Tie2 activation protects against prothrombotic endothelial dysfunction in COVID-19

JCI Insight. 2021 Oct 22;6(20):e151527. doi: 10.1172/jci.insight.151527.


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.

Keywords: COVID-19; Coagulation; Vascular Biology.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Angiopoietin-2 / metabolism
  • Aniline Compounds
  • COVID-19 Drug Treatment*
  • Endothelial Cells / drug effects*
  • Female
  • Gene Expression
  • Humans
  • Lung
  • Male
  • Middle Aged
  • Protective Agents / pharmacology*
  • Receptor, TIE-2 / genetics
  • Receptor, TIE-2 / metabolism*
  • SARS-CoV-2
  • Signal Transduction
  • Sulfonic Acids
  • Vascular Diseases / metabolism
  • Young Adult


  • AKB-9778
  • ANGPT2 protein, human
  • Angiopoietin-2
  • Aniline Compounds
  • Protective Agents
  • Sulfonic Acids
  • Receptor, TIE-2
  • TEK protein, human