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

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.

SARS‐CoV‐2 infection results in upregulation of Plasminogen Activator Inhibitor‐1 and Neuroserpin in the lungs, and an increase in fibrinolysis inhibitors associated with disease severity

“…Figure 6A shows the H&E of the alveolar epithelium and abundant intra‐alveolar macrophages. Figure 6B reveals marked staining for PAI‐1 in cells morphologically consistent with epithelial cells as reported [29], but also in macrophages [30–32], with variable/weak staining in endothelial cells [33]. Figure 6C shows punctate Neuroserpin staining typically concentrated in vesicles located in close proximity to the plasma membrane of macrophages, as reported [34].…”

“…(A) H&E shows the accumulation of reactive pneumocytes (short arrow) and intraalveolar macrophages (arrowhead) (x500). (B) Upregulation of PAI‐1 in epithelial cells (arrows) [ 29 ] and in macrophages (arrowheads) [ 30 , 31 , 32 ], with variable/weak staining in endothelial cells (long arrow) [ 33 ] (x500). (C) Neuroserpin expression in macrophages (arrowheads) is typically associated with the plasma membrane as reported [ 34 ], but not in epithelial cells (arrows) (x500).…”

“…Of note, PAI‐1 is produced by adipose tissue and is elevated in obese patients [ 30 , 41 ], a morbidity associated with poor outcomes in the infection [ 1 , 2 , 3 , 4 ]. Notably, our autopsy cases revealed overexpression of PAI‐1 in epithelial cells [ 29 ] and macrophages [ 30 , 31 , 32 ], with variable/dim staining in endothelial cells [ 33 ], indicating a high anti‐fibrinolytic activity in the lungs. This interpretation is supported by high PAI‐1 antigen levels detected in bronchoalveolar lavage samples collected from critically ill patients with SARS‐CoV‐2 infection and suppressed fibrinolysis by gene expression analysis [ 15 , 36 ].…”

“…In the absence of a primary antibody, staining was negative (Figure 6D, inset). To confirm cell derivations, Figure 6E shows [29] and in macrophages (arrowheads) [30][31][32], with variable/weak staining in endothelial cells (long arrow) [33] (x500). (C) Neuroserpin expression in macrophages (arrowheads) is typically associated with the plasma membrane as reported [34], but not in epithelial cells (arrows) (x500).…”

Dysregulated miRNAs network in the critical COVID-19: An important clue for uncontrolled immunothrombosis/thromboinflammation

“…According to in vitro and in vivo studies, HIF-2α causes the upregulated and downregulated expressions of the PAI-1 and TFPI, respectively. Therefore, it can take part in the uncontrolled immunothrombosis [26] , [103] , [161] ( Fig. 1 C).…”