Abstract
Diabetic retinopathy is the leading cause of blindness in the industrialized world. Hyperglycaemia induces retinal hypoxia that upregulates a range of vasoactive factors which may lead to macular oedema and/or angiogenesis and hence potentially sight threatening retinopathy. In this study, we have focused on the association of CD105 and vascular endothelial growth factor (VEGF) with the development and progression of diabetic retinopathy by means of quantifying their expression in the plasma and vitreous of diabetic patients. CD105 levels were quantified in the plasma of 38 type I diabetic patients at various stages of retinopathy and 15 non‐diabetic controls. In an additional cohort of 11 patients with advanced proliferative retinopathy and 23 control subjects, CD105 and VEGF were measured in the vitreous. The values were expressed as median (range) and statistical analysis was carried out using the non‐parametric Mann‐Whitney U test. Plasma CD105 levels were significantly increased in diabetic patients [1.8(1.1‐2.4)ng/ml] compared with non‐diabetic controls [0.7 (0.3‐1.8) ng/ml] (p<0.01). Plasma CD105 levels were elevated in diabetic patients with all stages of retinopathy, the highest level was observed in background retinopathy [2.3 (2.1‐2.5) ng/ml] followed by proliferative retinopathy [2.1 (0.9‐2.8) ng/ml] and advanced proliferative retinopathy [1.4 (0.6‐1.8) ng/ml]. Vitreous contents of CD105 did not differ between controls and patients with advanced proliferative retinopathy, but vitreous levels of VEGF were elevated by ∼3‐ fold in patients with advanced proliferative retinopathy [7.2 (1.90‐15.60) ng/ml] compared with the control subjects [1.80 (1.10‐2.210)] (p<0.01). These observations indicate that plasma levels of CD105 and vitreous levels of VEGF are associated with diabetic retinopathy, suggesting that CD105 and the angiogenic factor VEGF may play a critical role in the development and progression of diabetic retinopathy. Further studies are required to determine whether circulating CD105 levels could serve as a surrogate marker for early stage retinopathy and for monitoring disease progression.
Keywords: diabetic retinopathy, angiogenesis, CD105, VEGF
References
- 1. Jawa A, Kcomt J, Fonseca VA. Diabetic nephropathy and retinopathy. Med Clin North Am. 2004; 88: 1001–36. [DOI] [PubMed] [Google Scholar]
- 2. Watanabe D, Suzuma K, Suzuma I, Ohashi H, Ojima T, Kurimoto M, Murakami T, Kimura T, Takagi H. Vitreous levels of angiopoietin 2 and vascular endothelial growth factor in patients with proliferative diabetic retinopathy. Am J Ophthalmol. 2005; 139: 476–81. [DOI] [PubMed] [Google Scholar]
- 3. Pages G, Pouyssegur J. Transcriptional regulation of the vascular endothelial growth factor gene‐a concert of activating factors. Cardiovasc Res. 2005; 65: 564–73. [DOI] [PubMed] [Google Scholar]
- 4. Li C, Issa R, Kumar P, Hampson IN, Lopez‐Novoa JM, Bernabeu C, Kumar S. CD105 prevents apoptosis in hypoxic endothelial cells. J Cell Sci. 2003; 116: 2677–85. [DOI] [PubMed] [Google Scholar]
- 5. Duff SE, Li C, Garland JM, Kumar S. CD105 is important for angiogenesis: evidence and potential applications. FASEB J. 2003; 17: 984–92. [DOI] [PubMed] [Google Scholar]
- 6. Li C, Hampson IN, Hampson L, Kumar P, Bernabeu C, Kumar S. CD105 antagonizes the inhibitory signaling of transforming growth factor β1 on human vascular endothelial cells. FASEB J. 2000; 14: 55–64. [DOI] [PubMed] [Google Scholar]
- 7. Charpin C, Dales JP, Garcia S, Carpentier S, Djemli A, Andrac L, Lavaut MN, Allasia C, Bonnier P. Tumor neoangiogenesis by CD31 and CD105 expression evaluation in breast carcinoma tissue microarrays. Clin Cancer Res. 2004; 10: 5815–9. [DOI] [PubMed] [Google Scholar]
- 8. Kumar S, Ghellal A, Li C, Byrne G, Haboubi N, Wang JM, Bundred N. Breast carcinoma: vascular density determined using CD105 antibody correlates with tumor prognosis. Cancer Res. 1999; 59: 856–861. [PubMed] [Google Scholar]
- 9. Arthur HM, Ure J, Smith AJ, Renforth G, Wilson DI, Torsney E, Charlton R, Parums DV, Jowett T, Marchuk DA, Burn J, Diamond AG. Endoglin, an ancillary TGFβ receptor, is required for extraembryonic angiogenesis and plays a key role in heart development. Dev Biol. 2000; 217: 42–53. [DOI] [PubMed] [Google Scholar]
- 10. Bourdeau A, Dumont DJ, Letarte M. Amurine model of hereditary hemorrhagic telangiectasia. J Clin Invest. 1999; 104: 1343–51. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11. Li DY, Sorensen LK, Brooke BS, Urness LD, Davis EC, Taylor DG, Boak BB, Wendel DP. Defective angiogenesis in mice lacking endoglin. Science 1999; 284: 1534–7. [DOI] [PubMed] [Google Scholar]
- 12. Li C, Guo B, Wilson PB, Stewart A, Byrne G, Bundred N, Kumar S. Plasma levels of soluble CD105 correlate with metastasis in patients with breast cancer. Int J Cancer 2000; 89: 122–6. [DOI] [PubMed] [Google Scholar]
- 13. Takahashi N, Kawanishi‐Tabata R, Haba A, Tabata M, Haruta Y, Tsai H, Seon BK. Association of serum endoglin with metastasis in patients with colorectal, breast, and other solid tumors, and suppressive effect of chemotherapy on the serum endoglin. Clin Cancer Res. 2001; 7: 524–32. [PubMed] [Google Scholar]
- 14. Li C, Bethell H, Wilson PB, Bhatnagar D, Walker MG, Kumar S. The significance of CD105, TGFβ and CD105/TGFβ complexes in coronary artery disease. Atherosclerosis 2000; 152: 249–56. [DOI] [PubMed] [Google Scholar]
- 15. Diabetic retinopathy study . Report Number 6. Design, methods, and baseline results. Report Number 7. A modification of the Airlie House classification of diabetic retinopathy. Prepared by the Diabetic Retinopathy. Invest Ophthalmol Vis Sci. 1981; 21: 1–226 21: 210–26. [PubMed] [Google Scholar]
- 16. Li C, Reynolds I, Ponting JM, Holt PJ, Hillarby MC, Kumar S. Serum levels of vascular endothelial growth factor (VEGF) are markedly elevated in patients with Wegener's granulomatosis. Br J Rheumatol. 1998; 37: 1303–6. [DOI] [PubMed] [Google Scholar]
- 17. Moulton KS. Plaque angiogenesis: its functions and regulation. Cold Spring Harb Symp Quant Biol. 2002; 67: 471–82. [DOI] [PubMed] [Google Scholar]
- 18. Botella LM, Sanchez‐Elsner T, Sanz‐Rodriguez F, Kojima S SJ, Guerrero‐Esteo M, Cooreman MP, Ratziu V, Langa C, Vary CP, Ramirez JR, Friedman S, Bernabeu C. Transcriptional activation of endoglin and transforming growth factor‐β signaling components by cooperative interaction between Sp1 and KLF6: their potential role in the response to vascular injury. Blood 2002; 100: 4001–10. [DOI] [PubMed] [Google Scholar]
- 19. Li C, Guo B, Ding S, Rius C, Langa C, Kumar P, Bernabeu C, Kumar S. TNFα down‐regulates CD105 expression in vascular endothelial cells: a comparative study with TGFβ1. Anticancer Res. 2003; 23: 1189–96. [PubMed] [Google Scholar]