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, M. Valeria
AU - Montaner, Silvia
AU - Sodhi, Akrit
N1 - 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.
UR - http://www.scopus.com/inward/record.url?scp=85125613649&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85125613649&partnerID=8YFLogxK
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 -