Abstract
Von Willebrand factor (VWF) is a plasma protein that circulates as an array of multimerized subunits. For decades, VWF has been known as a carrier for FVIII and a key element for the recruitment of platelets to the injured vessel wall, particularly under conditions of rapid blood flow. More recently,
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it has become apparent that VWF is doing more than just that. The aim of my study was to obtain more insight into the in vivo and in vitro behavior of VWF, with regard to its classical haemostatic function as well as its potential contribution to non-haemostasis related processes. In case of vascular injury, subendothelial matrix becomes exposed to the circulation. VWF bound to collagen can recruit platelets interacting with their receptor GPIbα. Platelets decelerate, interact with the matrix and become activated. VWF can subsequently bind to the integrin αIIbβ3, participating in platelet aggregation. The lack of information on the in vivo role of VWF-collagen and VWF-αIIbβ3, interactions lead us to develop a model allowing the transient expression of VWF in VWF-deficient mice by the hydrodynamic delivery of murine VWF cDNA. We showed that the expression of wild-type murine VWF could reverse the bleeding phenotype in VWF-deficient mice whereas GPIbα-binding mutant could not. Surprisingly, expression of collagen-binding or αIIbβ3-binding mutants resulted in a full correction of the bleeding. VWF appeared to be also directly involved in non-heamostatic processes such as metastasis. In vitro, VWF is able to promote adhesion of tumor cells via its RGD sequence. Surprisingly, VWF-deficient mice injected with tumor cells developed more metastases than wild-type mice. The absence of VWF seemed to increase tumor cells survival in the lungs. The potential implication of VWF in inflammation was also investigated. We showed that leukocytes (PMNs and monocytes) were able to adhere to VWF under both static and flow conditions. VWF provides binding sites for leukocyte receptors involved in rolling (P-selectin glycoprotein ligand (PSGL)-1) and stable adhesion (β2-integrins). Apart from participating in leukocyte recruitment, these interactions could potentially be involved in regulation of survival/apoptosis of neutrophils, or VWF clearance. Since PSGL1 and GpIbα share structural resemblance and common ligands such as VWF, we considered the possibility that other GpIbα ligands are able to bind PSGL1 as well. We investigated the potential interaction between PSGL1 and the recently identified GPIbα ligand dimeric β2-glycoprotein I (β2GPI). β2GPI is a major target for auto-antibodies in the Antiphospholipid Syndrome (APS). These antibodies can induce dimerization of β2GPI, which can consequently bind to platelets. PSGL1 bound selectively to the dimeric form of β2GPI in a Zn2+-dependant manner. Neutrophils adhered to dimeric β2GPI under both static and flow conditions. Aside from PSGL1, members of the LDL-Receptor family also participate in this adhesion. Interaction between dimeric β2GPI and neutrophils may contribute to the thrombotic tendency found in APS patients. In conclusion, this study showed that VWF is also involved in non-haemostatic processes such as metastasis and inflammation; illustrating the fact that one component originally identified as part of one biological system may fulfill several tasks.
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