The various states of von Willebrand factor and their function in physiology and pathophysiology
The various states of von Willebrand factor and their function in physiology and pathophysiology
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DOI：
10.1160/th13-09-0800
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发表时间：
2014-04-01
影响因子：
6.7
通讯作者：
Schneider, Stefan W.
中科院分区：
文献类型：
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作者：
Huck, Volker;Schneider, Matthias F.;Schneider, Stefan W.
血管性血友病因子 (VWF) 与血管壁、血小板或其他界面的特定相互作用强烈依赖于（剪切、诱导的）VVVF 激活。剪切流已被证明可诱导 VWF 的构象转变，但受其热力学状态（状态函数关系）的调节。状态又由 决定！物理（例如血管几何形状）、物理化学（例如 pH）和分子生物学（例如突变体、结合）因素。将既定结果与最新见解相结合，我们重建了 VVVF 生物学及其状态！人类脉管系统从内皮细胞释放到最终降解的功能关系。 VWF 分泌后，内皮锚定和剪切激活的 VWF 多聚体可以快速与周围的胶体（通常与血小板）相互作用。同时，这种 VWF 激活使 ADAMTS13 能够裂解 VWF 多聚体，从而限制 VWF 结合能力。随后的细胞表面解离 1 导致 VWF 弹回球状构象，从而防止 ADAMTS13 进一步降解。这些可溶性 VVVF 多聚体的局部浓度很高，被输送到下游脉管系统，能够立即重新激活和重新聚合，在发炎的内皮、血管损伤或病理性高剪切区域引发胶体结合或 VWF 胶体聚集。关注 VWF 生命周期中的这些功能步骤，不同 VWD 类型的定性和定量缺陷将有助于预防性治疗的更精确的诊断和可靠的风险分层。基本的生物物理学原理具有一般性，这拓宽了对 VWF 和 VWF 相关疾病的生理和病理生理影响的前瞻性研究，并希望对整个现象有更普遍的理解。
The specific interactions of von Willebrand factor (VWF) with the vessel wall, platelets or other interfaces strongly depend on (a shear, induced) VVVF activation. Shear flow has been shown to induce a conformational transition of VWF, but is modulated by its thermodynamic state (state-function relationship). The state in turn is determined by ! physical (e.g. vessel geometry), physico-chemical (e.g. pH) and molecular-biological (e.g. mutants, binding) factors. Combining established results with recent insights, we reconstruct VVVF biology and its state! function relationship from endothelial cell release to final degradation in the human vasculature. After VWF secretion, endothelial-anchored and shear activated VWF multimers can rapidly interact with surrounding colloids, typically with platelets. Simultaneously, this VWF activation enables ADAMTS13 to cleave VWF multimers thereby limiting VWF binding capacity. The subsequent cell-surface dissociation 1 leads to a VWF recoiling to a globular conformation, shielding from further degradation by ADAMTS13. High local concentrations of these soluble VVVF multimers, transported to the downstream vasculature, I are capable for an immediate reactivation and re-polymerisation initiating colloid-binding or VWF-colloid aggregation at the site of inflamed endothelium, vessel injuries or pathological high-shear areas. Focusing on these functional steps in the lifecycle of VWF, its qualitative and quantitative deficiencies in the different VWD types will facilitate more precise diagnostics and reliable risk stratification for prophylactic therapies. The underlying biophysical principles are of general character, which broadens prospective studies on the physiological and pathophysiological impact of VWF and VWF-associated diseases and beares hope for a more universal understanding of an entire class of phenomena.