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Shear stress and platelet‐induced tensile forces regulate ADAMTS13‐localization within the platelet thrombus
BACKGROUND: The multimeric glycoprotein von Willebrand factor (VWF) mediates platelet adhesion and aggregation at the site of vessel injury. The adhesive activity of VWF is influenced by its multimer length which is regulated by the metalloprotease ADAMTS13. The ability of ADAMTS13 to regulate plate...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6462754/ https://www.ncbi.nlm.nih.gov/pubmed/31011709 http://dx.doi.org/10.1002/rth2.12196 |
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author | Shida, Yasuaki Swystun, Laura L. Brown, Christine Mewburn, Jeffrey Nesbitt, Kate Danisment, Ozge Riches, Jonathan Jacob Hough, Christine Lillicrap, David |
author_facet | Shida, Yasuaki Swystun, Laura L. Brown, Christine Mewburn, Jeffrey Nesbitt, Kate Danisment, Ozge Riches, Jonathan Jacob Hough, Christine Lillicrap, David |
author_sort | Shida, Yasuaki |
collection | PubMed |
description | BACKGROUND: The multimeric glycoprotein von Willebrand factor (VWF) mediates platelet adhesion and aggregation at the site of vessel injury. The adhesive activity of VWF is influenced by its multimer length which is regulated by the metalloprotease ADAMTS13. The ability of ADAMTS13 to regulate platelet thrombus growth in a shear‐dependent manner has been described, however, the mechanistic basis of this action has not been well characterized. METHODS: We developed an mCherry‐tagged murine ADAMTS13 protein and utilized an ex vivo flow chamber system to visualize the localization of ADAMTS13 within the platelet thrombus under different conditions of shear. Using this system, we also assessed the influence of platelet‐mediated tensile force on ADAMTS13 localization within the thrombus using gain‐of‐function GPIb binding and loss‐of‐function GPIIbIIIa binding mutants in VWF/ADAMTS13 DKO mice. RESULTS: ADAMTS13 was visualized on the growing platelet thrombus under very high shear using ADAMTS13‐mcherry. ADAMTS13‐mCherry localized particularly at the top portion of the thrombus and reduced thrombus size as it grew to occlusion. At the pathological high shear of 7500 s(−1), platelet‐mediated tensile force, involving GPIb but not GPIIbIIIa receptors, influenced localization of ADAMTS13 to the thrombus under conditions of shear. CONCLUSIONS: Tensile force applied on VWF produced by shear stress and platelet GPIb binding has a crucial role in ADAMTS13 activity at the site of thrombus formation. These results suggest that ADAMTS13 activity at the site of platelet thrombus formation is regulated by a shear stress and platelet‐dependent feedback mechanism to prevent vessel occlusion and pathological thrombosis. |
format | Online Article Text |
id | pubmed-6462754 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-64627542019-04-22 Shear stress and platelet‐induced tensile forces regulate ADAMTS13‐localization within the platelet thrombus Shida, Yasuaki Swystun, Laura L. Brown, Christine Mewburn, Jeffrey Nesbitt, Kate Danisment, Ozge Riches, Jonathan Jacob Hough, Christine Lillicrap, David Res Pract Thromb Haemost Original Articles: Haemostasis BACKGROUND: The multimeric glycoprotein von Willebrand factor (VWF) mediates platelet adhesion and aggregation at the site of vessel injury. The adhesive activity of VWF is influenced by its multimer length which is regulated by the metalloprotease ADAMTS13. The ability of ADAMTS13 to regulate platelet thrombus growth in a shear‐dependent manner has been described, however, the mechanistic basis of this action has not been well characterized. METHODS: We developed an mCherry‐tagged murine ADAMTS13 protein and utilized an ex vivo flow chamber system to visualize the localization of ADAMTS13 within the platelet thrombus under different conditions of shear. Using this system, we also assessed the influence of platelet‐mediated tensile force on ADAMTS13 localization within the thrombus using gain‐of‐function GPIb binding and loss‐of‐function GPIIbIIIa binding mutants in VWF/ADAMTS13 DKO mice. RESULTS: ADAMTS13 was visualized on the growing platelet thrombus under very high shear using ADAMTS13‐mcherry. ADAMTS13‐mCherry localized particularly at the top portion of the thrombus and reduced thrombus size as it grew to occlusion. At the pathological high shear of 7500 s(−1), platelet‐mediated tensile force, involving GPIb but not GPIIbIIIa receptors, influenced localization of ADAMTS13 to the thrombus under conditions of shear. CONCLUSIONS: Tensile force applied on VWF produced by shear stress and platelet GPIb binding has a crucial role in ADAMTS13 activity at the site of thrombus formation. These results suggest that ADAMTS13 activity at the site of platelet thrombus formation is regulated by a shear stress and platelet‐dependent feedback mechanism to prevent vessel occlusion and pathological thrombosis. John Wiley and Sons Inc. 2019-03-23 /pmc/articles/PMC6462754/ /pubmed/31011709 http://dx.doi.org/10.1002/rth2.12196 Text en © 2019 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals, Inc on behalf of International Society on Thrombosis and Haemostasis. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. |
spellingShingle | Original Articles: Haemostasis Shida, Yasuaki Swystun, Laura L. Brown, Christine Mewburn, Jeffrey Nesbitt, Kate Danisment, Ozge Riches, Jonathan Jacob Hough, Christine Lillicrap, David Shear stress and platelet‐induced tensile forces regulate ADAMTS13‐localization within the platelet thrombus |
title | Shear stress and platelet‐induced tensile forces regulate ADAMTS13‐localization within the platelet thrombus |
title_full | Shear stress and platelet‐induced tensile forces regulate ADAMTS13‐localization within the platelet thrombus |
title_fullStr | Shear stress and platelet‐induced tensile forces regulate ADAMTS13‐localization within the platelet thrombus |
title_full_unstemmed | Shear stress and platelet‐induced tensile forces regulate ADAMTS13‐localization within the platelet thrombus |
title_short | Shear stress and platelet‐induced tensile forces regulate ADAMTS13‐localization within the platelet thrombus |
title_sort | shear stress and platelet‐induced tensile forces regulate adamts13‐localization within the platelet thrombus |
topic | Original Articles: Haemostasis |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6462754/ https://www.ncbi.nlm.nih.gov/pubmed/31011709 http://dx.doi.org/10.1002/rth2.12196 |
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