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

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

  • Sci Adv. 2022 Mar 4;8(9):eabm1896. doi: 10.1126/sciadv.abm1896.
Yaowu Qin 1 2,  Jing Zhang 1 3,  Savalan Babapoor-Farrokhran 1,  Brooks Applewhite 1,  Monika Deshpande 1,  Haley Megarity 1,  Miguel Flores-Bellver 4,  Silvia Aparicio-Domingo 4,  Tao Ma 5,  Yuan Rui 6,  Stephany Y Tzeng 6,  Jordan J Green 1 6,  M Valeria Canto-Soler 4,  Silvia Montaner 5,  Akrit Sodhi 1
Affiliations

Affiliations

  • 1 Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
  • 2 EENT Hospital, Fudan University, Shanghai 200031, China.
  • 3 State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou 510064, China.
  • 4 CellSight Ocular Stem Cell and Regeneration Research Program, Department of Ophthalmology, Sue Anschutz-Rodgers Eye Center, University of Colorado School of Medicine, Aurora, CO 80045, USA.
  • 5 Department of Oncology and Diagnostic Sciences, Greenebaum Cancer Center, University of Maryland, Baltimore, MD 21201, USA.
  • 6 Department of Biomedical Engineering, Institute for NanoBioTechnology, and the Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
PMID: 35235351 DOI: 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.

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