Von Willebrand factor under inflammatory conditions - Von Willebrand factor-induced collective networks
Biophysik
Zusammenfassung der Projektergebnisse
The active role of endothelium is one of the key factors for the initial step of inflammation. Endothelial cell (EC) activation leads to an immediate release of various proteins, cytokines and the adhesive glycoprotein von Willebrand factor (VWF). Exposed to the blood flow, VWF shows a state-function-relationship: the glycoprotein multimers become stretched and form fibre-like structures immobilised on EC surface. As a consequence of the critical coiled-stretched transition and subsequent binding, VWF is a shearactivated protein and thereby uncovers formerly shielded binding sites. Hereafter, the regular repressive function on inflammation and coagulation subsides and the endothelium converts to a proinflammatory and procoagulatory surface. VWF can be therefore also considered as a shear-dependent inflammatory molecule bridging coagulation and inflammation. Within the overall funding period, we elucidate the formation of EC-secreted VWF and the impact of large VWF multimers on platelet-, leukocyte-, bacteria- and DNA-adhesion under defined shear rates upon inflammatory conditions. Therefore, we addressed the role of shear flow conditions for the activation and self-assembly of endothelium-derived VWF and the impact of an inflammatory milieu on the activity of VWF and its degrading protease ADAMTS13. Focusing on VWF-induced collective networks, we started to discover the mechanistic, functional and pathophysiological background of their formation, activation and degradation. We demonstrated an autoinhibition of VWF mediated by force-dependent interdomain interactions between the A1 and A2 domains, offering the molecular basis for the shear-sensitive growth of VWF-platelet networks. We furthermore characterised VWF behaviour in blood flow demonstrating that the compact shape of VWF is important for its margination toward vessel walls and thereby necessary to achieve its vital function in primary and secondary haemostasis These conducted studies provided the basis for a better understanding of VWF-induced collective network formation. In this context, we identified a VWF variant residing within the C4 domain to be an independent risk factor for suffering from myocardial infarction. As a cooperative task of the whole SHENC consortium, we proved this gain-of-function mutation to affect VWF-platelet collective network formation by inducing hypermechanosensitivity of VWF. At this, our established in vitro vascular model system allowed a capacious characterisation of the shear-induced activation capacity and collective network behaviour of VWF. This polymorphic VWF C4 domain variant, so far failed to be functionally diagnosed by standard assays, has been reliably identified und mechanistically analysed. In the remaining timeframe of the current funding period (till June 2019), our group will perform and finalise studies addressing the functional characterisation of further clinically relevant VWF variants. By working together in a highly interdisciplinary environment, the SHENC groups were able to bridge the gap between biophysics, biochemistry and clinical findings – illustrated by numerous project-related multidisciplinary publications – to enter new paths for the development of novel diagnostic and potential therapeutic targets.
Projektbezogene Publikationen (Auswahl)
- Highly invasive melanoma cells activate the vascular endothelium via an MMP-2/integrin alphavbeta5-induced secretion of VEGF-A. Am. J. Pathol. 2012;181:693-705
Desch A, Strozyk EA, Bauer AT, Huck V, Niemeyer V, Wieland T, Schneider SW
(Siehe online unter https://doi.org/10.1016/j.ajpath.2012.04.012) - Blood-clotting-inspired reversible polymer-colloid composite assembly in flow. Nat Commun. 2013;4:1333
Chen H, Fallah MA, Huck V, Angerer JI, Reininger AJ, Schneider SW, Schneider MF, Alexander-Katz A
(Siehe online unter https://doi.org/10.1038/ncomms2326) - Circulating but not immobilized N-deglycosylated von Willebrand factor increases platelet adhesion under flow conditions. Biomicrofluidics. 2013;7:44124
Fallah MA & Huck V, Niemeyer V, Desch A, Angerer JI, McKinnon TA, Wixforth A, Schneider SW, Schneider MF
(Siehe online unter https://doi.org/10.1063/1.4819746) - Ultralarge von Willebrand Factor Fibers Mediate Luminal Staphylococcus aureus Adhesion to an Intact Endothelial Cell Layer Under Shear Stress. Circulation. 2013;128:50-59
Pappelbaum KI, Gorzelanny C, Grassle S, Suckau J, Laschke MW, Bischoff M, Bauer C, Schorpp- Kistner M, Weidenmaier C, Schneppenheim R, Obser T, Sinha B, Schneider SW
(Siehe online unter https://doi.org/10.1161/CIRCULATIONAHA.113.002008) - The various states of von Willebrand factor and their function in physiology and pathophysiology. Thromb. Haemost. 2014;111:598-609
Huck V, Schneider MF, Gorzelanny C, Schneider SW
(Siehe online unter https://doi.org/10.1160/TH13-09-0800) - von Willebrand disease type 2A phenotypes IIC, IID and IIE: A day in the life of shear-stressed mutant von Willebrand factor. Thromb. Haemost. 2014;112:96-108
Brehm MA & Huck V, Aponte-Santamaria C, Obser T, Grassle S, Oyen F, Budde U, Schneppenheim S, Baldauf C, Grater F, Schneider SW, Schneppenheim R
(Siehe online unter https://doi.org/10.1160/TH13-11-0902) - von Willebrand factor directly interacts with DNA from neutrophil extracellular traps. Arterioscler. Thromb. Vasc. Biol. 2014;34:1382-1389
Grassle S, Huck V, Pappelbaum KI, Gorzelanny C, Aponte-Santamaria C, Baldauf C, Grater F, Schneppenheim R, Obser T, Schneider SW
(Siehe online unter https://doi.org/10.1161/ATVBAHA.113.303016) - Force-sensitive autoinhibition of the von Willebrand factor is mediated by interdomain interactions. Biophys. J. 2015;108:2312-2321
Aponte-Santamaria C, Huck V, Posch S, Bronowska AK, Grassle S, Brehm MA, Obser T, Schneppenheim R, Hinterdorfer P, Schneider SW, Baldauf C, Grater F
(Siehe online unter https://doi.org/10.1016/j.bpj.2015.03.041) - Mechanism and functional impact of CD40 ligand-induced von Willebrand factor release from endothelial cells. Thromb. Haemost. 2015;113:1095-1108
Moller K, Adolph O, Grunow J, Elrod J, Popa M, Ghosh S, Schwarz M, Schwale C, Grassle S, Huck V, Bruehl C, Wieland T, Schneider SW, Nobiling R, Wagner AH, Hecker M
(Siehe online unter https://doi.org/10.1160/TH14-04-0336) - Monocyte induction of E-selectin-mediated endothelial activation releases VE-cadherin junctions to promote tumor cell extravasation in the metastasis cascade. Cancer Res. 2016
Haeuselmann I, Roblek M, Protsyuk D, Huck V, Knopfova L, Grassle S, Bauer AT, Schneider SW, Borsig L
(Siehe online unter https://doi.org/10.1158/0008-5472.can-16-0784) - Margination and stretching of von Willebrand factor in the blood stream enable adhesion. Sci Rep. 2017;7:14278
Rack K, Huck V, Hoore M, Fedosov DA, Schneider SW, Gompper G
(Siehe online unter https://doi.org/10.1038/s41598-017-14346-4) - Cellular stress induces erythrocyte assembly on intravascular von Willebrand factor strings and promotes microangiopathy. Sci Rep. 2018;8:10945
Nicolay JP, Thorn V, Daniel C, Amann K, Siraskar B, Lang F, Hillgruber C, Goerge T, Hoffmann S, Gorzelanny C, Huck V, Mess C, Obser T, Schneppenheim R, Fleming I, Schneider MF, Schneider SW
(Siehe online unter https://doi.org/10.1038/s41598-018-28961-2)
