Emerging mechanisms to modulate VWF release from endothelial cells
Emerging mechanisms to modulate VWF release from endothelial cells
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DOI：
10.1016/j.biocel.2020.105900
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发表时间：
2021-02-01
影响因子：
4
通讯作者：
Nightingale, Thomas D.
中科院分区：
文献类型：
--
作者：
El-Mansi, Sammy;Nightingale, Thomas D.
激动剂介导的韦伯-帕拉德体的胞吐作用支持内皮对损伤或感染的反应能力。这种重要的反应大部分是由韦伯-帕拉德体的主要成分介导的：超大型糖蛋白血管性血友病因子。在调节WPB胞吐作用后，血管性血友病因子多聚体展开成长的血小板捕获“线”，其引发促止血反应。不能适当地切割血管性血友病因子串导致血栓性血小板减少性紫癜，这是一种以组织缺血和多个微血管闭塞为特征的危及生命的病理。从历史上看，血栓性血小板减少性紫癜的治疗在很大程度上依赖于血浆置换疗法。然而，利妥昔单抗和Caplacizumab在治疗获得性血栓性血小板减少性紫癜中的有效性突出了对病理生理学的见解如何改善血管性血友病因子相关疾病的治疗选择。直接限制从韦伯-帕拉德小体释放的血管性血友病因子具有治疗心血管疾病的潜力。细胞生物学家的目标是绘制WPB的生物合成和分泌途径，以找到新的方法来控制血管性血友病因子的释放。新兴的范例包括调制的韦伯-帕拉德身体大小，贩运和机制的融合。本文就靶向韦伯-帕拉德小体抑制血管性血友病因子释放的前景、进展和挑战作一综述。
Agonist-mediated exocytosis of Weibel-Palade bodies underpins the endothelium's ability to respond to injury or infection. Much of this important response is mediated by the major constituent of Weibel-Palade bodies: the ultra-large glycoprotein von Willebrand factor. Upon regulated WPB exocytosis, von Willebrand factor multimers unfurl into long, platelet-catching 'strings' which instigate the pro-haemostatic response. Accordingly, excessive levels of VWF are associated with thrombotic pathologies, including myocardial infarction and ischaemic stroke.Failure to appropriately cleave von Willebrand Factor strings results in thrombotic thrombocytopenic purpura, a life-threatening pathology characterised by tissue ischaemia and multiple microvascular occlusions. Historically, treatment of thrombotic thrombocytopenic purpura has relied heavily on plasma exchange therapy. However, the demonstrated efficacy of Rituximab and Caplacizumab in the treatment of acquired thrombotic thrombocytopenic purpura highlights how insights into pathophysiology can improve treatment options for von Willebrand factor-related disease. Directly limiting von Willebrand factor release from Weibel-Palade bodies has the potential as a therapeutic for cardiovascular disease. Cell biologists aim to map the WPB biogenesis and secretory pathways in order to find novel ways to control von Willebrand factor release. Emerging paradigms include the modulation of Weibel-Palade body size, trafficking and mechanism of fusion. This review focuses on the promise, progress and challenges of targeting Weibel-Palade bodies as a means to inhibit von Willebrand factor release from endothelial cells.