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    PAI-1 is a vascular cell-specific HIF-2-dependent angiogenic factor that promotes retinal neovascularization in diabetic patients.

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    Author
    Qin, Yaowu
    Zhang, Jing
    Babapoor-Farrokhran, Savalan
    Applewhite, Brooks
    Deshpande, Monika
    Megarity, Haley
    Flores-Bellver, Miguel
    Aparicio-Domingo, Silvia
    Ma, Tao
    Rui, Yuan
    Tzeng, Stephany Y
    Green, Jordan J
    Canto-Soler, M Valeria
    Montaner, Silvia
    Sodhi, Akrit
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    Date
    2022-03-02
    Journal
    Science Advances
    Publisher
    American Association for the Advancement of Science
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://doi.org/10.1126/sciadv.abm1896
    Abstract
    For patients with proliferative diabetic retinopathy (PDR) who do not respond adequately to pan-retinal laser photocoagulation (PRP) or anti-vascular endothelial growth factor (VEGF) therapies, we hypothesized that vascular cells within neovascular tissue secrete autocrine/paracrine angiogenic factors that promote disease progression. To identify these factors, we performed multiplex ELISA angiogenesis arrays on aqueous fluid from PDR patients who responded inadequately to anti-VEGF therapy and/or PRP and identified plasminogen activator inhibitor-1 (PAI-1). PAI-1 expression was increased in vitreous biopsies and neovascular tissue from PDR eyes, limited to retinal vascular cells, regulated by the transcription factor hypoxia-inducible factor (HIF)-2α, and necessary and sufficient to stimulate angiogenesis. Using a pharmacologic inhibitor of HIF-2α (PT-2385) or nanoparticle-mediated RNA interference targeting Pai1, we demonstrate that the HIF-2α/PAI-1 axis is necessary for the development of retinal neovascularization in mice. These results suggest that targeting HIF-2α/PAI-1 will be an effective adjunct therapy for the treatment of PDR patients.
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/18221
    ae974a485f413a2113503eed53cd6c53
    10.1126/sciadv.abm1896
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