Angiopoietins bind thrombomodulin and inhibit its function as a thrombin cofactor

Abstract

Angiopoietin-1 (Ang1) and Angiopoietin-2 (Ang2) are ligands for Tie2, an endothelial-specific receptor tyrosine kinase that is an essential regulator of angiogenesis. Here we report the identification, via expression cloning, of thrombomodulin (TM) as another receptor for Ang1 and Ang2. Thrombomodulin is an endothelial cell surface molecule that plays an essential role as a coagulation inhibitor via its function as a cofactor in the thrombin-mediated activation of protein C, an anticoagulant protein, as well as thrombin-activatable fibrinolysis inhibitor (TAFI). Ang1 and Ang2 inhibited the thrombin/TM-mediated generation of activated protein C and TAFI in cultured endothelial cells, and inhibited the binding of thrombin to TM in vitro. Ang2 appears to bind TM with higher affinity than Ang1 and is a more potent inhibitor of TM function. Consistent with a potential role for angiopoietins in coagulation, administration of thrombin to mice rapidly increased plasma Ang1 levels, presumably reflecting release from activated platelets (previously shown to contain high levels of Ang1). In addition, Ang1 levels were significantly elevated in plasma prepared from wound blood, suggesting that Ang1 is released from activated platelets at sites of vessel injury. Our results imply a previously undescribed role for angiopoietins in the regulation of hemostasis.

Angiopoietin‐Tie signaling in kidney diseases: an updated review

“…A recent study found another new Ang1/2 receptor, thrombomodulin (TM), which acts as a coagulation inhibitor. Ang1 and Ang2 inhibited the binding of thrombin to TM and regulated hemostasis [36]. In summary, the Ang-Tie pathway tightly controls vascular permeability, inflammation, and pathological angiogenesis in adult tissues [21,37], and dysregulation of the Ang-Tie system has been implicated in many pathological vascular disorders.…”

“…Ang1 and Ang2 inhibited the binding of thrombin to TM and regulated hemostasis [36]. Ang1 and Ang2 inhibited the binding of thrombin to TM and regulated hemostasis [36].…”

C‐type lectin domain group 14 proteins in vascular biology, cancer and inflammation

“…Therefore, by redirecting its cleavage activity towards the activation of anticoagulant and antifibrinolytic proteins, thrombomodulin can dampen the coagulation cascade by different mechanisms. Recently, the regulators of angiogenesis angiopoietin‐1 (Ang‐1) and angiopoietin‐2 (Ang‐2) have both been described as ligands for thrombomodulin in vitro . Ang‐2 binds with higher affinity than Ang‐1 but both, by competing with thrombin, can disrupt thrombomodulin–thrombin interactions leading to suppression of thrombin‐mediated anticoagulant functions.…”

“…Thrombomodulin binding to heat shock protein 70 (HSP70‐1) on the endothelial cell surface can also inhibit thrombomodulin function in vitro by reducing protein C activation by as yet unknown mechanisms . The wide‐ranging roles of thrombomodulin in coagulation are well‐documented elsewhere and hence will not be discussed in any depth. We also direct the reader towards a recent extensive review exploring the ‘nontraditional roles’ of thrombomodulin .…”

Anti-thrombotic effect of Zingiber officinale (ginger) in sprague dawley rats

“…25 Thrombomodulin which is a product of endothelial cells, acting independently, binds to and removes thrombin from circulation. 26 These anticoagulants ensure that blood remain in a fluid state that can easily be transported inside the blood vessels. As already noted, calcium serves as a co factor in numerous steps of the coagulation pathway besides being involved in release reaction of platelets during platelet activation.…”