Osteoprotegerin modulates platelet adhesion to von Willebrand factor during release from endothelial cells.

Abstract

BACKGROUND:

Platelet-binding Von Willebrand Factor (VWF) strings assemble upon stimulated secretion from endothelial cells.

OBJECTIVES:

To investigate the efficiency of platelet binding to multi-molecular VWF bundles secreted from endothelial cells and to investigate the role of osteoprotegerin, a protein located in Weibel-Palade bodies that interacts with the VWF platelet binding domain.

METHODS:

The nanobody VWF/AU-a11 that specifically binds to VWF in its active platelet-binding conformation was used to investigate the conformation of VWF.

RESULTS:

Upon stimulated secretion from endothelial cells, VWF strings were only partially covered with platelets, while a VWD-type 2B mutation or ristocetin enhanced platelet binding by 2-3-fold. Osteoprotegrin, reduces platelet adhesion to VWF by 40% ± 18% in perfusion assays. siRNA-mediated down-regulation of endothelial osteoprotegerin expression resulted in a 1.8-fold increase in platelet adhesion to VWF strings. Upon viral infection, there is a concordant rise in VWF and osteoprotegerin plasma levels. Unexpectedly, no such increase was observed in plasma of desmopressin-treated hemophilia A-patients. In a mouse model, osteoprotegerin expression was low in liver endothelial cells of vehicle-treated mice, and concanavalin A-treatment increased VWF and osteoprotegerin expression 4- and 40-fold, respectively. This increase was translated in a 30-fold increased osteoprotegerin/VWF ratio in plasma.

CONCLUSIONS:

Release of VWF from endothelial cells opens the platelet-binding site, irrespective of the presence of flow. However, not all available platelet-binding sites are being occupied, suggesting some extent of regulation. Part of this regulation involves endothelial proteins that are co-secreted with VWF, like osteoprotegerin. This regulatory mechanism may be of more relevance under inflammatory conditions.

• Authors: Nikolett Wohner, Silvie Sebastian, Vincent Muczynski, Dana Huskens, Bas de Laat, Philip G de Groot, Peter J Lenting
• Journal: Journal of thrombosis and haemostasis : JTH (J Thromb Haemost) Vol. 20 Issue 3 Pg. 755-766 (03 2022) ISSN: 1538-7836 [Electronic] England
• PMID: 34816579 (Publication Type: Journal Article)
• Copyright: © 2021 International Society on Thrombosis and Haemostasis.

Chemical References

• Osteoprotegerin
• von Willebrand Factor
• Ristocetin

Topics

• Animals
• Blood Platelets (metabolism)
• Endothelial Cells (metabolism)
• Humans
• Mice
• Osteoprotegerin (metabolism)
• Platelet Adhesiveness
• Ristocetin
• von Willebrand Diseases (genetics)
• von Willebrand Factor (metabolism)