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 3

Upregulation of ANGPTL4 in patients with DME.

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Upregulation of ANGPTL4 in patients with DME. (A and B) Levels of ANGPTL...
(A and B) Levels of ANGPTL4 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) (A) and its correlation with EC permeability. r = –0.8; P < 0.0001 (B). (C and D) ANGPTL4 (C) and VEGF (D) protein levels in DME patients without previous treatment with anti-VEGF therapy (DME Untx) or DME patients who have received a single treatment with anti-VEGF therapy in the sample eye within 6 weeks of sample collection (DME Tx) compared with nondiabetic (control) patients. Mann-Whitney U test (A), Pearson correlation (B), or 1-way ANOVA (C and D). *P < 0.05; **P < 0.01; ****P < 0.0001.