Tie2 activation protects against prothrombotic endothelial dysfunction in COVID-19

Area of Science:

• Vascular Biology
• Immunothrombosis
• COVID-19 Pathophysiology

Background:

• Severe COVID-19 is linked to microvascular thrombosis and endothelial dysfunction.
• The Tie2 receptor and its ligand angiopoietin-2 (Angpt-2) regulate endothelial anticoagulant properties.
• Inflammation can lead to Angpt-2 release, inhibiting Tie2 and promoting a prothrombotic state.

Purpose of the Study:

• To investigate procoagulant endothelial dysfunction in severe COVID-19.
• To assess alterations in the Tie2/angiopoietin axis in COVID-19 patients.
• To evaluate the therapeutic potential of Tie2 activation.

Main Methods:

• Primary human umbilical vein endothelial cells (HUVECs) were treated with plasma from severe COVID-19 patients.
• Gene expression and coagulation assays were performed on endothelial cells.
• Lung autopsies and circulating endothelial markers from 98 COVID-19 patients were analyzed.
• The effect of Tie2 activation with AKB-9778 was assessed.

Main Results:

• COVID-19 plasma induced a prothrombotic phenotype in endothelial cells, upregulating inflammatory genes and promoting coagulation.
• Lung tissues showed a prothrombotic endothelial signature in COVID-19.
• Circulating Angpt-2 levels increased with COVID-19 severity and correlated with poorer survival.
• AKB-9778 treatment reversed the prothrombotic endothelial state.

Conclusions:

• Severe COVID-19 disrupts Tie2/angiopoietin signaling, leading to procoagulant endothelial dysfunction.
• Elevated Angpt-2 is a marker of disease severity and poor prognosis.
• Tie2-activating therapy, like AKB-9778, shows promise for treating COVID-19-associated thrombosis.