Manuscript handled by: P. H. Reitsma
ADAMTS13 modulates atherosclerotic plaque progression in mice via a VWF-dependent mechanism
Article first published online: 7 FEB 2014
© 2013 International Society on Thrombosis and Haemostasis
Journal of Thrombosis and Haemostasis
Volume 12, Issue 2, pages 255–260, February 2014
How to Cite
ADAMTS13 modulates atherosclerotic plaque progression in mice via a VWF-dependent mechanism. J Thromb Haemost 2014; 12: 255–60., , ,
Final decision: P. H. Reitsma, 12 November 2013
- Issue published online: 7 FEB 2014
- Article first published online: 7 FEB 2014
- Accepted manuscript online: 21 NOV 2013 09:23AM EST
- Manuscript Received: 27 AUG 2013
- American Heart Association. Grant Number: #7520015
- ADAMTS13 protein;
- von Willebrand Factor
ADAMTS13 reduces the adhesiveness of hyperactive ultra-large von Willebrand factor (ULVWF) multimers by cleaving them into smaller, less active multimers. Recently, we and others have demonstrated that ADAMTS13 reduces atherosclerosis in hypercholesteremic apolipoprotein E (ApoE−/−) deficient mice. It is not known whether ADAMTS13 modulates atherosclerosis directly or indirectly by cleaving ULVWF multimers.
We generated triple knockout Adamts13−/−/Vwf−/−/ApoE−/− mice to determine whether ADAMTS13 modulates atherosclerosis through its proteolytic effects on VWF or other potential mechanisms.
Female mice were fed a high-fat Western diet beginning at 6 weeks of age until they were sacrificed at 4 months. We compared the extent of atherosclerosis in the serial cross-sections of the aortic sinus using the Verhoeff-Van Gieson stain. Macrophage and neutrophil infiltration were quantified by immunohistochemistry. Under plain polarized light interstitial collagen content in the serial cross-sections of the aortic sinus was quantified using picrosirius red stain.
Deficiency of VWF in Adamts13−/−/ApoE−/− mice (Adamts13−/−/Vwf−/−/ApoE−/−) completely reversed exacerbated atherosclerosis (P < 0.05 vs. Adamts13−/−/ApoE−/− mice). The lesion size, macrophage and neutrophil infiltration in the aortic sinus of Adamts13−/−/Vwf−/−/ApoE−/− mice were significantly decreased compared with Adamts13−/−/ApoE−/− mice (P < 0.05), but similar to Vwf−/−/ApoE−/− mice. Additionally, interstitial collagen content in the aortic sinus of Adamts13−/−/Vwf−/−/ApoE−/− mice was significantly reduced compared with Adamts13−/−/ApoE−/− mice (P < 0.05), but similar to Vwf−/−/ApoE−/− mice. Total cholesterol and triglyceride levels were similar among groups.
ADAMTS13 modulates inflammatory plaque progression in hypercholesterolemic mice through a VWF-dependent mechanism. These findings provide further evidence on the pathophysiological role for the ADAMTS13/VWF axis in atherosclerosis.