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• W3215672728 abstract "BackgroundPlatelet‐binding Von Willebrand Factor (VWF) strings assemble upon stimulated secretion from endothelial cells.ObjectivesTo 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.MethodsThe nanobody VWF/AU‐a11 that specifically binds to VWF in its active platelet‐binding conformation was used to investigate the conformation of VWF.ResultsUpon 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.ConclusionsRelease 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." @default.
• W3215672728 created "2021-12-06" @default.
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• W3215672728 date "2022-03-01" @default.
• W3215672728 modified "2023-10-15" @default.
• W3215672728 title "Osteoprotegerin modulates platelet adhesion to von Willebrand factor during release from endothelial cells" @default.
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• W3215672728 doi "https://doi.org/10.1111/jth.15598" @default.
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