Abstract
Disturbed blood flow has been recognized to promote platelet aggregation and thrombosis via increasing accumulation of von Willebrand factor (VWF) at the arterial post-stenotic sites. The mechanism underlying the disturbed-flow regulated endothelial VWF production remains elusive. Here we described a mouse model, in which the left external carotid artery (LECA) is ligated to generate disturbed flow in the common carotid artery. Ligation of LECA increased VWF accumulation in the plasma. Carotid arterial thrombosis was induced by ferric chloride (FeCl3) application and the time to occlusion in the ligated vessels was reduced in comparison with the unligated vessels. In vitro, endothelial cells were subjected to oscillatory shear (OS, 0.5 ± 4 dynes/cm2) or pulsatile shear (PS, 12 ± 4 dynes/cm2). OS promoted VWF secretion as well as the cell conditioned media-induced platelet aggregation by regulating the intracellular localization of vesicle-associated membrane protein 3 (VAMP3) and synaptosomal-associated protein 23 (SNAP23). Disruption of vimentin intermediate filaments abolished the OS-induced translocation of SNAP23 to the cell membrane. Knockdown of VAMP3 and SNAP23 reduced the endothelial secretion of VWF. Systemic inhibition of VAMP3 and SNAP23 by treatment of mice with rapamycin significantly ameliorated the FeCl3-induced thrombogenesis, whereas intraluminal overexpression of VAMP3 and SNAP23 aggravated it. Our findings demonstrate VAMP3 and SNAP23 as potential targets for preventing the disturbed flow-accelerated thrombus formation.
Highlights
Arterial thrombosis is thought to initiate with events such as rupture or erosion of atherosclerotic plaques, vessel damage, and dysfunction of vascular endothelium
Based on the flow curve measured by ultrasonography, blood flow fields and hemodynamic parameters such as flow velocity (Figures 1F,G), time-averaged wall shear stress (TAWSS) (Figure 1H), relative residence time (RRT) (Figure 1I) and oscillatory shear index (OSI) (Figure 1J) in the common carotid arteries were calculated by the computational fluid dynamics (CFD) analysis (Figures 1F–J)
Since the low and reverse flow, the lower time average wall shear stress (TAWSS), higher RRT and higher Oscillation Shear Index (OSI) that have been previously suggested as athero-prone parameters appeared in the left common carotid arteries (LCA) (Lee et al, 2009), these results indicated that ligation of left external carotid artery (LECA) causes blood flow disturbance in the common carotid artery
Summary
Arterial thrombosis is thought to initiate with events such as rupture or erosion of atherosclerotic plaques, vessel damage, and dysfunction of vascular endothelium. Plaques become stenotic and can cause progressive obstruction of the arterial lumen, and correspondingly, the local arterial geometries change to result in alteration of the hemodynamic microenvironment (Hyun et al, 2000). Fluid layers may separate from each other as it decelerates downstream of the stenosis to form stagnation zones (with near-zero wall shear stress) and areas of recirculation, resulting in a transition of laminar to disturbed flow (Hyun et al, 2000; Hathcock, 2006). Chaotic flow regime has been recognized to influence vascular endothelial behavior and favors platelet aggregation by increasing accumulation of von Willebrand factor (VWF) at post-stenotic sites (Westein et al, 2013). Appropriate animal models to study the flow-regulated thrombosis formation are ill-defined
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