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Synthesis and Secretion of von Willebrand Factor …

Third is to determine 1) if measuring VWF activity and rates of VWF synthesis?

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In vivo regulation of von Willebrand factor synthesis…

AB - The mechanisms by which Von Willebrand factor (VWF) achieves hemostasis lie in its structure. Whereas low-molecular-weight forms have diminished hemostatic potential, ultralarge VWF (ULVWF) in excess is potentially thrombogenic. VWF comprises many subunits, which themselves comprise many repeated domains/assemblies possessing characteristic function(s). Organization of these domains/assemblies into a multimeric structure effectively links and replicates these functions. Each domain/assembly influences the synthesis, assembly, secretion, or hemostatic potential of plasma VWF. The C-terminal CT/CK domain mediates dimerization of VWF subunits in the endoplasmic reticulum, while the N-terminal D1D2 assemblies catalyzes disulfide binding between juxtaposed D3 assemblies in the trans-Golgi, creating multimers. The pH-sensitive domains (A2-CT/CK) allow ULVWF multimers to orderly pack into tubules that unravel upon secretion into the circulation. Hemodynamic forces regulate the conformation of the A2 domain and thus, its accessibility to proteolytic enzyme(s) that regulate VWF's hemostatic potential. Binding to the VWF D'D3 assemblies stabilizes coagulation factor VIII. The VWF A1 and A3 domains facilitate platelet capture onto exposed collagen(s) at sites of vascular injury. Our deeper understanding of VWF provided through the recent growth in VWF structure-function studies may potentially guide novel therapeutics for clotting or bleeding disorders.

This sialic acid modification is critical for VWF synthesis and activity.

Blood-brain barrier opening is a hallmark pathology of many pathological conditions of the CNS including hypoxia, epilepsy, multiple sclerosis and ischemic stroke.- While it is known that VWF is expressed abundantly by cerebral endothelial cells, very little is known about the role of VWF in general and in the regulation of the BBB in particular. VWF is a glycoprotein that is only synthesized by endothelial cells and megakaryocytes. Endothelial cell-derived VWF is secreted constitutively and stored in Weibel-Palade bodies (WPBs) from where it is released by regulated secretion into the plasma and basement membrane in response to endothelial activation. Interestingly, studies have shown that VWF protein is up-regulated in plasma of patients with neurological conditions as diverse as stroke, severe head injury, cerebral malaria and cerebral venous sinus thrombosis. While it has been published that all of these conditions involve BBB disruption, there has been very little literature examining the potential role of VWF in BBB regulation under pathological conditions. Interestingly, a role for endothelial VWF in regulation of angiogenesis has recently been reported indicating that it may play a role in endothelial biology.

Hematopoietic factor-induced synthesis of von …

Study of plasminogen activator and its inhibitor suggest a decrease of  synthesis during ..

N2 - Fluid shear stress generated by blood flow on arterial wall may play a role in the process of atherosclerosis, not only affecting the mass transport phenomena that take place in blood, but also by modulation of synthesis and secretion of humoral factors released by vascular endothelium that mediate platelet-vessel wall interactions. The present study was designed to investigate whether shear stress, induced by laminar flow, modulates von Willebrand factor [vWF) release from cultured human umbilical vein endothelial cells (HUVEC) and whether this physical stimulation can affect vWF synthesis. Monolayers of HUVEC were exposed to laminar flow of varying magnitude (from 2 to 12 dynes/cm2) using a cone-and-plate device. The release of vWF in cell supernatant and in extracellular matrix by cells exposed to flow or maintained in static conditions was evaluated by enzyme-linked immunosorbent assay. HUVEC exposed tolaminar flow released higher amounts of vWF into the cell supernatant within few hours of exposure and vWF secretion was dependent on shear stress magnitude. vWF released in extracellular matrix was also higher in cell monolayers exposed to shear than in static controls. vWF mRNA expression in HUVEC was not affected by exposure of cells to laminar flow, indicating that shear-induced vWF release reflected enhanced secretion without de novo protein synthesis. Immunofluorescence studies showed that the release of vWF is due to exocytosis from Weibel-Palade bodies, the storage organelles of vWF. These data indicate a novel mechanism by which local hemodynamic shear forces modulate endothelial cell function and may play a role in development of arterial thrombotic events.

AB - Fluid shear stress generated by blood flow on arterial wall may play a role in the process of atherosclerosis, not only affecting the mass transport phenomena that take place in blood, but also by modulation of synthesis and secretion of humoral factors released by vascular endothelium that mediate platelet-vessel wall interactions. The present study was designed to investigate whether shear stress, induced by laminar flow, modulates von Willebrand factor [vWF) release from cultured human umbilical vein endothelial cells (HUVEC) and whether this physical stimulation can affect vWF synthesis. Monolayers of HUVEC were exposed to laminar flow of varying magnitude (from 2 to 12 dynes/cm2) using a cone-and-plate device. The release of vWF in cell supernatant and in extracellular matrix by cells exposed to flow or maintained in static conditions was evaluated by enzyme-linked immunosorbent assay. HUVEC exposed tolaminar flow released higher amounts of vWF into the cell supernatant within few hours of exposure and vWF secretion was dependent on shear stress magnitude. vWF released in extracellular matrix was also higher in cell monolayers exposed to shear than in static controls. vWF mRNA expression in HUVEC was not affected by exposure of cells to laminar flow, indicating that shear-induced vWF release reflected enhanced secretion without de novo protein synthesis. Immunofluorescence studies showed that the release of vWF is due to exocytosis from Weibel-Palade bodies, the storage organelles of vWF. These data indicate a novel mechanism by which local hemodynamic shear forces modulate endothelial cell function and may play a role in development of arterial thrombotic events.

to sixfold increase in vWF synthesis.

Increased nitric oxide synthesis in uraemic platelets is dependent on L-arginine transport via system y(+)L.

When activated, they release over 300 proteins and molecules—some (including chemokines, angiogenic factors, ADP/ATP, coagulation factors) preformed and stored in dense bodies or alpha-granules, others (thromboxane, reactive oxygen species, IL-1b) synthesised upon stimulation[].In addition to secreting these various biologically active factors, activated platelets have also been shown to shed membrane microparticles (MPs)[].

It has been reported that hypoxia induces WPB secretion. To determine the state of endothelial activation in our model of H/R, we analyzed WT mice for plasma VWF antigen levels. Mice that were exposed to 24 hours of hypoxia or 24 hours of hypoxia plus one hour of reoxygenation both showed increased VWF antigen levels when compared to normoxic controls (normoxia: 99.94 ± 5.73 vs. hypoxia: 128.2 ± 12.37 P=0.03; normoxia vs. H/R: 146.2 ± 9.16; P). It is possible that the prolonged period of hypoxia may have enhanced VWF synthesis in addition to its known effect on WPB secretion.

We discuss potential mechanisms through which these intronic SNPs regulate ST3GAL4 biosynthesis and the activity that affects VWF and FVIII.
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    is synthesized by the , the cell from which platelets bud, and fibrinogen is delivered to alpha-granules by ..

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    RESULTS: increased NO synthesis and , as evidenced by increased [3H] production and cGMP accrual, respectively..

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UNIVERSITY OF FLORENCE – Analysis of synthesis of VWF …

N2 - The mechanisms by which Von Willebrand factor (VWF) achieves hemostasis lie in its structure. Whereas low-molecular-weight forms have diminished hemostatic potential, ultralarge VWF (ULVWF) in excess is potentially thrombogenic. VWF comprises many subunits, which themselves comprise many repeated domains/assemblies possessing characteristic function(s). Organization of these domains/assemblies into a multimeric structure effectively links and replicates these functions. Each domain/assembly influences the synthesis, assembly, secretion, or hemostatic potential of plasma VWF. The C-terminal CT/CK domain mediates dimerization of VWF subunits in the endoplasmic reticulum, while the N-terminal D1D2 assemblies catalyzes disulfide binding between juxtaposed D3 assemblies in the trans-Golgi, creating multimers. The pH-sensitive domains (A2-CT/CK) allow ULVWF multimers to orderly pack into tubules that unravel upon secretion into the circulation. Hemodynamic forces regulate the conformation of the A2 domain and thus, its accessibility to proteolytic enzyme(s) that regulate VWF's hemostatic potential. Binding to the VWF D'D3 assemblies stabilizes coagulation factor VIII. The VWF A1 and A3 domains facilitate platelet capture onto exposed collagen(s) at sites of vascular injury. Our deeper understanding of VWF provided through the recent growth in VWF structure-function studies may potentially guide novel therapeutics for clotting or bleeding disorders.

Polypeptide Synthesis - YouTube

Environmental and genetic factors are known to contribute to variations in VWF synthesis, stability, adhesiveness, and clearance, but crucial questions remain.

Von Willebrand factor - Wikipedia

Fluid shear stress generated by blood flow on arterial wall may play a role in the process of atherosclerosis, not only affecting the mass transport phenomena that take place in blood, but also by modulation of synthesis and secretion of humoral factors released by vascular endothelium that mediate platelet-vessel wall interactions. The present study was designed to investigate whether shear stress, induced by laminar flow, modulates von Willebrand factor [vWF) release from cultured human umbilical vein endothelial cells (HUVEC) and whether this physical stimulation can affect vWF synthesis. Monolayers of HUVEC were exposed to laminar flow of varying magnitude (from 2 to 12 dynes/cm2) using a cone-and-plate device. The release of vWF in cell supernatant and in extracellular matrix by cells exposed to flow or maintained in static conditions was evaluated by enzyme-linked immunosorbent assay. HUVEC exposed tolaminar flow released higher amounts of vWF into the cell supernatant within few hours of exposure and vWF secretion was dependent on shear stress magnitude. vWF released in extracellular matrix was also higher in cell monolayers exposed to shear than in static controls. vWF mRNA expression in HUVEC was not affected by exposure of cells to laminar flow, indicating that shear-induced vWF release reflected enhanced secretion without de novo protein synthesis. Immunofluorescence studies showed that the release of vWF is due to exocytosis from Weibel-Palade bodies, the storage organelles of vWF. These data indicate a novel mechanism by which local hemodynamic shear forces modulate endothelial cell function and may play a role in development of arterial thrombotic events.

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