Abstract
BackgroundAtherosclerotic 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. ObjectivesWe sought to discover whether MMP‐13 can cleave VWF and whether this might regulate its interaction with both collagen and platelets. MethodsWe have used platelet adhesion assays and whole blood flow experiments to assess the effects of VWF cleavage by MMP‐13 on platelet adhesion and thrombus formation. ResultsUnlike the shear‐dependent cleavage of VWF by a disintegrin and metalloprotease with thrombospondin motif member 13 (ADAMTS13), MMP‐13 is able to cleave VWF under static conditions. Following cleavage by MMP‐13, immobilized 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 upregulation 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. ConclusionsOur 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.
Highlights
Von Willebrand Factor (VWF) is a large multimeric adhesive glycoprotein selectively produced in megakaryocytes (MKs) and endothelial cells (ECs)[1]
The initial rolling of platelets on von Willebrand Factor (VWF) under shear is mediated largely by its interactions with the glycoprotein-Ibα (GPIbα) subunit of the platelet GPIb-IX-V complex and subsequently with the integrin αIIbβ3. αIIbβ3, the primary platelet fibrinogen receptor, can bind the VWF C4-8 module[26], while glycoprotein GpIbα binds to the A1 domain of VWF, both attached to platelets and immobilised on collagen exposed in the vessel wall[27]
Most matrix metalloproteinase (MMP), have many substrates and here we show that MMP-13 can cleave VWF under static conditions
Summary
Von Willebrand Factor (VWF) is a large multimeric adhesive glycoprotein selectively produced in megakaryocytes (MKs) and endothelial cells (ECs)[1]. MMPs are proteolytic enzymes which mediate the degradation of many extracellular matrix and cell surface proteins, and are secreted as pro–enzymes which are activated following cleavage of the pro–peptide domain. Under inflammatory conditions such as those in the vulnerable plaque, increased MMP-13 expression and release following plaque rupture[6,7,8] brings the MMP into contact with plasma proteins, blood cells and platelets. 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. 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
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