Top

Graefe's Archive for Clinical and Experimental Ophthalmology

Published in:

01-01-2021 | Diabetic Retinopathy | Retinal Disorders

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

Authors: Ali Keles, Kenan Sonmez, Yasemin Ozdamar Erol, Sema Nur Ayyıldız, Elmas Ogus

Published in: Graefe's Archive for Clinical and Experimental Ophthalmology | Issue 1/2021

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.

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/10.1159/000329603CrossRefPubMed

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.i3.489CrossRefPubMedPubMedCentral

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

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

Pepper MS (1996) Positive and negative regulation of angiogenesis: from cell biology to the clinic. Vasc Med 1:259–266. https://doi.org/10.1177/1358863X9600100404CrossRefPubMed

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)00043-5CrossRefPubMed

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-2005-6-2-209CrossRefPubMedPubMedCentral

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.xCrossRefPubMedPubMedCentral

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

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/dc11-0943CrossRefPubMedPubMedCentral

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.2015.08.004CrossRefPubMed

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.1989.01070010250031CrossRefPubMed

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.2010.86CrossRef

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.2016.246CrossRef

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.61.2.26CrossRefPubMedPubMedCentral

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/10.1080/08977194.2018.1477140CrossRefPubMed

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/10.4103/0301-4738.151464CrossRefPubMedPubMedCentral

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.2014.05.006CrossRefPubMed

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/dc10-0493CrossRefPubMedPubMedCentral

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.2012.1043CrossRefPubMed

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.07-0187CrossRefPubMed

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.25.12.2352CrossRefPubMed

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/NEJM199412013312203CrossRefPubMed

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/s00417-014-2586-6CrossRefPubMed

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.7800200CrossRefPubMed

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.2007.08.050CrossRefPubMed

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 123:984–988PubMed

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.2008.05.001CrossRefPubMedPubMedCentral

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.xCrossRef

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.0131176CrossRefPubMedPubMedCentral

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.113.303116CrossRefPubMed

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.113.000201CrossRefPubMedPubMedCentral

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.2009.08.003CrossRefPubMed

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.2010.090865CrossRefPubMedPubMedCentral

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-11-1758CrossRefPubMed

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-11-3878CrossRefPubMed

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/dc12-0166CrossRefPubMed

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/s00125-016-4066-5CrossRefPubMed

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.2007.10.003CrossRefPubMed

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.2014.03.012CrossRefPubMed

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-2011-301005CrossRefPubMed

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)01568-4CrossRefPubMed

Title: Vitreous levels of vascular endothelial growth factor, stromal cell–derived factor-1α, and angiopoietin-like protein 2 in patients with active proliferative diabetic retinopathy
Authors: Ali Keles
Kenan Sonmez
Yasemin Ozdamar Erol
Sema Nur Ayyıldız
Elmas Ogus
Publication date: 01-01-2021
Publisher: Springer Berlin Heidelberg
Keywords: Diabetic Retinopathy
Diabetic Retinopathy
Vitrectomy
Published in: Graefe's Archive for Clinical and Experimental Ophthalmology / Issue 1/2021
Print ISSN: 0721-832X
Electronic ISSN: 1435-702X
DOI: https://doi.org/10.1007/s00417-020-04889-0

At a glance: The STEP trials

Springer Medicine

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

Abstract

Purpose

Methods

Results

Conclusion

At a glance: The STEP trials

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 1/2021

Progression of myopic maculopathy in a Caucasian cohort of highly myopic patients with long follow-up: a multistate analysis

Evaluation of 20-MHz high-frequency ultrasonography for the diagnosis of choroidal nevi

Silicone oils compared and found wanting

Descemet membrane endothelial keratoplasty (DMEK): clinical results of precut versus surgeon-cut grafts

Correction to: Analysis of clinical features of RPE adenoma

Transcanalicular endoscopic dacryoplasty in patients with primary acquired nasolacrimal duct obstruction