Disease relevance of Vwf

• With this model, we evaluated thrombus growth in mice lacking von Willebrand factor (vWF) and fibrinogen (Fg), the two key ligands known to mediate platelet adhesion and aggregation [1].
• Cell-adhesion activity of the bovine propolypeptide of von Willebrand factor (pp-vWF) was assessed by means of an in vitro assay with several cell lines of both normal and tumor-cell origin. pp-vWF promoted adhesion and spreading of B16 mouse melanoma cells and G-361 human melanoma cells [2].
• Although increased P-selectin expression and vWF release were also noted during reoxygenation, hypoxia alone (even in the presence of antioxidants) was sufficient to increase WP body exocytosis [3].
• Injection of the anti-FVIII/vWF inhibitor plasma into mice caused a decrease in vWF antigen, in some animals with a complete loss of vWF multimers comparable to severe von Willebrand disease [4].
• In addition, five individual mutations within the leucine-rich repeats of GPIb alpha associated with the bleeding disorder Bernard-Soulier syndrome, that result in dysfunctional vWF binding, were mapped to the model of human GPIb alpha [5].
• VWF knockout (KO) mice did not show significant thrombocytopenia after adenovirus administration [6].

High impact information on Vwf

• Human platelet aggregation induced by vWF or low-dose thrombin was inhibited by PKG inhibitors but enhanced by cGMP [7].
• PKG knockout mice showed impaired platelet responses to vWF or low doses of thrombin and prolonged bleeding time [7].
• Furthermore, a cGMP-enhancing agent, sildenafil, promoted vWF- or thrombin-induced platelet aggregation [7].
• These results indicate that TSP-1 regulates the multimeric size and therefore hemostatic activity of vWF [8].
• A protein disulfide bond reductase in plasma reduces the average multimer size of vWF secreted by endothelial cells [8].

Chemical compound and disease context of Vwf

• Functional characteristics, including vWF release upon histamine stimulation and upregulated expression of VEGF and VEGF type 1 receptor in response to hypoxia, were indistinguishable between the MOMC-derived endothelial-like cells and cultured mature endothelial cells [9].
• Using an intravital microscopy mouse model, it was previously established that vWF plays a critical role in mediating platelet adhesion and thrombus formation following mesenteric arteriolar injury induced by ferric chloride [10].
• Facilitating roles of murine platelet glycoprotein Ib and alphaIIbbeta3 in phosphatidylserine exposure during vWF-collagen-induced thrombus formation [11].

Biological context of Vwf

• Penetrance of VWD is incomplete, and expression of the bleeding phenotype is highly variable [12].
• Interaction between von Willebrand factor (vWF) and glycoprotein Ib (GPIb) stimulates tyrosine kinases and subsequent tyrosine phosphorylation events in human platelets [13].
• Genetic linkage analysis of 104 backcross progeny showed no correlation between vWF antigen level and vWF genotype [14].
• To study the molecular genetics of murine vWD, a portion of the vWF gene surrounding exon 28 was cloned, sequenced, and used to develop two informative DNA sequence polymorphisms for rapid genotyping by DNA polymerase chain reaction [14].
• The epitope for this monoclonal antibody lies in a central 8-kDa portion of pp-vWF, suggesting that this region is important for the cell-adhesion activity [2].

Anatomical context of Vwf

• Lectin binding (Dolichos biflorus agglutinin) was used to identify newly sprouting endothelial cells (angiogenesis), while an antibody to the von Willebrand factor (vWF) was employed to identify endothelial cells in general.(ABSTRACT TRUNCATED AT 400 WORDS)[15]
• Within the endothelium, expression of vWF varies between different vascular beds [16].
• We have previously shown that the human vWF promoter spanning a region between -2182 (relative to the start site of transcription) and the end of the first intron contains information for environmentally responsive, vascular bed-specific expression in the heart, skeletal muscle, and brain [16].
• Expression of the von Willebrand factor (vWF) gene is restricted to the endothelial and megakaryocyte lineages [16].
• Immunofluorescence staining with 2C6 showed the lysosomes, and also elongated structures identified as Weibel-Palade bodies by their shape, distribution, and positive staining with anti-vWF antibodies, CD63 was also found by Western blotting of subcellular fractions highly enriched in Weibel-Palade bodies [17].

Associations of Vwf with chemical compounds

• The cell-adhesion activity was also observed with human pp-vWF and, furthermore, the adhesion to both bovine and human pp-vWF was not affected by a peptide containing the Arg-Gly-Asp sequence while the peptide abolished the cell adhesion to vWF [2].
• In this study, we have built molecular models of the seven leucine-rich repeats of human, canine and mouse GPIb alpha, providing novel insights into the species-specific interaction between human vWF and its receptor [5].
• These findings suggest that a major T-cell epitope in the C2 domain recognized by hemophilic mice is located within the same region that binds to inhibitors, vWF, and activated membranes [18].
• A cluster of Asp and Tyr residues occurs also in a region of the platelet glycoprotein (GP) Ib alpha amino terminal domain known to be critically involved in vWF binding [19].
• We pretreated human aortic endothelial cells with simvastatin for 24 hours, then stimulated the cells with thrombin, and measured the amount of vWF released into the media [20].

Other interactions of Vwf

• Overexpression of Lfng had no effect on mesenchymal cell marker (alpha-sma, vWF, PECAM-1) expression [21].
• However, they did not express mRNA for vascular endothelial-cadherin (VE-cadherin) or von Willebrand factor (vWF), which are markers specific for endothelial cells and mature endothelial cells [22].
• Compared with the aggregation response of wild-type platelets, that of FcR gamma-chain-deficient platelets in response to vWF plus botrocetin was impaired, implying that FcR gamma-chain is required for the full activation of platelets mediated by GPIb [13].
• Co-localization analysis showed that ICAM-1 and VCAM-1 expression increased over endothelial cells (staining positive for von Willebrand factor, vWF) in EAE and that LA decreased the expression levels to that observed in naïve mice [23].
• Protein levels of PECAM-1 and vWF were significantly increased, while protein levels of alpha-SMA were substantially decreased in the shear stress-cultured cells [24].

Analytical, diagnostic and therapeutic context of Vwf

• In addition, immunofluorescence showed abundant granules stained with anti-vWF antibody in the cytoplasm [22].
• CS samples obtained at the start and conclusion of the ischemic period demonstrated an increase in CS vWF antigen (by ELISA) consisting of predominantly high molecular weight multimers (by immunoelectrophoresis) [3].
• An animal model for human type 1 VWD, the RIIIS/J mouse strain, exhibits a prolonged bleeding time and reduced plasma VWF levels [25].
• In in vitro coculture assays, expression of both the transgene and the endogenous vWF gene in cardiac microvascular endothelial cells (CMEC) was upregulated in the presence of cardiac myocytes [26].
• Total vWF antigen (vWF:Ag), free propeptide, and pro-vWF were measured using enzyme-linked immunosorbent assay techniques in blood samples drawn before and after infusion. vWF:Ag increased promptly [27].

References