Cellular stress induces erythrocyte assembly on intravascular von Willebrand factor strings and promotes microangiopathy

  • Microangiopathy with subsequent organ damage represents a major complication in several diseases. The mechanisms leading to microvascular occlusion include von Willebrand factor (VWF), notably the formation of ultra-large von Willebrand factor fibers (ULVWFs) and platelet aggregation. To date, the contribution of erythrocytes to vascular occlusion is incompletely clarified. We investigated the platelet-independent interaction between stressed erythrocytes and ULVWFs and its consequences for microcirculation and organ function under dynamic conditions. In response to shear stress, erythrocytes interacted strongly with VWF to initiate the formation of ULVWF/erythrocyte aggregates via the binding of Annexin V to the VWF A1 domain. VWF-erythrocyte adhesion was attenuated by heparin and the VWF-specific protease ADAMTS13. In an in vivo model of renal ischemia/reperfusion injury, erythrocytes adhered to capillaries of wild-type but not VWF-deficient mice and later resulted in less renal damage. In vivo imaging in mice confirmed the adhesion of stressed erythrocytes to the vessel wall. Moreover, enhanced eryptosis rates and increased VWF binding were detected in blood samples from patients with chronic renal failure. Our study demonstrates that stressed erythrocytes have a pronounced binding affinity to ULVWFs. The discovered mechanisms suggest that erythrocytes are essential for the pathogenesis of microangiopathies and renal damage by actively binding to ULVWFs.
Metadaten
Author:Jan Peter Nicolay, Verena Thorn, Christoph Daniel, Kerstin Amann, Balasaheb Siraskar, Florian Lang, Carina Hillgruber, Tobias Görge, Stefan Hoffmann, Christian Gorzelanny, Volker Huck, Christian Mess, Tobias Obser, Reinhard Schneppenheim, Ingrid FlemingORCiD, Matthias F. Schneider, Stefan W. Schneider
URN:urn:nbn:de:hebis:30:3-471729
DOI:https://doi.org/10.1038/s41598-018-28961-2
ISSN:2045-2322
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/30026593
Parent Title (English):Scientific reports
Publisher:Macmillan Publishers Limited, part of Springer Nature
Place of publication:[London]
Document Type:Article
Language:English
Year of Completion:2018
Date of first Publication:2018/07/19
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2018/09/06
Tag:Experimental models of disease; Thrombosis
Volume:8
Issue:1, Art. 10945
Page Number:15
First Page:1
Last Page:15
Note:
Rights and permissions: Open Access: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
HeBIS-PPN:437751201
Institutes:Medizin / Medizin
Wissenschaftliche Zentren und koordinierte Programme / Sonderforschungsbereiche / Forschungskollegs
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung 4.0