Centre for Microvascular Research, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom.
Centre for Microvascular Research, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom.
Int J Biochem Cell Biol. 2021 Feb;131:105900. doi: 10.1016/j.biocel.2020.105900. Epub 2020 Dec 7.
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.
Weibel-Palade 体的激动剂介导的胞吐作用是内皮细胞对损伤或感染作出反应的能力的基础。这种重要反应的大部分是由 Weibel-Palade 体的主要成分：超大糖蛋白 von Willebrand 因子介导的。在受调节的 WPB 胞吐作用下，von Willebrand 因子多聚体展开成长的、血小板捕获的“字符串”，引发促止血反应。因此，过量的 VWF 与血栓性病理有关，包括心肌梗死和缺血性中风。von Willebrand 因子链不能适当切割会导致血栓性血小板减少性紫癜，这是一种危及生命的病理，其特征是组织缺血和多个微血管阻塞。从历史上看，血栓性血小板减少性紫癜的治疗严重依赖于血浆置换疗法。然而，利妥昔单抗和卡普雷珠单抗在治疗获得性血栓性血小板减少性紫癜中的疗效表明，对病理生理学的认识如何改善 von Willebrand 因子相关疾病的治疗选择。直接限制 Weibel-Palade 体从 Weibel-Palade 体释放具有作为心血管疾病治疗的潜力。细胞生物学家旨在绘制 WPB 生物发生和分泌途径，以寻找控制 von Willebrand 因子释放的新方法。新兴范例包括调节 Weibel-Palade 体的大小、贩运和融合机制。本综述重点介绍了靶向 Weibel-Palade 体作为抑制内皮细胞 von Willebrand 因子释放的一种手段的前景、进展和挑战。
