PAI-1 is a vascular cell-specific HIF-2-dependent angiogenic factor that promotes retinal neovascularization in diabetic patients.
Author
Qin, YaowuZhang, 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
Date
2022-03-02Journal
Science AdvancesPublisher
American Association for the Advancement of ScienceType
Article
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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/10713/18221ae974a485f413a2113503eed53cd6c53
10.1126/sciadv.abm1896
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