Pro-permeability Factors in Diabetic Macular Edema; the Diabetic Macular Edema Treated With Ozurdex Trial

Published:April 26, 2016DOI:


      The Diabetic Macular Edema Treated with Ozurdex (DMEO) Trial measured aqueous pro-permeability factors (PPFs) in diabetic macular edema (DME) patients before and after injection of dexamethasone implant or vascular endothelial growth factor (VEGF)-neutralizing protein and correlated changes in levels with changes in excess foveal thickness (EFT) to identify potential PPFs contributing to DME.


      Prospective, randomized crossover clinical trial.


      Twenty DME patients randomized to dexamethasone implant or VEGF-neutralizing protein had aqueous taps and spectral-domain optical coherence tomography (SDOCT) at baseline and every 4 weeks for 28 weeks. Aqueous levels of 55 vasoactive proteins were measured with protein array. Crossover at week 16 provided changes in protein levels after each intervention in all 20 patients.


      After dexamethasone implant there was significant correlation between changes in levels of 13 vasoactive proteins with changes in EFT, including 3 known PPFs: angiopoietin-2 (r = 0.40, P = .001), hepatocyte growth factor (HGF; r = 0.31, P = .02), and endocrine gland-VEGF (EG-VEGF, r = 0.43, P < .001). Reduction of prolactin, insulin-like growth factor binding protein-3, and matrix metalloproteinase-9 correlated with edema reduction after injection of a VEGF-neutralizing protein as well as dexamethasone implant, suggesting their modulation is likely secondary to changes in edema rather than causative.


      Correlation of edema reduction with reduction in the PPFs angiopoietin-2, HGF, and EG-VEGF provides potential insight into the multifactorial molecular mechanism by which dexamethasone implants reduce edema and suggest that additional study is needed to investigate the contributions of these 3 factors to chronic DME.
      To read this article in full you will need to make a payment


      Subscribe to American Journal of Ophthalmology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Varma R.
        • Bressler N.M.
        • Doan Q.V.
        • et al.
        Prevalence of risk factors for diabetic macular edema in the United States.
        JAMA Ophthalmol. 2014; 132: 1334-1340
        • Wild S.
        • Roglic G.
        • Green A.
        • et al.
        Global prevalence of diabetes: estimates for the year 2000 and projections for 2030.
        Diabetes Care. 2004; 27: 1047-1053
        • Nguyen Q.D.
        • Shah S.M.
        • Van Anden E.
        • et al.
        Supplemental inspired oxygen improves diabetic macular edema; a pilot study.
        Invest Ophthalmol Vis Sci. 2003; 45: 617-624
        • Ozaki H.
        • Yu A.
        • Della N.
        • et al.
        Hypoxia inducible factor-1a is increased in ischemic retina: temporal and spatial correlation with VEGF expression.
        Invest Ophthalmol Vis Sci. 1999; 40: 182-189
        • Nguyen Q.D.
        • Tatlipinar S.
        • Shah S.M.
        • et al.
        Vascular endothelial growth factor is a critical stimulus for diabetic macular edema.
        Am J Ophthalmol. 2006; 142: 961-969
        • Nguyen Q.D.
        • Shah S.M.
        • Heier J.S.
        • et al.
        Primary end point (six months) results of the Ranibizumab for Edema of the mAcula in Diabetes (READ-2) Study.
        Ophthalmology. 2009; 116: 2175-2181
        • Nguyen Q.D.
        • Brown D.M.
        • Marcus D.M.
        • et al.
        Ranibizumab for diabetic macular edema. Results from 2 phase iii randomized trials: RISE and RIDE.
        Ophthalmology. 2012; 119: 789-801
        • Heier J.S.
        • Clark W.L.
        • Boyer D.S.
        • et al.
        Intravitreal aflibercept injection for macular edema due to central retinal vein occlusion: two-year results from the COPERNICUS study.
        Ophthalmology. 2014; 121: 1414-1420
        • The Diabetic Retinopathy Clinical Research Network
        Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema.
        N Engl J Med. 2015; 372: 1193-1203
        • Do D.V.
        • Nguyen Q.D.
        • Khwaja A.A.
        • et al.
        Ranibizumab for edema of the macula in diabetes study: 3-year outcomes and the need for prolonged frequent treatment.
        JAMA Ophthalmol. 2013; 131: 139-145
        • Channa R.
        • Sophie R.
        • Khwaja A.A.
        • et al.
        Factors affecting visual outcomes in patients with diabetic macular edema treated with ranibizumab.
        Eye (Lond). 2013; 28: 269-278
        • Yang-Yen H.F.
        • Chambard J.C.
        • Sun Y.L.
        • et al.
        Transciptional interference between c-Jun and the glucocorticoid receptor: mutual inhibition of DNA binding due to direct protein-protein interaction.
        Cell. 1990; 62: 1205-1215
        • Schule R.
        • Rangarajan P.
        • Kliewer S.
        • et al.
        Runctional antagonism between oncoprotein c-Jun and the glucocorticoid receptor.
        Cell. 1990; 62: 1217-1226
        • Heck S.
        • Kullmann M.
        • Gast A.
        • et al.
        A distinct modulating domain in glucocorticoid receptor monomers in the repression of activity of the transcription factor AP1.
        EMBO J. 1994; 13: 4087-4095
        • Boyer D.S.
        • Yoon Y.H.
        • Belfort R.J.
        • et al.
        Three-year, randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with diabetic macular edema.
        Ophthalmology. 2014; 121: 1904-1914
        • Campochiaro P.A.
        • Hafiz G.
        • Mir T.A.
        • et al.
        Pro-permeability factors after dexamethasone implant in retinal vein occlusion; the Ozurdex for Retinal Vein Occlusion (ORVO) Study.
        Am J Ophthalmol. 2015; 160: 313-321
        • Clermont A.C.
        • Cahill M.
        • Salti H.
        • et al.
        Hepatocyte growth factor induces retinal vascular permeability via MAP-kinase and PI-3 kinase without altering retinal hemodynamics.
        Invest Ophthalmol Vis Sci. 2006; 47: 2701-2708
        • LeCouter J.
        • Kowalski J.
        • Foster J.
        • et al.
        Identification of an angiogenic mitogen selective for endocrine gland endothelium.
        Nature. 2001; 412: 877-884
        • LeCouter J.
        • Lin R.
        • Ferrara N.
        Endocrine gland-derived VEGF and the emerging hypothesis of organ-specific regulation of angiogenesis.
        Nat Med. 2002; 8: 913-917
        • Hackett S.F.
        • Ozaki H.
        • Strauss R.W.
        • et al.
        Angiopoietin 2 expression in the retina: upregulation during physiologic and pathologic neovascularization.
        J Cell Physiol. 2000; 184: 275-284
        • Hackett S.F.
        • Wiegand S.J.
        • Yancopoulos G.
        • Campochiaro P.
        Angiopoietin-2 plays an important role in retinal angiogenesis.
        J Cell Physiol. 2002; 192: 182-187
        • Oshima Y.
        • Deering T.
        • Oshima S.
        • et al.
        Angiopoietin-2 enhances retinal vessel sensitivity to vascular endothelial growth factor.
        J Cell Physiol. 2004; 199: 412-417
        • Shen J.
        • Frye M.
        • Lee B.L.
        • et al.
        Targeting VE-PTP activates TIE2 and stabilizes the ocular vasculature.
        J Clin Invest. 2014; 124: 4564-4576
        • Campochiaro P.A.
        • Sophie R.
        • Tolentino M.
        • et al.
        Treatment of diabetic macular edema with an inhibitor of vascular endothelial-protein tyrosine phosphatase that activates Tie2.
        Ophthalmology. 2015; 122: 545-554
        • Takahashi K.
        • Saishin Y.
        • Saishin Y.
        • et al.
        Intraocular expression of endostatin reduces VEGF-induced retinal vascular permeability, neovascularization, and retinal detachment.
        FASEB J. 2003; 17: 896-898
        • Wu Z.
        • Wang S.
        • Sorenson C.M.
        • Sheibani N.
        Attenuation of retinal vascular development and neovascularization in transgenic mice over-expressing thrombospondin-1.
        Dev Dyn. 2006; 235: 1908-1920
        • Sohn H.J.
        • Han D.H.
        • Kim I.T.
        • et al.
        Changes in aqueous concentrations of various cytokines after intravitreal triamcinolone versus bevacizumab for diabetic macular edema.
        Am J Ophthalmol. 2011; 152: 686-694
        • Funatsu H.
        • Yamashita H.
        • Noma H.
        • et al.
        Increased levels of vascular endothelial growth factor and interleukin-6 in the aqueous humor of diabetics with macular edema.
        Am J Ophthalmol. 2002; 133: 70-77
        • Funatsu H.
        • Yamashita H.
        • Ikeda T.
        • et al.
        Vitreous levels of interleukin-6 and vascular endothelial growth factor are related to diabetic macular edema.
        Ophthalmology. 2003; 110: 1690-1696
        • Dong N.
        • Xu B.
        • Chu L.
        • Tang X.
        Study of 27 aqueous humor cytokines in type 2 diabetic patients with or without macular edema.
        PLos One. 2015; 10: e0125329
        • Lee W.J.
        • Kang M.H.
        • Seong M.
        • Cho H.Y.
        Comparison of aqueous concentrations of angiogenic and inflammatory cytokines in diabetic macular oedema and macular oedema due to branch vein occlusion.
        Br J Ophthalmol. 2012; 96: 1426-1430
        • Funk M.
        • Schmidinger G.
        • Maar N.
        • et al.
        Angiogenic and inflammatory markers in the intaocular fluid of eyes with diabetic macular edema and influence of therapy with bevacizumab.
        Retina. 2010; 30: 1412-1419
        • Kwon S.H.
        • Shin J.P.
        • Kim I.T.
        • Park D.H.
        Aqueous levels of angiopoietin-like 4 and semaphorin 3E correlate with nonperfusion area and macular volume in diabetic retinopathy.
        Ophthalmology. 2015; 122: 968-975
        • Babapoor-Farrokhran S.
        • Jee K.
        • Puchner B.
        • et al.
        Angiopoietin-like 4 is a potent angiogenic factor and a novel therapeutic target for patients with proliferative diabetic retinopathy.
        Proc Natl Acad Sci U S A. 2015; 112: E3030-3039

      Linked Article