Von Willebrand Factor: Drug and Drug Target

Meyer, Simon F. De; Maeyer, Bauke De; Deckmyn, Hans; Vanhoorelbeke, Karen

doi:10.2174/187152909787581327

Cited by 26 publications

(20 citation statements)

References 111 publications

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“…These insights provide compelling evidence that inhibition of VWF-mediated platelet adhesion may provide a novel therapeutic option in stroke management. It is encouraging that several antithrombotic compounds blocking VWF-collagen or VWF-GPIb␣ interactions are currently being developed, 15,16 which could have beneficial effects in treatment of stroke. Further studies using ultrahigh-field MRI are necessary to disclose whether and in what time window inhibition of VWF-mediated platelet adhesion results in better cortical reperfusion, as one would expect.…”

Section: Discussionmentioning

confidence: 99%

Binding of von Willebrand Factor to Collagen and Glycoprotein Ibα, But Not to Glycoprotein IIb/IIIa, Contributes to Ischemic Stroke in Mice—Brief Report

Meyer

Schwarz²,

Deckmyn³

et al. 2010

ATVB

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Objective— To unravel crucial von Willebrand factor (VWF) interactions that are detrimental in stroke development. Methods and Results— VWF −/− mice received gene transfer to express mutants of VWF defective either in binding to fibrillar collagen, glycoprotein (GP)Ibα or GPIIb/IIIa, and underwent 60 minutes of transient middle cerebral artery occlusion. In VWF −/− mice reconstituted with VWF mutants defective in binding to collagen or GPIbα, protection against stroke was sustained, whereas VWF lacking the GPIIb/IIIa binding site restored full susceptibility similar to normal VWF. Conclusion— VWF-collagen and VWF-GPIbα (but not VWF-GPIIb/IIIa) interactions are instrumental in thrombus formation after transient middle cerebral artery occlusion, and their inhibition could be a promising target for stroke treatment.

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Section: Discussionmentioning

confidence: 99%

Binding of von Willebrand Factor to Collagen and Glycoprotein Ibα, But Not to Glycoprotein IIb/IIIa, Contributes to Ischemic Stroke in Mice—Brief Report

Meyer

Schwarz²,

Deckmyn³

et al. 2010

ATVB

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“…8͑a͔͒, PLL-HA exhibited higher expression of VWF, VEGFA, and ICAM1 compared to PLL-HP and PLL-CS. VWF is a secreted blood glycoprotein involved in hemostasis [60][61][62] and plays an important role in stopping the bleeding process during blood vessel injury. VEGFA is a key cytokine involved in the regulation of angiogenesis, 63 while ICAM1 is a gene marker for cell migration.…”

Section: Discussionmentioning

confidence: 99%

Adhesion, proliferation, and gene expression profile of human umbilical vein endothelial cells cultured on bilayered polyelectrolyte coatings composed of glycosaminoglycans

et al. 2010

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This study characterized human umbilical vein endothelial cell ͑HUVEC͒ adhesion, proliferation, and gene expression on bilayered polyelectrolyte coatings composed of an outermost layer of glycosaminoglycans ͑hyaluronan, heparin, or chondroitin sulfate͒, with an underlying layer of poly-L-lysine or chitosan. The proportion of cells that adhered to the various polyelectrolyte coatings after 1 and 2 h incubations was quantified by the WST-8 assay. Interchanging poly-L-lysine with chitosan resulted in significant differences in cellular adhesion to the outermost glycosaminoglycan layer after 1 h, but these differences became insignificant after 2 h. The proliferation of HUVEC on the various bilayered polyelectrolyte coatings over 10 days was characterized using the WST-8 assay. Regardless of whether the underlying layer was poly-L-lysine or chitosan, HUVEC proliferation on the hyaluronan outermost layer was significantly less than on heparin or chondroitin sulfate. Additionally, it was observed that there was more proliferation with poly-L-lysine as the underlying layer, compared to chitosan. Subsequently, real-time polymerase chain reaction was used to analyze the expression of seven genes related to adhesion, migration, and endothelial function ͑VWF, VEGFR, VEGFA, endoglin, integrin-␣5, ICAM1, and ICAM2͒ by HUVEC cultured on the various bilayered polyelectrolyte coatings for 3 days. With poly-L-lysine as the underlying layer, biologically significant differences ͑greater than twofold͒ in the expression of VWF, VEGFR, VEGFA, endoglin, and ICAM1 were observed among the three glycosaminoglycans. With chitosan as the underlying layer, all three glycosaminoglycans displayed biologically significant differences in the expression of VWF and VEGFR compared to the chitosan control. CT-HA displayed the highest level of expression of VWF, whereas expression levels of VEGFR were almost similar among the three glycosaminoglycans.

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“…Although the role of VWF and UL-VWF has been clearly demonstrated in arterial thrombosis, 74 the absence of plateletdecorated VWF strings in damaged arterioles of Adamts13 Ϫ/Ϫ mice 41,42,59 suggests that VWF strings, per se, might not contribute to arterial thrombosis, at least in mice. Recently, it was demonstrated in a mouse model that deep vein thrombosis is dependent on VWF.…”

Section: What Is the Physiologic Role Of Vwf Strings?mentioning

confidence: 99%

Unwinding the von Willebrand factor strings puzzle

Ceunynck

Meyer

Vanhoorelbeke

2013

Blood

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Introductionvon Willebrand factor (VWF) strings correspond to ultra-large (UL) VWF multimers that, after secretion from the endothelium, remain anchored to the cell surface. As a result of this tethering and the rheologic forces of flow, these VWF multimers unravel, can bind platelets, and wave in the direction of the blood flow 1 (Figure 1). Since their discovery, platelet-decorated VWF strings have proved fascinating, and yet puzzling entities, with interesting and rather unique characteristics. VWF strings can be extraordinarily long, can be anchored to endothelial cells through a discrete number of attachment sites, contain active platelet binding sites, and are susceptible to specific proteolysis by its regulating protease, ADAMTS13 (a disintegrin-like and metalloprotease domain with thrombospondin type-1 motif, number 13). VWF strings are considered prothrombotic and might therefore contribute to the pathophysiology of thrombotic disorders, such as thrombotic thrombocytopenic purpura (TTP) and arterial thrombosis. In addition, platelet-decorated VWF strings can also provide a reactive surface for leukocytes and parasite-infected red blood cells, which has suggested possible roles in both inflammation and malaria.In this review, we discuss the typical features of these intriguing VWF strings and highlight questions that remain to be resolved and that would provide a better understanding of VWF string biochemistry. VWF strings were first discovered and studied in the absence of ADAMTS13, a situation that does not mimic normal physiologic conditions. In the majority of pathophysiologic conditions, plasma ADAMTS13 activity levels are at most decreased, but very rarely absent. To this end, a discussion on the possible involvement of VWF strings in disease pathology might serve to put VWF string research into perspective. VWF, UL-VWF multimers, and ADAMTS13VWF is the largest biopolymer present in plasma, and consists of multimers ranging in size from 500 to 10 000 kDa, with the largest multimers being the most hemostatically active. 2,3 The building block of these multimers is a mature VWF subunit consisting of D, A, B, C, and CK domains, 4,5 although the domain organization of VWF has recently been reannotated. 6 In circulation, VWF multimers adopt a folded, globular conformation that shields the platelet glycoprotein Ib (GPIb) binding sites in the VWF A1 domain. 7,8 This folding serves to prevent spontaneous binding of platelets to VWF in circulation. However, immobilization of VWF at sites of vascular injury (via the VWF A3-collagen interaction) leads to VWF unfolding in response to the shear forces exerted by the flowing blood. This exposes VWF A1 domains that, in turn, reveal the binding sites for the platelet GPIb receptor. The VWF-GPIb interaction is characterized by a fast association/dissociation rate, which enables platelets to "roll" over the VWF surface and provide the opportunity to establish firm platelet adhesion through the collagen receptors. [9][10][11][12] This adhesion step, which is partic...

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Von Willebrand Factor: Drug and Drug Target

Cited by 26 publications

References 111 publications

Binding of von Willebrand Factor to Collagen and Glycoprotein Ibα, But Not to Glycoprotein IIb/IIIa, Contributes to Ischemic Stroke in Mice—Brief Report

Binding of von Willebrand Factor to Collagen and Glycoprotein Ibα, But Not to Glycoprotein IIb/IIIa, Contributes to Ischemic Stroke in Mice—Brief Report

Adhesion, proliferation, and gene expression profile of human umbilical vein endothelial cells cultured on bilayered polyelectrolyte coatings composed of glycosaminoglycans

Unwinding the von Willebrand factor strings puzzle

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