Angiopoietin-like 4 binds neuropilins and cooperates with VEGF to induce diabetic macular edema
Akrit Sodhi, … , Daoyuan Lu, Silvia Montaner
Akrit Sodhi, … , Daoyuan Lu, Silvia Montaner
Published September 23, 2019
Citation Information: J Clin Invest. 2019;129(11):4593-4608. https://doi.org/10.1172/JCI120879.
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Research Article Angiogenesis Ophthalmology

Angiopoietin-like 4 binds neuropilins and cooperates with VEGF to induce diabetic macular edema

Abstract

The majority of patients with diabetic macular edema (DME), the most common cause of vision loss in working-age Americans, do not respond adequately to current therapies targeting VEGFA. Here, we show that expression of angiopoietin-like 4 (ANGPTL4), a HIF-1–regulated gene product, is increased in the eyes of diabetic mice and patients with DME. We observed that ANGPTL4 and VEGF act synergistically to destabilize the retinal vascular barrier. Interestingly, while ANGPTL4 modestly enhanced tyrosine phosphorylation of VEGF receptor 2, promotion of vascular permeability by ANGPTL4 was independent of this receptor. Instead, we found that ANGPTL4 binds directly to neuropilin 1 (NRP1) and NRP2 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 and blocked ANGPTL4-induced activation of RhoA as well as EC permeability in vitro and retinal vascular leakage in diabetic animals in vivo. In addition, sNRP1 reduced the stimulation of EC permeability by aqueous fluid from patients with DME. Collectively, these data identify the ANGPTL4/NRP/RhoA pathway as a therapeutic target for the treatment of DME.

Authors

Akrit Sodhi, Tao Ma, Deepak Menon, Monika Deshpande, Kathleen Jee, Aumreetam Dinabandhu, Jordan Vancel, Daoyuan Lu, Silvia Montaner

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Figure 1

Vasoactive factors in the aqueous fluid from DME patients besides VEGF promote EC permeability in vitro and correlate with ME in patients.

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Vasoactive factors in the aqueous fluid from DME patients besides VEGF p...
(A) Induction of in vitro EC permeability by aqueous samples from nondiabetic (control) patients and diabetic patients with active DME (see Supplemental Table 1). DME patients show a 52% mean increase in the induction of EC permeability compared with control patients. (B) Correlation of vascular permeability with the CST on sdOCT for 3 representative DME patients (D4, D8, D10). FA, fluorescein angiogram. Arrowheads indicate leakage of fluorescein dye from retinal vasculature. (C) Correlation of the promotion of EC permeability by aqueous fluid from DME patients with their CST on sdOCT, r = 0.7; P = 0.03. (D) Levels of VEGF in aqueous samples from nondiabetic (control) patients and diabetic patients with DME who have not previously received anti-VEGF therapy or have not received anti-VEGF therapy for 12 weeks or longer in the sample eye (see Supplemental Table 2) (E) Correlation of EC permeability with levels of VEGF in aqueous samples from diabetic patient with DME. r = 0.1; P = 0.8 (E). (F and G) Correlation of EC permeability (r = 0.5; P = 0.1) (F) and CST on sdOCT (r = 0.7; P = 0.04) (G) with levels of VEGF in aqueous samples from diabetic patients with DME (see Supplemental Table 2). Two-tailed unpaired Student’s t test (A), Mann-Whitney U test (D), Pearson’s correlation (C, E, F, G). ***P < 0.001.