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

Autor: Qin Y; Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.; EENT Hospital, Fudan University, Shanghai 200031, China., Zhang J; Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.; State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou 510064, China., Babapoor-Farrokhran S; Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA., Applewhite B; Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA., Deshpande M; Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA., Megarity H; Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA., Flores-Bellver M; 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., Aparicio-Domingo S; 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., Ma T; Department of Oncology and Diagnostic Sciences, Greenebaum Cancer Center, University of Maryland, Baltimore, MD 21201, USA., Rui Y; Department of Biomedical Engineering, Institute for NanoBioTechnology, and the Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA., Tzeng SY; Department of Biomedical Engineering, Institute for NanoBioTechnology, and the Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA., Green JJ; Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.; Department of Biomedical Engineering, Institute for NanoBioTechnology, and the Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA., Canto-Soler MV; 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., Montaner S; Department of Oncology and Diagnostic Sciences, Greenebaum Cancer Center, University of Maryland, Baltimore, MD 21201, USA., Sodhi A; Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Jazyk: angličtina
Zdroj: Science advances [Sci Adv] 2022 Mar 04; Vol. 8 (9), pp. eabm1896. Date of Electronic Publication: 2022 Mar 02.
DOI: 10.1126/sciadv.abm1896
Abstrakt: 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.
Databáze: MEDLINE