Skip to main content

Advertisement

Log in

Vitreous levels of vascular endothelial growth factor, stromal cell–derived factor-1α, and angiopoietin-like protein 2 in patients with active proliferative diabetic retinopathy

  • Retinal Disorders
  • Published:
Graefe's Archive for Clinical and Experimental Ophthalmology Aims and scope Submit manuscript

Abstract

Purpose

To determine the vitreous levels of vascular endothelial growth factor (VEGF), stromal cell–derived factor-1α (SDF-1α) and angiopoietin-like protein 2 (ANGPTL2) in patients with active proliferative diabetic retinopathy (PDR), and to ascertain their contribution on different clinical presentation of active PDR.

Methods

This case–control study included 31 eyes with active PDR and 10 eyes with idiopathic macular hole (MH) (control group). Eyes with active PDR were divided into three subgroups: vitreous hemorrhage (VH), tractional retinal detachment (TRD) caused by active fibrovascular membrane (FVM), and coexistence of VH and TRD with FVM. Vitreous samples obtained during vitrectomy were analyzed for concentrations of VEGF, SDF-1α, and ANGPTL2.

Results

Vitreous level of VEGF (2021 (168–6550) pg/ml vs 110.1 (74.5–236) pg/ml), SDF-1α (517 (194–1044) pg/ml vs 388 (320–535) pg/ml), and ANGPTL2 (725 (131–1590) ng/ml vs 196 (75.9–437) ng/ml) were significantly higher in eyes with active PDR than in control group (p < 0.001, p = 0.002, and p < 0.001, respectively). The concentrations of these meaditors in each active PDR subgroups were also significantly higher than control group (p < 0.05). The vitreous level of ANGPTL2 was significantly higher in eyes with TRD caused by FVM (1033 ± 401 ng/ml) than in eyes with VH (561 ± 237 ng/ml; p = 0.008).

Conclusion

High levels of SDF-1α, ANGPTL2 and particularly VEGF seem to be associated with PDR. Since the vitreous levels of ANGPTL2 tend to be higher in eyes with active fibrovascular tractional detachment, vitreous levels of this chemokine seem to be affected by the clinical presentation of vascularly active PDR eyes.

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

Similar content being viewed by others

References

  1. Prokofyeva E, Zrenner E (2012) Epidemiology of major eye diseases leading to blindness in Europe: a literature review. Ophthalmic Res 47:171–188. https://doi.org/10.1159/000329603

    Article  PubMed  Google Scholar 

  2. Nentwich MM, Ulbig MW (2015) Diabetic retinopathy—ocular complications of diabetes mellitus. World J Diabetes 6:489–499. https://doi.org/10.4239/wjd.v6.i3.489

    Article  PubMed  PubMed Central  Google Scholar 

  3. Stitt AW (2010) AGEs and diabetic retinopathy. Investig Ophthalmol Vis Sci 51:4867–4874. https://doi.org/10.1167/iovs.10-5881

    Article  Google Scholar 

  4. Durham JT, Herman IM (2011) Microvascular modifications in diabetic retinopathy. Curr Diab Rep 11:253–264. https://doi.org/10.1007/s11892-011-0204-0

    Article  PubMed  Google Scholar 

  5. Pepper MS (1996) Positive and negative regulation of angiogenesis: from cell biology to the clinic. Vasc Med 1:259–266. https://doi.org/10.1177/1358863X9600100404

    Article  CAS  PubMed  Google Scholar 

  6. Witmer AN, Vrensen GF, Van Noorden CJ, Schlingemann RO (2003) Vascular endothelial growth factors and angiogenesis in eye disease. Prog Retin Eye Res 22:1–29. https://doi.org/10.1016/s1350-9462(02)00043-5

    Article  CAS  PubMed  Google Scholar 

  7. Holmes DI, Zachary I (2005) The vascular endothelial growth factor (VEGF) family: angiogenic factors in health and disease. Genome Biol 6:209. https://doi.org/10.1186/gb-2005-6-2-209

    Article  PubMed  PubMed Central  Google Scholar 

  8. Byrne AM, Bouchier-Hayes DJ, Harmey JH (2005) Angiogenic and cell survival functions of vascular endothelial growth factor (VEGF). J Cell Mol Med 9:777–794. https://doi.org/10.1111/j.1582-4934.2005.tb00379.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Dreyfuss JL, Giordano RJ, Regatieri CV (2015) Ocular angiogenesis. J Ophthalmol 2015:892043. https://doi.org/10.1155/2015/892043

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Jones CD, Greenwood RH, Misra A, Bachmann MO (2012) Incidence and progression of diabetic retinopathy during 17 years of a population-based screening program in England. Diabetes Care 35:592–596. https://doi.org/10.2337/dc11-0943

    Article  PubMed  PubMed Central  Google Scholar 

  11. Dutra Medeiros M, Mesquita E, Gardete-Correia L, Moita J, Genro V, Papoila AL, Amaral-Turkman A, Raposo JF (2015) First incidence and progression study for diabetic retinopathy in Portugal, the RETINODIAB study: evaluation of the screening program for Lisbon region. Ophthalmology 122:2473–2481. https://doi.org/10.1016/j.ophtha.2015.08.004

    Article  PubMed  Google Scholar 

  12. Klein R, Klein BE, Moss SE, Davis MD, DeMets DL (1989) The Wisconsin epidemiologic study of diabetic retinopathy. X. Four-year incidence and progression of diabetic retinopathy when age at diagnosis is 30 years or more. Arch Ophthalmol 107:244–249. https://doi.org/10.1001/archopht.1989.01070010250031

    Article  CAS  PubMed  Google Scholar 

  13. Mahdy RA, Nada WM, Hadhoud KM, El-Tarhony SA (2010) The role of vascular endothelial growth factor in the progression of diabetic vascular complications. Eye (Lond) 24:1576–1584. https://doi.org/10.1038/eye.2010.86

    Article  CAS  Google Scholar 

  14. Al Kahtani E, Xu Z, Al Rashaed S et al (2017) Vitreous levels of placental growth factor correlate with activity of proliferative diabetic retinopathy and are not influenced by bevacizumab treatment. Eye (Lond) 31:529–536. https://doi.org/10.1038/eye.2016.246

    Article  CAS  Google Scholar 

  15. Wu F, Phone A, Lamy R et al (2020) Correlation of aqueous, vitreous, and plasma cytokine levels in patients with proliferative diabetic retinopathy. Invest Ophthalmol Vis Sci 61:26. https://doi.org/10.1167/iovs.61.2.26

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Mesquita J, Castro-de-Sousa JP, Vaz-Pereira S, Neves A, Passarinha LA, Tomaz CT (2018) Evaluation of the growth factors VEGF-a and VEGF-B in the vitreous and serum of patients with macular and retinal vascular diseases. Growth Factors 36:48–57. https://doi.org/10.1080/08977194.2018.1477140

    Article  CAS  PubMed  Google Scholar 

  17. Chernykh VV, Varvarinsky EV, Smirnov EV, Chernykh DV, Trunov AN (2015) Proliferative and inflammatory factors in the vitreous of patients with proliferative diabetic retinopathy. Indian J Ophthalmol 63:33–36. https://doi.org/10.4103/0301-4738.151464

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Korobelnik JF, Do DV, Schmidt-Erfurth U et al (2014) Intravitreal aflibercept for diabetic macular edema. Ophthalmology 121:2247–2254. https://doi.org/10.1016/j.ophtha.2014.05.006

    Article  PubMed  Google Scholar 

  19. Massin P, Bandello F, Garweg JG et al (2010) Safety and efficacy of ranibizumab in diabetic macular edema (RESOLVE study): a 12-month, randomized, controlled, double-masked, multicenter phase II study. Diabetes Care 33:2399–2405. https://doi.org/10.2337/dc10-0493

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Ip MS, Domalpally A, Sun JK, Ehrlich JS (2015) Long-term effects of therapy with ranibizumab on diabetic retinopathy severity and baseline risk factors for worsening retinopathy. Ophthalmology 122:367–374. https://doi.org/10.1001/archophthalmol.2012.1043

    Article  CAS  PubMed  Google Scholar 

  21. You JJ, Yang CH, Huang JS, Chen MS, Yang CM (2007) Fractalkine, a CX3C chemokine, as a mediator of ocular angiogenesis. Invest Ophthalmol Vis Sci 48:5290–5298. https://doi.org/10.1167/iovs.07-0187

    Article  PubMed  Google Scholar 

  22. Mitamura Y, Tashimo A, Nakamura Y, Tagawa H, Ohtsuka K, Mizue Y, Nishihira J (2002) Vitreous levels of placenta growth factor and vascular endothelial growth factor in patients with proliferative diabetic retinopathy. Diabetes Care 25:2352. https://doi.org/10.2337/diacare.25.12.2352

    Article  PubMed  Google Scholar 

  23. Aiello LP, Avery RL, Arrigg PG et al (1994) Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med 331:1480–1487. https://doi.org/10.1056/NEJM199412013312203

    Article  CAS  PubMed  Google Scholar 

  24. Song Z, Sun M, Zhou F, Qu J, Chen D (2014) Increased intravitreous interleukin-18 correlated to vascular endothelial growth factor in patients with active proliferative diabetic retinopathy. Graefes Arch Clin Exp Ophthalmol 252:1229–1234. https://doi.org/10.1007/s00417-014-2586-6

    Article  CAS  PubMed  Google Scholar 

  25. Salcedo R, Oppenheim JJ (2003) Role of chemokines in angiogenesis: CXCL12/SDF-1 and CXCR4 interaction, a key regulator of endothelial cell responses. Microcirculation 10:359–370. https://doi.org/10.1038/sj.mn.7800200

    Article  CAS  PubMed  Google Scholar 

  26. Sonmez K, Drenser KA, Capone A Jr, Trese MT (2008) Vitreous levels of stromal cell-derived factor 1 and vascular endothelial growth factor in patients with retinopathy of prematurity. Ophthalmology 115:1065–1070. https://doi.org/10.1016/j.ophtha.2007.08.050

    Article  PubMed  Google Scholar 

  27. Chen LY, Zhuo YH, Li YH, Huang XH, Zhang JL, Li SY, Wang XG, Lü L (2010) Expression of stromal cell-derived factor-1 in diabetic retinopathy. Chin Med J 123:984–988

    CAS  PubMed  Google Scholar 

  28. Penn JS, Madan A, Caldwell RB, Bartoli M, Caldwell RW, Hartnett ME (2008) Vascular endothelial growth factor in eye disease. Prog Retin Eye Res 27:331–371. https://doi.org/10.1016/j.preteyeres.2008.05.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Ito Y, Oike Y, Tanihara H (2013) Angiopoietin-like protein 2 contributes to pathogenesis of diabetic retinopathy. Acta Opthalmologica 91:s252. https://doi.org/10.1111/j.1755-3768.2013.T082.x

    Article  Google Scholar 

  30. Sasaki Y, Ohta M, Desai D et al (2015) Angiopoietin like protein 2 (ANGPTL2) promotes adipose tissue macrophage and T lymphocyte accumulation and leads to insulin resistance. PLoS One 10:e0131176. https://doi.org/10.1371/journal.pone.0131176

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Horio E, Kadomatsu T, Miyata K et al (2014) Role of endothelial cell-derived ANGPTL2 in vascular inflammation leading to endothelial dysfunction and atherosclerosis progression. Arterioscler Thromb Vasc Biol 34:790–800. https://doi.org/10.1161/ATVBAHA.113.303116

    Article  CAS  PubMed  Google Scholar 

  32. Farhat N, Thorin-Trescases N, Mamarbachi M et al (2013) Angiopoietin-like 2 promotes atherogenesis in mice. J Am Heart Assoc 2:e000201. https://doi.org/10.1161/JAHA.113.000201

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Tabata M, Kadomatsu T, Fukuhara S et al (2009) Angiopoietin-like protein 2 promotes chronic adipose tissue inflammation and obesity-related systemic insulin resistance. Cell Metab 10:178–188. https://doi.org/10.1016/j.cmet.2009.08.003

    Article  CAS  PubMed  Google Scholar 

  34. Okada T, Tsukano H, Endo M et al (2010) Synoviocyte-derived angiopoietin-like protein 2 contributes to synovial chronic inflammation in rheumatoid arthritis. Am J Pathol 176:2309–2319. https://doi.org/10.2353/ajpath.2010.090865

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Aoi J, Endo M, Kadomatsu T et al (2011) Angiopoietin-like protein 2 is an important facilitator of inflammatory carcinogenesis and metastasis. Cancer Res 71:7502–7512. https://doi.org/10.1158/0008-5472.CAN-11-1758

    Article  CAS  PubMed  Google Scholar 

  36. Endo M, Nakano M, Kadomatsu T et al (2012) Tumor cell-derived angiopoietin-like protein ANGPTL2 is a critical driver of metastasis. Cancer Res 72:1784–1794. https://doi.org/10.1158/0008-5472.CAN-11-3878

    Article  CAS  PubMed  Google Scholar 

  37. Doi Y, Ninomiya T, Hirakawa Y et al (2013) Angiopoietin-like protein 2 and risk of type 2 diabetes in a general Japanese population: the Hisayama study. Diabetes Care 36:98–100. https://doi.org/10.2337/dc12-0166

    Article  PubMed  Google Scholar 

  38. Gellen B, Thorin-Trescases N, Sosner P et al (2016) ANGPTL2 is associated with an increased risk of cardiovascular events and death in diabetic patients. Diabetologia 59:2321–2330. https://doi.org/10.1007/s00125-016-4066-5

    Article  CAS  PubMed  Google Scholar 

  39. Hato T, Tabata M, Oike Y (2008) The role of angiopoietin-like proteins in angiogenesis and metabolism. Trends Cardiovasc Med 18:6–14. https://doi.org/10.1016/j.tcm.2007.10.003

    Article  CAS  PubMed  Google Scholar 

  40. Kadomatsu T, Endo M, Miyata K, Oike Y (2014) Diverse roles of ANGPTL2 in physiology and pathophysiology. Trends Endocrinol Metab 25:245–254. https://doi.org/10.1016/j.tem.2014.03.012

    Article  CAS  PubMed  Google Scholar 

  41. Van Geest RJ, Lesnik-Oberstein SY, Tan HS, Mura M, Goldschmeding R, VanNoorden CJ, Klaassen I, Schlingemann RO (2012) A shift in the balance of vascular endothelial growth factor and connective tissue growth factor by bevacizumab causes the angiofibrotic switch in proliferative diabetic retinopathy. Br J Ophthalmol 96:587–590. https://doi.org/10.1136/bjophthalmol-2011-301005

    Article  PubMed  Google Scholar 

  42. Ogata N, Nishikawa M, Nishimura T, Mitsuma Y, Matsumura M (2002) Unbalanced vitreous levels of pigment epithelium-derived factor and vascular endothelial growth factor in diabetic retinopathy. Am J Ophthalmol 134:348–353. https://doi.org/10.1016/s0002-9394(02)01568-4

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Contributions

Design of the study (KS, AK), conduct of the study (AK, KS, and YOE), analysis and interpretation (AK, KS, YOE, SNA, and EO), and literature search (AK, KS, and YOE).

Corresponding author

Correspondence to Kenan Sonmez.

Ethics declarations

Competing interests

The authors declare that they have no conflict of interest.

Ethics approval

The study adhered to the tenets of Declaration of Helsinki and was approved by the Institutional Review Board/Ethics Committee of Numune Training and Research Hospital, Ankara, Turkey (protocol no: E-17-1405).

Informed consent

Informed consent was obtained from all individual participants included in the study.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Keles, A., Sonmez, K., Erol, Y.O. et al. Vitreous levels of vascular endothelial growth factor, stromal cell–derived factor-1α, and angiopoietin-like protein 2 in patients with active proliferative diabetic retinopathy. Graefes Arch Clin Exp Ophthalmol 259, 53–60 (2021). https://doi.org/10.1007/s00417-020-04889-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00417-020-04889-0

Keywords

Navigation