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Cleavage by MMP-13 renders VWF unable to bind to collagen but increases its platelet-reactivity

Howes, Joanna-Marie, Knauper, Vera, Malcor, Jean-Daniel and Farndale, Richard W 2020. Cleavage by MMP-13 renders VWF unable to bind to collagen but increases its platelet-reactivity. Journal of Thrombosis and Haemostatis 18 (4) , pp. 942-954. 10.1111/jth.14729

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Abstract

Background Atherosclerotic plaque rupture and subsequent thrombosis underpin thrombotic syndromes. Under inflammatory conditions in the unstable plaque, perturbed endothelial cells secrete von Willebrand Factor (VWF) which, via its interaction with GpIbα, enables platelet rolling across and adherence to the damaged endothelium. Following plaque rupture, VWF and platelets are exposed to subendothelial collagen which supports stable platelet adhesion, activation and aggregation. Plaque‐derived matrix metalloproteinase (MMP)‐13 is also released into the surrounding lumen where it may interact with VWF, collagen and platelets. Objectives We sought to discover whether MMP‐13 can cleave VWF and whether this might regulate its interaction with both collagen and platelets. Methods We have used platelet adhesion assays and whole blood flow experiments assess the effects of VWF cleavage by MMP‐13 on platelet adhesion and thrombus formation. Results Unlike the shear‐dependent cleavage of VWF by ADAMTS13, MMP‐13 is able to cleave VWF under static conditions. Following cleavage by MMP‐13, immobilised VWF cannot bind to collagen but interacts more strongly with platelets, supporting slower platelet rolling in whole blood under shear. Compared with intact VWF, the interaction of cleaved VWF with platelets results in greater GpIbα up‐regulation and P‐selectin expression, and the thrombi formed on cleaved VWF–collagen co‐coatings are larger and more contractile than platelet aggregates on intact VWF‐collagen co‐coatings or on collagen alone. Conclusions Our data suggest a VWF‐mediated role for MMP‐13 in the recruitment of platelets to the site of vascular injury and may provide new insights into the association of MMP‐13 in atherothrombotic and stroke pathologies.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Dentistry
Publisher: Wiley-Blackwell
ISSN: 1538-7933
Date of First Compliant Deposit: 20 January 2020
Date of Acceptance: 30 December 2019
Last Modified: 20 Jan 2021 01:09
URI: http://orca.cf.ac.uk/id/eprint/128819

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