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 human endothelial cells treated with plasma from patients with severe COVID-19 upregulated expression of thromboinflammatory genes, inhibited 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 COVID-19 patients 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 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

Fundamentals in Covid-19-Associated Thrombosis: Molecular and Cellular Aspects

“…Besides the direct effects of SARS-CoV-2 on endothelial integrity, evidence from recent studies points that endothelial cells can be activated by humoral factors presented in the blood of SARS-CoV-2 infected patients (44,45). Stimulation of human umbilical vein endothelial cells (HUVECs) with plasma or sera from COVID-19 patients resulted in activation of the endothelial cells, determined by overexpression of adhesion molecules and upregulation of thromboinflammatory genes associated with downregulation of antithrombotic genes (44,45). This shift toward a prothrombotic surface appears to be triggered by alterations in the Tie2-angiopoietin axis (44).…”

“…Stimulation of human umbilical vein endothelial cells (HUVECs) with plasma or sera from COVID-19 patients resulted in activation of the endothelial cells, determined by overexpression of adhesion molecules and upregulation of thromboinflammatory genes associated with downregulation of antithrombotic genes (44,45). This shift toward a prothrombotic surface appears to be triggered by alterations in the Tie2-angiopoietin axis (44). Tie2, or angiopoietin receptor 2, is a tyrosine kinase receptor selectively expressed on vascular endothelial cells, and its activation by angiopoietin 1 maintains the endothelial quiescence and suppresses vessel inflammation (46).…”

“…Tie2, or angiopoietin receptor 2, is a tyrosine kinase receptor selectively expressed on vascular endothelial cells, and its activation by angiopoietin 1 maintains the endothelial quiescence and suppresses vessel inflammation (46). It has been experimentally demonstrated that pharmacological activation of Tie2 effectively reversed the expression of thromboinflammatory genes induced by COVID-19 plasma in vitro (44). Another mechanism whereby COVID-19 may induce activation of endothelial cells appears to be mediated by antiphospholipid (aPL) antibodies.…”

“…Under normal circumstances, endothelial cells possess anticoagulant functions by expressing several molecules that limit or inhibit the coagulation process, however after inflammatory stimuli (e.g., interleukin (IL)-1 and tumor necrosis factor (TNF)α), these cells acquire pro-coagulant functions, such as shedding of microparticles with exposed phosphatidylserine (PS) that enable the assembly of clotting enzyme complexes and the generation of thrombin (49,50). Interestingly, activation of HUVECs with plasma from severe COVID-19 patients incited externalization of PS, creating a suitable surface for the assembly of coagulation complexes on the endothelium (44). Indeed, generation of factor Xa and thrombin were detected in HUVECs following exposure to COVID-19 plasma (44).…”

“…Interestingly, activation of HUVECs with plasma from severe COVID-19 patients incited externalization of PS, creating a suitable surface for the assembly of coagulation complexes on the endothelium (44). Indeed, generation of factor Xa and thrombin were detected in HUVECs following exposure to COVID-19 plasma (44). Nevertheless, IL-1 and TNF-α, cytokines that are markedly increased in COVID-19 patients, also induce endothelial cells to synthesize tissue factor (TF), the primary initiator of coagulation (51,52).…”