Flow-driven assembly of VWF fibres and webs in in vitro microvessels.
Flow-driven assembly of VWF fibres and webs in in vitro microvessels.
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DOI：
10.1038/ncomms8858
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发表时间：
2015-07-30
影响因子：
16.6
通讯作者：
López JA
中科院分区：
文献类型：
--
作者：
Zheng Y;Chen J;López JA
包括血栓性血小板减少性紫癜在内的几种全身性疾病通过内皮激活和小血管血栓性闭塞表现出大部分病理学，通常导致多器官衰竭和死亡。这些疾病的建模受到微脉管系统复杂的三维结构和流动模式的阻碍。在这里，我们采用复杂几何形状的工程微血管来检查内皮激活的病理反应。我们最引人注目的发现是内皮分泌的血管性血友病因子 (VWF) 组装成厚束或复杂网状的能力，具体取决于血管几何形状和流动特征。在直径≤300 μm、具有高剪切应力或强流动加速以及急转弯的容器中装配效果最佳。 VWF 束和网结合血小板、白细胞和红细胞，阻碍血流，有时还会剪切通过的红细胞。我们的研究结果揭示了引发微血管血栓形成的生物物理要求，并提出了微血管疾病发生和进展的机制。 具有复杂几何形状和完整内皮的 3D 微血管可以在体外构建。作者利用这些工程化微血管表明，血液蛋白冯维勒布兰德因子病理网络的生成受到 ADAMTS13 的血管结构、血流和蛋白水解活性的影响。
Several systemic diseases, including thrombotic thrombocytopenic purpura, manifest much of their pathology through activation of endothelium and thrombotic occlusion of small blood vessels, often leading to multi-organ failure and death. Modelling these diseases is hampered by the complex three-dimensional architecture and flow patterns of the microvasculature. Here, we employ engineered microvessels of complex geometry to examine the pathological responses to endothelial activation. Our most striking finding is the capacity of endothelial-secreted von Willebrand factor (VWF) to assemble into thick bundles or complex meshes, depending on the vessel geometry and flow characteristics. Assembly is greatest in vessels of diameter ≤300 μm, with high shear stress or strong flow acceleration, and with sharp turns. VWF bundles and webs bind platelets, leukocytes and erythrocytes, obstructing blood flow and sometimes shearing passing erythrocytes. Our findings uncover the biophysical requirements for initiating microvascular thrombosis and suggest mechanisms for the onset and progression of microvascular diseases. 3D microvessels with complex geometries and intact endothelium can be built in vitro. Using these engineered microvessels, here the authors show that the generation of the pathologic meshwork of the blood protein von Willebrand factor is affected by vessel architecture, flow and the proteolytic activity of ADAMTS13.