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.
【저자키워드】 COVID-19, Coagulation, Vascular Biology, 【초록키워드】 Inflammation, therapy, Trial, thrombosis, severe COVID-19, disease severity, Autopsy, Endothelial dysfunction, Coagulation, angiopoietin, Cohort, survival, Endothelial markers, endothelial cells, Patient, Mild, plasma, small molecule, receptor, assessment, expression, moderate, Endothelial cell, Anticoagulant, Signaling, Antithrombotic, Concentration, Disruption, dysfunction, Microvascular thrombosis, endothelial, Activation, These data, alteration, rationale, property, circulating, phenotypic, prothrombotic state, Pharmacologic, AKB-9778, Genes, prothrombotic, procoagulant, highlight, highest, inhibit, inhibited, treated, changes in, demonstrated, upregulated, released, reversed, promoted, accompany, endothelial marker, patients with COVID-19, 【제목키워드】 Activation, prothrombotic, PROTECT,