VAMP3 and SNAP23 as Potential Targets for Preventing the Disturbed Flow-Accelerated Thrombus Formation

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 (FeCl 3) 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/cm 2) or pulsatile shear (PS, 12 ± 4 dynes/cm 2). 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 FeCl 3-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.

Combination of Genomic and Transcriptomic Approaches Highlights Vascular and Circadian Clock Components in Multiple Sclerosis

“…The PER3 rs2640909 (Met1037Thr) and rs2640908 (synonymous), not in linkage disequilibrium, were found to predict in arterial tissues the expression levels of the adjacent VAMP3 , involved in synaptic vesicles biology and potential target for preventing disturbed flow-dependent thrombus formation [ 84 ]. The relationship of PER3 variations/circadian clock/MS is supported by a PER3 VNTR polymorphism, found to impact the sleep disturbances in MS [ 85 ].…”

Rictor maintains endothelial integrity under shear stress

“…VE-cadherin is involved in the regulation of VWF protein levels stimulated by LSS. Applying oscillatory shear stress to ECs for 6 h enhanced the exocytosis of VWF, triggering platelet aggregation and thrombosis ( Zhu et al, 2020 ). Nevertheless, the permeability of the blood‒brain barrier in VWF knockout mice was increased, suggesting that VWF negatively regulates vascular endothelial permeability ( Noubade et al, 2008 ).…”

Flow-Responsive Noncoding RNAs in the Vascular System: Basic Mechanisms for the Clinician

“…On the other hand, the overexpression of miR-126 in ECs attenuates TNF-αinduced VCAM-1 expression, reducing leukocyte adhesion to the endothelium [118]. The regulatory proteins Vesicle-Associated Membrane Protein 3 (VAMP3) and Synaptosomal-Associated Protein 23 (SNAP23) are key mediators of vascular dysfunction and associated thrombosis in response to disturbed flow [119]. Both VAPM3 and SNAP23 were recently shown to mediate nonmembrane-bound secretion of miR-126 and its transfer from ECs to VSMCs [120].…”