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

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    Author
    Ma, T.
    Menon, D.
    Dinabandhu, A.
    Lu, D.
    Montaner, S.
    Date
    2019
    Journal
    Journal of Clinical Investigation
    Publisher
    American Society for Clinical Investigation
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://doi.org/10.1172/JCI120879
    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.
    Sponsors
    This work was supported by NIH grant 5R01EY025705 to SM and AS.
    Keyword
    diabetic macular edema
    Angiopoietin-like 4 Protein
    Vascular Endothelial Growth Factors
    Identifier to cite or link to this item
    https://www.scopus.com/inward/record.uri?eid=2-s2.0-85074378230&doi=10.1172%2fJCI120879&partnerID=40&md5=ef2a2f4c2f64c5931d81393187443b7d; http://hdl.handle.net/10713/11417
    ae974a485f413a2113503eed53cd6c53
    10.1172/JCI120879
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    UMB Open Access Articles 2019

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