TY - JOUR
T1 - PAI-1 is a vascular cell-specific HIF-2-dependent angiogenic factor that promotes retinal neovascularization in diabetic patients
AU - Qin, Yaowu
AU - Zhang, Jing
AU - Babapoor-Farrokhran, Savalan
AU - Applewhite, Brooks
AU - Deshpande, Monika
AU - Megarity, Haley
AU - Flores-Bellver, Miguel
AU - Aparicio-Domingo, Silvia
AU - Ma, Tao
AU - Rui, Yuan
AU - Tzeng, Stephany Y.
AU - Green, Jordan J.
AU - Canto Soler, Maria
AU - Montaner, Silvia
AU - Sodhi, Akrit
N1 - Funding Information:
This work was supported by the National Institutes of Health grants R01EY029750 to A.S., R01EY025705 to S.M. and A.S., R01CA228133 to J.J.G., and EY001765 (the Wilmer Core Grant for Vision Research, Microscopy, and Imaging Core Module); the CellSight Development Fund to M.V.C.-S.; the Doni Solich Family Chair in Ocular Stem Cell Research to M.V.C.-S.; the National Science Foundation to Y.R.; unrestricted grants from the Research to Prevent Blindness Inc. to the Wilmer Eye Institute, Johns Hopkins School of Medicine, and to the Department of Ophthalmology at the University of Colorado; and the Branna and Irving Sisenwein Professorship in Ophthalmology to A.S. The funding organizations had no role in the design or conduct of this research.
Publisher Copyright:
Copyright © 2022 The Authors.
PY - 2022/3
Y1 - 2022/3
N2 - 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.
AB - 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.
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U2 - 10.1126/sciadv.abm1896
DO - 10.1126/sciadv.abm1896
M3 - Article
C2 - 35235351
AN - SCOPUS:85125613649
SN - 2375-2548
VL - 8
JO - Science advances
JF - Science advances
IS - 9
M1 - eabm1896
ER -