Endothelial Cell-Derived Von Willebrand Factor, But Not Platelet-Derived, Promotes Atherosclerosis in Apolipoprotein E-Deficient Mice.
Endothelial Cell-Derived Von Willebrand Factor, But Not Platelet-Derived, Promotes Atherosclerosis in Apolipoprotein E-Deficient Mice.
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DOI：
10.1161/atvbaha.117.309918
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发表时间：
2018-03
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：
Doddapattar P;Dhanesha N;Chorawala MR;Tinsman C;Jain M;Nayak MK;Staber JM;Chauhan AK
von Willebrand factor (VWF) is synthesized by endothelial cells and megakaryocytes, and is known to contribute to atherosclerosis. In vitro studies suggest that platelet-derived VWF (Plt-VWF) is biochemically and functionally different from endothelial cell-derived VWF (EC-VWF). We determined the role of different pools of VWF in the pathophysiology of atherosclerosis. Using bone marrow (BM) transplantation, we generated chimeric Plt-VWF, EC-VWF, and Plt-VWF mice lacking ADAMTS13 in platelets and plasma (Plt-VWF/ADAMTS13−/−) on apolipoprotein-deficient (Apoe−/−) background. Controls were chimeric Apoe−/− mice transplanted with BM from Apoe−/− mice (wild-type; WT) and Vwf −/−Apoe−/− mice transplanted with BM from Vwf −/−Apoe−/− mice (VWF-KO). Susceptibility to atherosclerosis was evaluated in whole aortae and cross sections of the aortic sinus in female mice fed a high fat “Western” diet for 14 weeks. VWF-KO, Plt-VWF, and Plt-VWF/ADATS13−/− mice exhibited reduced plaque size characterized by smaller necrotic cores, reduced neutrophil and monocytes/macrophages content, decreased MMP9, MMP2, and CX3CL1-positive area and abundant interstitial collagen (P<0.05 versus WT or EC-VWF mice). Atherosclerotic lesion size and composition was comparable between WT or EC-VWF mice. Together these findings suggest that EC-VWF, but not Plt-VWF, promotes atherosclerosis exacerbation. Furthermore, intravital microscopy experiments revealed that EC-derived VWF, but not Plt-derived VWF, contributes to platelet and leukocyte adhesion under inflammatory conditions at the arterial shear rate. EC-VWF, but not Plt-VWF, contributes to VWF-dependent atherosclerosis by promoting platelet adhesion and vascular inflammation. Plt-VWF even in the absence of ADAMTS13, both in platelet and plasma, was not sufficient to promote atherosclerosis.
