Role of fluid shear stress in regulating VWF structure, function and related blood disorders.
Role of fluid shear stress in regulating VWF structure, function and related blood disorders.
复制标题
DOI：
10.3233/bir-15061
复制
发表时间：
2015
期刊：
影响因子：
1.1
通讯作者：
Neelamegham S
中科院分区：
文献类型：
--
作者：
Gogia S;Neelamegham S
血管性血友病因子（VWF）是血液中最大的糖蛋白。它通过与血小板和内皮细胞表面受体、其他血液蛋白和细胞外基质组分的结合相互作用，在原发性止血中发挥关键作用。这种蛋白质被发现为一系列重复单元，其通过二硫键连接形成多聚体结构。一旦进入血液，蛋白质多聚体分布就会受到流体剪切力的动态调节，流体剪切力具有两种相反的作用：它促进多个VWF单元的聚集或自结合，同时通过促进蛋白质的力依赖性切割来减少多聚体大小各种蛋白酶，最著名的是ADAMTS 13（一种具有血小板反应蛋白类型重复的去整合素和金属蛋白酶，基序1类型13）。除了这些作用外，流体剪切还控制VWF的溶液和底物固定结构、血小板和底物之间的接触性质以及GpIbα-VWF键的生物力学。这些特征共同调节不同的生理和病理过程，包括正常止血、动脉和静脉血栓形成、血管性血友病、血栓性血小板减少性紫癜和获得性血管性血友病综合征。本文讨论了目前的知识VWF结构功能关系，重点是流体动力学剪切的影响，包括快速的方法来估计这些力量的性质和大小在选定的条件下。它表明，许多研究人员使用溶液和基于基底的剪切装置进行的观察可以在考虑VWF的物理尺寸和在这些不同几何形状中施加的机械力后得到调和。
Von Willebrand factor (VWF) is the largest glycoprotein in blood. It plays a crucial role in primary hemostasis via its binding interaction with platelet and endothelial cell surface receptors, other blood proteins and extra-cellular matrix components. This protein is found as a series of repeat units that are disulfide bonded to form multimeric structures. Once in blood, the protein multimer distribution is dynamically regulated by fluid shear stress which has two opposing effects: it promotes the aggregation or self-association of multiple VWF units, and it simultaneously reduces multimer size by facilitating the force-dependent cleavage of the protein by various proteases, most notably ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type repeats, motif 1 type 13). In addition to these effects, fluid shear also controls the solution and substrate-immobilized structure of VWF, the nature of contact between blood platelets and substrates, and the biomechanics of the GpIbα–VWF bond. These features together regulate different physiological and pathological processes including normal hemostasis, arterial and venous thrombosis, von Willebrand disease, thrombotic thrombocytopenic purpura and acquired von Willebrand syndrome. This article discusses current knowledge of VWF structure–function relationships with emphasis on the effects of hydrodynamic shear, including rapid methods to estimate the nature and magnitude of these forces in selected conditions. It shows that observations made by many investigators using solution and substrate-based shearing devices can be reconciled upon considering the physical size of VWF and the applied mechanical force in these different geometries.