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Endothelial Cell-Derived Von Willebrand Factor, But Not Platelet-Derived, Promotes Atherosclerosis in Apolipoprotein E-Deficient Mice
Journal article   Open access   Peer reviewed

Endothelial Cell-Derived Von Willebrand Factor, But Not Platelet-Derived, Promotes Atherosclerosis in Apolipoprotein E-Deficient Mice

Prakash Doddapattar, Nirav Dhanesha, Mehul R Chorawala, Chandler Tinsman, Manish Jain, Manasa K Nayak, Janice M Staber and Anil K Chauhan
Arteriosclerosis, thrombosis, and vascular biology, Vol.38(3), pp.520-528
03/2018
DOI: 10.1161/ATVBAHA.117.309918
PMCID: PMC5823769
PMID: 29348121
url
https://doi.org/10.1161/ATVBAHA.117.309918View
Published (Version of record) Open Access

Abstract

VWF (von Willebrand factor) 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 transplantation, we generated chimeric Plt-VWF, EC-VWF, and Plt-VWF mice lacking a disintegrin and metalloprotease with thrombospondin type I repeats-13 in platelets and plasma on apolipoprotein E-deficient ( ) background. Controls were chimeric mice transplanted with bone marrow from mice (wild type) and mice transplanted with bone marrow from mice (VWF-knock out). 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-knock out, Plt-VWF, and Plt-VWF mice lacking a disintegrin and metalloprotease with thrombospondin type I repeats-13 exhibited reduced plaque size characterized by smaller necrotic cores, reduced neutrophil and monocytes/macrophages content, decreased MMP9 (matrix metalloproteinase), MMP2, and CX CL1 (chemokine [C-X3-C motif] ligand 1)-positive area, and abundant interstitial collagen ( <0.05 versus wild-type or EC-VWF mice). Atherosclerotic lesion size and composition were comparable between wild-type 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-VWF, but not Plt-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 a disintegrin and metalloprotease with thrombospondin type I repeats-13, both in platelet and plasma, was not sufficient to promote atherosclerosis.
 Bone Marrow Transplantation Leukocytes - pathology Platelet Adhesiveness von Willebrand Diseases - blood Atherosclerosis - genetics Aortic Diseases - blood von Willebrand Factor - genetics Aorta - metabolism Aortic Diseases - metabolism Sinus of Valsalva - metabolism von Willebrand Diseases - metabolism Diet, High-Fat Female Sinus of Valsalva - pathology von Willebrand Diseases - genetics Aortic Diseases - pathology Disease Models, Animal von Willebrand Factor - metabolism Atherosclerosis - pathology Endothelial Cells - metabolism Mice, Inbred C57BL Mice, Knockout, ApoE Plaque, Atherosclerotic Cell Adhesion Atherosclerosis - metabolism ADAMTS13 Protein - metabolism Aorta - pathology Atherosclerosis - blood Aortic Diseases - genetics Animals Blood Platelets - metabolism ADAMTS13 Protein - genetics Endothelial Cells - pathology Leukocytes - metabolism

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