Von Willebrand factor regulates complement on endothelial cells.
Von Willebrand factor regulates complement on endothelial cells.
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DOI：
10.1016/j.kint.2016.03.023
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发表时间：
2016-07
影响因子：
19.6
通讯作者：
Licht C
中科院分区：
文献类型：
--
作者：
Noone DG;Riedl M;Pluthero FG;Bowman ML;Liszewski MK;Lu L;Quan Y;Balgobin S;Schneppenheim R;Schneppenheim S;Budde U;James P;Atkinson JP;Palaniyar N;Kahr WH;Licht C
非典型溶血性尿毒症综合征和血栓性血小板减少性紫癜传统上被认为是独立的实体。补体旁路途径的调节缺陷发生在非典型溶血性尿毒综合征中，血管性血友病因子（VWF）多聚体的裂解缺陷出现在血栓性血小板减少性紫癜中。然而，最近的研究表明，这两个实体是相关的，因为致病途径的缺陷重叠或显示功能性相互作用。在这里，我们调查可能的功能联系的VWF-多聚体和补体系统的内皮细胞。从3名健康个体和2名缺乏VWF的3型血管性血友病患者中获得血液生长内皮细胞（BOEC）。通过经典途径和旁路途径活化的组合和50%正常人血清将细胞暴露于标准化补体激发，导致补体固定至内皮表面。在这些条件下，我们发现了VWF多聚体的预期释放，导致血小板粘附到来自健康个体的BOEC上。重要的是，在来自血管性血友病患者的BOEC中，补体C3 c沉积和细胞毒性比来自正常个体的BOEC更明显。这是特别重要的，因为原代肾小球内皮细胞显示VWF的异质表达模式，VWF丰度总体降低。因此，我们的结果支持VWF-多聚体和补体系统之间的机制联系。然而，我们的研究结果也确定VWF作为一种新的补体调节血管内皮细胞，并表明VWF对内皮细胞和补体介导的损伤具有保护作用。
Atypical hemolytic uremic syndrome and thrombotic thrombocytopenic purpura have traditionally been considered separate entities. Defects in the regulation of the complement alternative pathway occur in atypical hemolytic uremic syndrome, and defects in the cleavage of von Willebrand factor (VWF)-multimers arise in thrombotic thrombocytopenic purpura. However, recent studies suggest that both entities are related as defects in the disease-causing pathways overlap or show functional interactions. Here we investigate the possible functional link of VWF-multimers and the complement system on endothelial cells. Blood outgrowth endothelial cells (BOECs) were obtained from 3 healthy individuals and 2 patients with Type 3 von Willebrand disease lacking VWF. Cells were exposed to a standardized complement challenge via the combination of classical and alternative pathway activation and 50% normal human serum resulting in complement fixation to the endothelial surface. Under these conditions we found the expected release of VWF-multimers causing platelet adhesion onto BOECs from healthy individuals. Importantly, in BOECs derived from patients with von Willebrand disease complement C3c deposition and cytotoxicity were more pronounced than on BOECs derived from normal individuals. This is of particular importance as primary glomerular endothelial cells display a heterogeneous expression pattern of VWF with overall reduced VWF abundance. Thus, our results support a mechanistic link between VWF-multimers and the complement system. However, our findings also identify VWF as a new complement regulator on vascular endothelial cells and suggest that VWF has a protective effect on endothelial cells and complement-mediated injury.
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影响因子：
4.4
作者：
Nakashima, S;Qian, ZP;Baldwin, WM
通讯作者：
Baldwin, WM
影响因子：
4.4
作者：
Barilla-LaBarca, ML;Liszewski, MK;Atkinson, JP
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影响因子：
20.3
作者：
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通讯作者：
Afshar-Kharghan, Vahid
影响因子：
10.4
作者：
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通讯作者：
James, P.
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1
作者：
Kawanami, Oichi;Jin, Enjing;Ferrans, Victor J.
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Ferrans, Victor J.