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Silvia Montaner Sodhi, Deepak Menon, Tao Ma, Monika Deshpande, Kathleen Jee, Aumreetam Dinabandhu, Jordan Vancel, Akrit Sodhi; ANGPTL4 and VEGF cooperate to promote diabetic macular edema.. Invest. Ophthalmol. Vis. Sci. 2020;61(7):305.
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© ARVO (1962-2015); The Authors (2016-present)
Therapies targeting VEGF have had a profound impact on the treatment of patients with diabetic macular edema (DME). However, most patients with DME do not demonstrate a clinically-significant improvement in vision despite treatment with anti-VEGF therapy, suggesting that other vasoactive factors may also contribute its development. Our goal was to identify novel therapeutic strategies for the treatment of DME.
Cell lines and reagents: Human umbilical vein endothelial cells (HUVECs) and human retinal microvascular endothelial cells (hRECs).Protein analysis: Western Blot, Immunoprecipitation, Immunofluorescence and ELISA.Permeability Assays. Passage of FITC-dextran (in vitro) or measurement of extravascular FITC-dextran (in vivo).Streptozotocin (STZ) mouse model for diabetes.Human samples. JHU-approved IRB for the acquisition of samples from patients with DME.Statistical Analysis Two-tailed unpaired Student’s t-test, Mann-Whitney test, or one-way ANOVA with post hoc Tukey HSD.
Expression of the hypoxia-inducible factor (HIF)-1-regulated gene product, angiopoietin-like 4 (ANGPTL4), was increased in the eyes of diabetic mice and in DME patients, and promoted vascular permeability in vitro and in vivo. Moreover, levels of ANGPTL4 in aqueous from DME patients correlated with their ability to promote vascular permeability. We further observed that ANGPTL4 promotion of vascular permeability was independent of, but synergistic with, VEGF. Indeed, exposure of endothelial cells with these two vasoactive factors augmented phosphorylation of the VEGF receptor, KDR, on Tyr951 and Tyr1059, while ANGPTL4 treatment alone stimulated the recycling and intracellular trafficking of KDR. Interestingly, ANGPTL4 did not bind directly to KDR. Rather, we observed that ANGPTL4 binds directly to neuropilins (NRPs) 1 and 2 on endothelial cells (ECs), leading to rapid activation of the RhoA/ROCK signaling pathway, and breakdown of EC-EC junctions. Treatment with a soluble fragment of NRP1 (sNRP1) prevented ANGPTL4 from binding to NRP1, blocked ANGPTL4-induced activation of RhoA, and inhibited EC permeability in vitro and retinal vascular leakage in diabetic mice. sNRP1 further reduced the stimulation of EC permeability by aqueous fluid from patients with DME.
Conclusions:Our results suggest that therapeutic strategies targeting both ANGPTL4 and VEGF may be an effective approach for the treatment of DME.
This is a 2020 ARVO Annual Meeting abstract.
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