title: ADAMTS13 modulates atherosclerotic plaque progression in mice via a VWF-dependent mechanism.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  We generated triple knockout Adamts13-/-/Vwf-/-/ApoE-/- mice to determine whether ADAMTS13 modulates atherosclerosis through its proteolytic effects on VWF or other potential mechanisms.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Internal Medicine, University of Iowa, Iowa City, IA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Gandhi
authors.forename: A
authors.initials: A
authors.lastname: Ahmad
authors.forename: K M
authors.initials: KM
authors.lastname: Wilson
authors.forename: A K
authors.initials: AK
authors.lastname: Chauhan
mesh_terms: D000071120:ADAMTS13 Protein; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000503:physiopathology*; D018450:Disease Progression; D008666:Metalloendopeptidases / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D014841:von Willebrand Factor / Q000502:physiology*
chemical_list: D001057:Apolipoproteins E; D014841:von Willebrand Factor; C502939:ADAMTS13 protein, mouse; D008666:Metalloendopeptidases; D000071120:ADAMTS13 Protein
keywords: ADAMTS13 protein; atherosclerosis; inflammation; neutrophils; thrombosis; von Willebrand Factor