res 74:90–99

    Article  PubMed  CAS  Google Scholar 

  7. Aiello LP, Avery RL, Arrigg PG, Keyt BA, Jampel HD, Shah ST, Pasquale LR, Thieme H, Iwamoto MA, Park JE, Nguyen HV, Aiello LM, Ferrara N, King GL (1994) Vascular endothelial growth factor in ocular fluid in patients with diabetic retinopathy and other retinal disorders. N Engl J Med 331:1480–1487

    Article  PubMed  CAS  Google Scholar 

  8. Rota R, Riccioni T, Zaccarini M, Lamartina S, Gallo AD, Fusco A, Kovesdi I, Balestrazzi E, Abeni DC, Ali RR, Capogrossi MC (2004) Marked inhibition of retinal neovascularization in rats following soluble-flt-1 gene transfer. J Gene Med 6:992–1002

    Article  PubMed  CAS  Google Scholar 

  9. Kyriakides TR, Tam JW (1999) Bornstein. Accelerated wound healing in mice with a disruption of the thrombospondin 2 gene. J Invest Dermatol 113:782–787

    Article  PubMed  CAS  Google Scholar 

  10. Lin T-N, Kim G-M, Chen J-J, Cheung W-M, He YY, Hsu CY (2003) Differential regulation of thrombospondin-1 and thrombospondin-2 after focal cerebral ischemia/reperfusion. Stroke 34:177–186

    Article  PubMed  CAS  Google Scholar 

  11. Hawighorst T, Velasco P, Streit M, Hong Y-K, Kyriakides TR, Brown LF, Bornstein P, Detmar M (2001) Thrombospondin-2 plays a protective role in multistep carcinogenesis: a novel host anti-tumor defense mechanism. EMBO J 20:2631–2640

    Article  PubMed  CAS  Google Scholar 

  12. Streit M, Riccardi L, Velasco P, Brown LF, Hawighorst T, Bornstein P, Detmar M (1999) Thrombospondin-2: a potent endogenous inhibitor of tumor growth and angiogenesis. Proc Natl Acad Sci USA 96:14888–14893

    Article  PubMed  CAS  Google Scholar 

  13. Noh Y-H, Matsuda K, Hong Y-K, Kunstfeld R, Riccardi L, Koch M, Oura H, Dadras SS, Streit M, Detmar M (2003) An N-terminal 80 kDa recombinant fragment of human thrombopsondin-2 inhibits vascular endothelial growth factor induced endothelial cell migration in vitro and tumor growth and angiogenesis in vivo. J Invest Dermatol 121:1536–1543

    Article  PubMed  CAS  Google Scholar 

  14. Koch M, Hussein F, Woeste A, Gründker C, Frontzek K, Emons G, Hawighorst T (2011) CD36-mediated activation of endothelial cell apoptosis by an N-terminal recombinant fragment of thrombospondin-2 inhibits breast cancer growth and metastasis in vivo. Breast Cancer Res Treat 128:337–346

    Article  PubMed  CAS  Google Scholar 

  15. MacLauchlan S, Skokos EA, Agah A, Zeng J, Tian W, Davidson JM, Bornstein P, Kyriakides TR (2009) Enhanced angiogenesis and reduced contraction in thrombospondin-2-null wounds is associated with increased levels of matrix metalloproteinases-2 and-9 and soluble VEGF. J Histochem Cytochem 57:301–313

    Article  PubMed  CAS  Google Scholar 

  16. Kyriakides TR, Zhu Y-H, Yang Z, Huynh G, Bornstein P (2001) Altered extracellular matrix remodeling and angiogenesis in sponge granulomas of thrombospondin 2-null mice. Am J Pathol 159:1255–1262

    Article  PubMed  CAS  Google Scholar 

  17. Krady MM, Zeng J, Yu J, MacLauchlan S, Skokos EA, Tian W, Bornstein P, Sessa WC, Kyriakides TR (2008) Thrombospondin-2 modulates extracellular matrix remodeling during physiological angiogenesis. Am J Pathol 173:879–891

    Article  PubMed  CAS  Google Scholar 

  18. Park YW, Kang YM, Butterfield J, Detmar M, Goronzy JJ, Weyand CM (2004) Thrombospondin 2 functions as an endogenous regulator of angiogenesis and inflammation in rheumatoid arthritis. Am J Pathol 165:2087–2098

    Article  PubMed  CAS  Google Scholar 

  19. Armstrong LC, Björkblom B, Hankenson KD, Siadak AW, Stiles CE, Bornstein P (2002) Thrombospondin 2 inhibits microvascular endothelial cell proliferation by a caspase-independent mechanism. Mol Biol Cell 13:1893–1905

    Article  PubMed  CAS  Google Scholar 

  20. Simantov R, Febbraio M, Silverstein RL (2005) The antiangiogenic effect of thrombospondin-2 is mediated by CD36 and modulated by histidine-rich glycoprotein. Matrix Biol 24:27–34

    Article  PubMed  CAS  Google Scholar 

  21. Adri VC, Kupriyanova TA, Deryugina EI, Quigley JP (2007) Human neutrophils uniquely release TIMP-Free MMP-9 to provide a potent catalytic stimulator of angiogenesis. Proc Natl Acad Sci USA 104:20262–20267

    Article  Google Scholar 

  22. Bergers G, Prekken R, McMahon G, Vu TH, Itoh T, Tamaki K, Tanzawa K, Thorpe P, Itohara S, Werb Z, Hanahan D (2000) Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Natl Cell Biol 2:737–744

    Article  CAS  Google Scholar 

  23. Lee S, Jilani SM, Nikolova GV, Carpizo D, Iruela-Arispe ML (2005) Processing of VEGF-A by matrix metalloproteinases regulates bioavailability and vascular patterning in tumors. J Cell Biol 169:681–691

    Article  PubMed  CAS  Google Scholar 

  24. Abu El-Asrar AM, Struyf S, Kangave D, Geboes K, Van Damme J (2006) Chemokines in proliferative diabetic retinopathy and proliferative vitreoretinopathy. Eur Cytokine Netw 17:155–165

    PubMed  CAS  Google Scholar 

  25. Ogata N, Ando A, Uyama M, Matsumura M (2001) Expression of cytokines and transcription factors in photocoagulated human retinal pigment epithelial cells. Graefes Arch Exp Ophthalmol 239:87–95

    Article  CAS  Google Scholar 

  26. Xiao M, McLeod D, Cranley J, Williams G, Boulton M (1999) Growth factor staining patterns in the pig retina following retinal laser photocoagulation. Br J Ophthalmol 83:728–736

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors thank Ms. Connie B. Unisa-Marfil for secretarial work. This work was supported by Dr. Nasser Al-Rasheed Research Chair in Ophthalmology (Abu El-Asrar AM).

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., Nawaz, M.I., Kangave, D. et al. Angiogenesis regulatory factors in the vitreous from patients with proliferative diabetic retinopathy. Acta Diabetol 50, 545–551 (2013). https://doi.org/10.1007/s00592-011-0330-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00592-011-0330-9

Keywords

Navigation