Endothelial Cell-Derived von Willebrand Factor Is the Major Determinant That Mediates von Willebrand Factor-Dependent Acute Ischemic Stroke by Promoting Postischemic Thrombo-Inflammation.
Endothelial Cell-Derived von Willebrand Factor Is the Major Determinant That Mediates von Willebrand Factor-Dependent Acute Ischemic Stroke by Promoting Postischemic Thrombo-Inflammation.
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DOI：
10.1161/atvbaha.116.307660
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发表时间：
2016-09
期刊：
影响因子：
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通讯作者：
Chauhan AK
中科院分区：
文献类型：
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作者：
Dhanesha N;Prakash P;Doddapattar P;Khanna I;Pollpeter MJ;Nayak MK;Staber JM;Chauhan AK
血管性血友病因子（VWF）是在内皮细胞和巨核细胞中合成的，已知会使卒中结局恶化。体外研究表明，血小板衍生的VWF是从内皮细胞衍生的VWF的生化不同。然而，关于不同VWF库在卒中中的相对贡献知之甚少。使用骨髓移植，我们产生了嵌合血小板衍生的VWF小鼠（Plt-VWF），血小板和血浆中缺乏ADAMTS 13的血小板衍生的VWF小鼠（Plt-VWF/Adamts 13-/-），以及内皮细胞衍生的VWF小鼠（EC-VWF），以确定不同VWF库在中风中的相对贡献。在脑缺血/再灌注损伤模型中，我们发现EC-VWF和WT小鼠之间的梗死面积、缺血后脑内血栓炎症（纤维蛋白（原）沉积、中性粒细胞浸润、IL-1β和TNF-α水平）在损伤内是相当的。Plt-VWF和Plt-VWF/Adamts 13 −/−小鼠之间的血小板大小和缺血后血栓炎症相当，但与EC-VWF和/或WT小鼠相比减少（P<0.05），与Vwf −/−小鼠相比增加（P<0.05）。WT和EC-VWF小鼠对FeCl 3损伤诱导的颈动脉血栓形成的易感性相当，而Plt-VWF和Plt-VWF/Adamts 13 −/−小鼠表现出血栓形成缺陷。尽管大多数受损血管没有闭塞，但随时间推移的斜率显示，与Vwf −/−小鼠相比，Plt-VWF和Plt-VWF/Adamts 13 −/−小鼠的血栓生长速率增加（P<0.05），但与WT或EC-VWF小鼠相比，血栓生长速率降低。血小板源性VWF，无论是否存在ADAMTS 13，都部分促进卒中后VWF依赖性损伤和缺血后血栓炎症。内皮细胞源性VWF是通过促进缺血后血栓炎症介导VWF依赖性缺血性卒中的主要决定因素。
Von Willebrand factor (VWF), which is synthesized in endothelial cells and megakaryocytes, is known to worsen stroke outcome. In vitro studies suggest that platelet-derived VWF is biochemically different from the endothelial cell-derived VWF. However, little is known about relative contribution of different pools of VWF in stroke. Using bone marrow transplantation, we generated chimeric platelet derived-VWF mice (Plt-VWF), platelet derived-VWF mice that lack ADAMTS13 in platelets and plasma (Plt-VWF/Adamts13−/−), and endothelial cell derived-VWF mice (EC-VWF) to determine relative contribution of different pools of VWF in stroke. In brain ischemia/reperfusion injury model, we found that infarct size, post-ischemic intracerebral thrombo-inflammation (fibrin(ogen) deposition, neutrophil infiltration, IL-1β and TNF-α levels) within lesions were comparable between EC-VWF and WT mice. Infarct size and post-ischemic thrombo-inflammation were comparable between Plt-VWF and Plt-VWF/Adamts13−/− mice, but decreased compared to EC-VWF and/or WT mice (P<0.05) and increased compared to Vwf −/− mice (P<0.05). Susceptibility to FeCl3 injury-induced carotid artery thrombosis was comparable between WT and EC-VWF mice, whereas Plt-VWF and Plt-VWF/Adamts13−/− mice exhibited defective thrombosis. Although most of the injured vessels did not occlude, slope over time showed that thrombus growth rate was increased in both Plt-VWF and Plt-VWF/Adamts13−/− mice compared to Vwf −/− mice (P<0.05), but decreased compared to WT or EC-VWF mice. Platelet-derived VWF, either in presence or absence of ADAMTS13, partially contributes to VWF-dependent injury and post-ischemic thrombo-inflammation following stroke. Endothelial cell-derived VWF is the major determinant that mediates VWF-dependent ischemic stroke by promoting post-ischemic thrombo-inflammation.