Tie2 activation protects against prothrombotic endothelial dysfunction in COVID-19
Alec A. Schmaier, Gabriel M. Pajares Hurtado, Zachary J. Manickas-Hill, Kelsey D. Sack, Siyu M. Chen, Victoria Bhambhani, Juweria Quadir, Anjali K. Nath, Ai-ris Y. Collier, Debby Ngo, Dan H. Barouch, Nathan I. Shapiro, Robert E. Gerszten, Xu G. Yu, MGH COVID-19 Collection and Processing Team, Kevin G. Peters, Robert Flaumenhaft, Samir M. Parikh
Alec A. Schmaier, Gabriel M. Pajares Hurtado, Zachary J. Manickas-Hill, Kelsey D. Sack, Siyu M. Chen, Victoria Bhambhani, Juweria Quadir, Anjali K. Nath, Ai-ris Y. Collier, Debby Ngo, Dan H. Barouch, Nathan I. Shapiro, Robert E. Gerszten, Xu G. Yu, MGH COVID-19 Collection and Processing Team, Kevin G. Peters, Robert Flaumenhaft, Samir M. Parikh
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Research Article COVID-19 Vascular biology

Tie2 activation protects against prothrombotic endothelial dysfunction in COVID-19

Abstract

Endothelial dysfunction accompanies the microvascular thrombosis commonly observed in severe COVID-19. Constitutively, the endothelial surface is anticoagulant, a property maintained at least in part via signaling through the Tie2 receptor. During inflammation, the Tie2 antagonist angiopoietin-2 (Angpt-2) is released from endothelial cells and inhibits Tie2, promoting a prothrombotic phenotypic shift. We sought to assess whether severe COVID-19 is associated with procoagulant endothelial dysfunction and alterations in the Tie2/angiopoietin axis. Primary HUVECs treated with plasma from patients with severe COVID-19 upregulated the expression of thromboinflammatory genes, inhibited the expression of antithrombotic genes, and promoted coagulation on the endothelial surface. Pharmacologic activation of Tie2 with the small molecule AKB-9778 reversed the prothrombotic state induced by COVID-19 plasma in primary endothelial cells. Lung autopsies from patients with COVID-19 demonstrated a prothrombotic endothelial signature. Assessment of circulating endothelial markers in a cohort of 98 patients with mild, moderate, or severe COVID-19 revealed endothelial dysfunction indicative of a prothrombotic state. Angpt-2 concentrations rose with increasing disease severity, and the highest levels were associated with worse survival. These data highlight the disruption of Tie2/angiopoietin signaling and procoagulant changes in endothelial cells in severe COVID-19. Our findings provide rationale for current trials of Tie2-activating therapy with AKB-9778 in COVID-19.

Authors

Alec A. Schmaier, Gabriel M. Pajares Hurtado, Zachary J. Manickas-Hill, Kelsey D. Sack, Siyu M. Chen, Victoria Bhambhani, Juweria Quadir, Anjali K. Nath, Ai-ris Y. Collier, Debby Ngo, Dan H. Barouch, Nathan I. Shapiro, Robert E. Gerszten, Xu G. Yu, MGH COVID-19 Collection and Processing Team, Kevin G. Peters, Robert Flaumenhaft, Samir M. Parikh

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Figure 1

Plasma from patients with COVID-19 induces thromboinflammatory gene expression in endothelial cells.

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Plasma from patients with COVID-19 induces thromboinflammatory gene expr...
HUVECs were cultured overnight in the presence of 10% pooled plasma from patients with severe (S, ICU patients), moderate (Mod, non-ICU hospitalized patients), or mild (nonhospitalized outpatients) COVID-19 or healthy controls (HC) and analyzed for relative fold mRNA expression change of tissue factor: (A) F3, (B) E selectin (SELE), (C) ANGPT2, (D) TIE2, (E) VE-PTP (PTPRB), (F) EPCR (PROCR), (G) TFPI, and (H) thrombomodulin (THBD). Where indicated, cells were pretreated with Angpt-1 (300 ng/mL) or AKB-9778 (5 μM) for 30 minutes prior to incubation with plasma (n = 3–4 individual biologic replicates performed in technical duplicate). Gene expression was normalized to that of actin and changes are shown relative to HC. Graphs represent the mean ± SD. Significance in comparison with severe (S) was determined by 1-way ANOVA using Dunnett’s post hoc test, *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.