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

Abstract

Objective: 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.

Approach and results: 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 (Apoe^-/-) background. Controls were chimeric Apoe^-/- mice transplanted with bone marrow from Apoe^-/- mice (wild type) and Vwf^-/-Apoe^-/- mice transplanted with bone marrow from Vwf^-/-Apoe^-/- 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 CX₃CL1 (chemokine [C-X3-C motif] ligand 1)-positive area, and abundant interstitial collagen (P<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.

Conclusions: 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.

Keywords: apolipoproteins E; bone marrow; diet, Western; endothelial cells; von Willebrand factor.