Abstract 43: The Metalloprotease ADAMTS13 Reduces VWF-Mediated Vascular Inflammation and Early Development of Atherosclerosis in Mice

Background and objective: ADAMTS13 prevents spontaneous thrombosis in the microvasculature by cleaving hyperactive ultra large von Willebrand factor (ULVWF) multimers into smaller and less active forms. Reduced ADAMTS13 activity and increased VWF levels have been described in many diseases associated with systemic inflammation. We hypothesized that, by cleaving ULVWF multimers and/or VWF multimers, ADAMTS13 reduces vascular inflammation and the development of early atherosclerotic plaques. Model and methods: ApoE -/-, Adamts13-/-/ApoE-/-, Adamts13 -/-/ Vwf -/-/ ApoE -/- and Vwf -/-/ApoE -/- mice were fed a high-fat Western diet (20% fat, 0.2% cholesterol) beginning at 6 weeks of age until they were sacrificed at 4 months. Intravital fluorescence microscopy was used to visualize leukocyte adhesion and plaque formation at the carotid sinus. We compared the extent of atherosclerosis in whole aortae, stained with Oil Red O and en face lesion area measured by morphometry, and in the cross section area of the aortic sinus using the VerHoeffs/Van Gieson stain. Inflammatory cells in the aortic lesions were quantitated by immunohistochemistry. Results: Using intravital microscopy, we observed a 4-fold increase ( P <0.001) in leukocyte adhesion and at the carotid sinus of Adamts13-/-/ApoE -/- mice compared with ApoE -/- mice. Interestingly, 100% of the Adamts13-/-/ApoE -/- mice had larger plaque (occluded vessel by ∼70-80 %) at the carotid sinus whereas only 20% of the ApoE- /- mice had plaques that were smaller in size ( P <0.0001). Next, we found that the atherosclerotic lesions in the aorta and aortic sinus of the Adamts13-/-/ApoE-/- mice were not only larger (2-fold, P <0.001) but also more inflammatory (increased neutrophil and macrophage infiltration) with decreased interstitial collagen compared with ApoE -/- mice, suggesting that ADAMTS13 reduces vascular inflammation and subsequent atherosclerotic plaque formation. Adamts13-/-/ApoE -/- mice fed a normal chow diet also demonstrated significantly accelerated atherosclerotic plaque formation compared with ApoE -/- mice. Total cholesterol and triglyceride levels were similar among groups fed high-fat Western or normal chow diets. Finally, atherosclerotic lesions in Adamts13-/-/Vwf-/-/ApoE -/- mice were similar to Vwf-/-/ApoE -/- mice, demonstrating that the accelerated atherosclerosis observed in ADAMTS13-deficient mice is VWF-dependent. Conclusion: These findings reveal a new role for the antithrombotic enzyme ADAMTS13 in reducing VWF-mediated plaque formation during early atherosclerosis.