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Wohner N, Sebastian S, Muczynski V, et al. Osteoprotegerin modulates platelet adhesion to von Willebrand factor during release from endothelial cells. J Thromb Haemost. 2021;doi: 10.1111/jth.15598.
Wohner, N., Sebastian, S., Muczynski, V., Huskens, D., de Laat, B., de Groot, P. G., & Lenting, P. J. (2021). Osteoprotegerin modulates platelet adhesion to von Willebrand factor during release from endothelial cells. Journal of thrombosis and haemostasis : JTH, . https://doi.org/10.1111/jth.15598
Wohner, Nikolett, et al. "Osteoprotegerin modulates platelet adhesion to von Willebrand factor during release from endothelial cells." Journal of thrombosis and haemostasis : JTH vol. (2021). doi: https://doi.org/10.1111/jth.15598
Wohner N, Sebastian S, Muczynski V, Huskens D, de Laat B, de Groot PG, Lenting PJ. Osteoprotegerin modulates platelet adhesion to von Willebrand factor during release from endothelial cells. J Thromb Haemost. 2021 Nov 24; doi: 10.1111/jth.15598. Epub 2021 Nov 24. PMID: 34816579.
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J Thromb Haemost. 2021 Nov 24; doi: 10.1111/jth.15598. Epub 2021 Nov 24.

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

Journal of thrombosis and haemostasis : JTH

Nikolett Wohner, Silvie Sebastian, Vincent Muczynski, Dana Huskens, Bas de Laat, Philip G de Groot, Peter J Lenting

Affiliations

  1. Laboratory for Hemostasis, Inflammation & Thrombosis, Unité Mixed de Recherche 1176, Institut National de la Santé et de la Recherche Médicale, Université Paris-Saclay, Le Kremlin-Bicêtre, France.
  2. Department of Clinical Chemistry and Haematology, Utrecht Medical Centre, Utrecht, The Netherlands.
  3. Synapse Research Institute, Maastricht, The Netherlands.
  4. CARIM, Maastricht University Medical Centre, Maastricht, The Netherlands.

PMID: 34816579 DOI: 10.1111/jth.15598

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.

© 2021 International Society on Thrombosis and Haemostasis.

Keywords: blood platelets; endothelial cells; inflammation; osteoprotegerin; von Willebrand factor

References

  1. Ruggeri ZM. Von Willebrand factor, platelets and endothelial cell interactions. J Thromb Haemost. 2003;1:1335-1342. - PubMed
  2. Zhou YF, Eng ET, Zhu J, Lu C, Walz T, Springer TA. Sequence and structure relationships within von Willebrand factor. Blood. 2012;120:449-458. - PubMed
  3. Lenting PJ, Christophe OD, Denis CV. von Willebrand factor biosynthesis, secretion, and clearance: connecting the far ends. Blood. 2015;125:2019-2028. - PubMed
  4. Rondaij MG, Bierings R, Kragt A, van Mourik JA, Voorberg J. Dynamics and plasticity of Weibel-Palade bodies in endothelial cells. Arterioscler Thromb Vasc Biol. 2006;26:1002-1007. - PubMed
  5. McCormack JJ, Lopes da Silva M, Ferraro F, Patella F, Cutler DF. Weibel-Palade bodies at a glance. J Cell Sci. 2017;130:3611-3617. - PubMed
  6. Shahbazi S, Lenting PJ, Fribourg C, Terraube V, Denis CV, Christophe OD. Characterization of the interaction between von Willebrand factor and osteoprotegerin. J Thromb Haemost. 2007;5:1956-1962. - PubMed
  7. Zannettino AC, Holding CA, Diamond P, et al. Osteoprotegerin (OPG) is localized to the Weibel-Palade bodies of human vascular endothelial cells and is physically associated with von Willebrand factor. J Cell Physiol. 2005;204:714-723. - PubMed
  8. Dong JF, Moake JL, Nolasco L, et al. ADAMTS-13 rapidly cleaves newly secreted ultralarge von Willebrand factor multimers on the endothelial surface under flowing conditions. Blood. 2002;100:4033-4039. - PubMed
  9. De Ceunynck K, Rocha S, Feys HB, et al. Local elongation of endothelial cell-anchored von Willebrand factor strings precedes ADAMTS13 protein-mediated proteolysis. J Biol Chem. 2011;286:36361-36367. - PubMed
  10. De Ceunynck K, De Meyer SF, Vanhoorelbeke K. Unwinding the von Willebrand factor strings puzzle. Blood. 2013;121:270-277. - PubMed
  11. Huang RH, Wang Y, Roth R, et al. Assembly of Weibel-Palade body-like tubules from N-terminal domains of von Willebrand factor. Proc Natl Acad Sci USA. 2008;105:482-487. - PubMed
  12. Valentijn KM, Eikenboom J. Weibel-Palade bodies: a window to von Willebrand disease. J Thromb Haemost. 2013;11:581-592. - PubMed
  13. Valentijn KM, Sadler JE, Valentijn JA, Voorberg J, Eikenboom J. Functional architecture of Weibel-Palade bodies. Blood. 2011;117:5033-5043. - PubMed
  14. Andre P, Denis CV, Ware J, et al. Platelets adhere to and translocate on von Willebrand factor presented by endothelium in stimulated veins. Blood. 2000;96:3322-3328. - PubMed
  15. Motto DG, Chauhan AK, Zhu G, et al. Shigatoxin triggers thrombotic thrombocytopenic purpura in genetically susceptible ADAMTS13-deficient mice. J Clin Invest. 2005;115:2752-2761. - PubMed
  16. Dong JF, Cruz MA, Aboulfatova K, et al. Magnesium maintains endothelial integrity, up-regulates proteolysis of ultra-large von Willebrand factor, and reduces platelet aggregation under flow conditions. Thromb Haemost. 2008;99:586-593. - PubMed
  17. Hulstein JJ, de Groot PG, Silence K, Veyradier A, Fijnheer R, Lenting PJ. A novel nanobody that detects the gain-of-function phenotype of von Willebrand factor in ADAMTS13 deficiency and von Willebrand disease type 2B. Blood. 2005;106:3035-3042. - PubMed
  18. Groot E, Fynheer R, Sebastian SAE, Lenting PJ, De Groot PG. Transition from non-platelet-binding to platelet-binding conformation of Von Willebrand factor occurs upon exocytosis. Blood. 2008;112:3917. - PubMed
  19. Sodetz JM, Pizzo SV, McKee PA. Relationship of sialic acid to function and in vivo survival of human factor VIII/von Willebrand factor protein. J Biol Chem. 1977;252:5538-5546. - PubMed
  20. Casari C, Du V, Wu YP, et al. Accelerated uptake of VWF/platelet complexes in macrophages contributes to VWD type 2B-associated thrombocytopenia. Blood. 2013;122:2893-2902. - PubMed
  21. Willems C, Astaldi GC, De Groot PG, et al. Media conditioned by cultured human vascular endothelial cells inhibit the growth of vascular smooth muscle cells. Exp Cell Res. 1982;139:191-197. - PubMed
  22. Sixma JJ, de Groot PG, van Zanten H, Ijsseldijk M. A new perfusion chamber to detect platelet adhesion using a small volume of blood. Thromb Res. 1998;92:S43-S46. - PubMed
  23. Lenting PJ, Westein E, Terraube V, et al. An experimental model to study the in vivo survival of von Willebrand factor. Basic aspects and application to the R1205H mutation. J Biol Chem. 2004;279:12102-12109. - PubMed
  24. Borchiellini A, Fijnvandraat K, ten Cate JW, et al. Quantitative analysis of von Willebrand factor propeptide release in vivo: effect of experimental endotoxemia and administration of 1-deamino-8-D-arginine vasopressin in humans. Blood. 1996;88:2951-2958. - PubMed
  25. Groot E, Fijnheer R, Sebastian SA, de Groot PG, Lenting PJ. The active conformation of von Willebrand factor in patients with thrombotic thrombocytopenic purpura in remission. J Thromb Haemost. 2009;7:962-969. - PubMed
  26. Djamiatun K, van der Ven AJ, de Groot PG, et al. Severe dengue is associated with consumption of von Willebrand factor and its cleaving enzyme ADAMTS-13. PLoS Negl Trop Dis. 2012;6:e1628. - PubMed
  27. Springer TA. von Willebrand factor, Jedi knight of the bloodstream. Blood. 2014;124:1412-1425. - PubMed
  28. Utgaard JO, Jahnsen FL, Bakka A, Brandtzaeg P, Haraldsen G. Rapid secretion of prestored interleukin 8 from Weibel-Palade bodies of microvascular endothelial cells. J Exp Med. 1998;188:1751-1756. - PubMed
  29. Vischer UM, Wagner DD. CD63 is a component of Weibel-Palade bodies of human endothelial cells. Blood. 1993;82:1184-1191. - PubMed
  30. Kobayashi-Sakamoto M, Hirose K, Isogai E, Chiba I. NF-kappaB-dependent induction of osteoprotegerin by Porphyromonas gingivalis in endothelial cells. Biochem Biophys Res Commun. 2004;315:107-112. - PubMed
  31. Buchtele N, Kovacevic KD, Brostjan C, et al. Differential osteoprotegerin kinetics after stimulation with desmopressin and lipopolysaccharides in vivo. Thromb Haemost. 2020;120:1108-1115. - PubMed
  32. Madge LA, Pober JS. TNF signaling in vascular endothelial cells. Exp Mol Pathol. 2001;70:317-325. - PubMed
  33. Cambien B, Bergmeier W, Saffaripour S, Mitchell HA, Wagner DD. Antithrombotic activity of TNF-alpha. J Clin Invest. 2003;112:1589-1596. - PubMed
  34. Li Y, Li L, Dong F, et al. Plasma von Willebrand factor level is transiently elevated in a rat model of acute myocardial infarction. Exp Ther Med. 2015;10:1743-1749. - PubMed

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