PAI-1 is a vascular cell–specific HIF-2–dependent angiogenic factor that promotes retinal neovascularization in diabetic patients
Yaowu Qin, Jing Zhang, Savalan Babapoor-Farrokhran, Brooks P. Applewhite, Monika Deshpande, Haley Megarity, Miguel Flores‐Bellver, Silvia Aparicio‐Domingo, Tao Ma, Yuan Rui, Stephany Y. Tzeng, Jordan J. Green, M. Valeria Canto-Soler, Silvia Montaner, Akrit Sodhi
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.