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ADAMTS13 modulates atherosclerotic plaque progression in mice via a VWF-dependent mechanism

C Gandhi1, A Ahmad, K M Wilson

  • 1Department of Internal Medicine, University of Iowa, Iowa City, IA, USA.

Journal of Thrombosis and Haemostasis : JTH
|November 23, 2013
PubMed
Abstract

Insights

ADAMTS13 reduces atherosclerosis by cleaving ultra-large von Willebrand factor (ULVWF) multimers. This study shows ADAMTS13

Area of Science:

  • Cardiovascular Biology
  • Hematology
  • Molecular Medicine

Background:

  • ADAMTS13 cleaves ultra-large von Willebrand factor (ULVWF) multimers, reducing their adhesiveness.
  • Previous studies indicated ADAMTS13 reduces atherosclerosis in hypercholesterolemic mice.
  • The precise mechanism by which ADAMTS13 affects atherosclerosis (direct vs. indirect via ULVWF) was unclear.

Purpose of the Study:

  • To investigate whether ADAMTS13 modulates atherosclerosis via its proteolytic activity on von Willebrand factor (VWF).
  • To differentiate between VWF-dependent and independent mechanisms of ADAMTS13 in atherosclerosis.
  • Generated triple knockout mice (Adamts13-/-/Vwf-/-/ApoE-/-) to address these questions.

Main Methods:

  • Utilized a Western diet model in female mice starting at 6 weeks of age.
  • Assessed atherosclerosis extent in aortic sinus cross-sections using Verhoeff-Van Gieson staining.
  • Quantified macrophage and neutrophil infiltration via immunohistochemistry and interstitial collagen using picrosirius red stain.

Main Results:

  • Complete reversal of exacerbated atherosclerosis in triple knockout mice (Adamts13-/-/Vwf-/-/ApoE-/-) compared to Adamts13-/-/ApoE-/- mice.
  • Significantly reduced lesion size, macrophage, and neutrophil infiltration in triple knockout mice, similar to Vwf-/-/ApoE-/- mice.
  • Interstitial collagen content was also significantly reduced in triple knockout mice, comparable to Vwf-/-/ApoE-/- mice; lipid profiles were similar across groups.

Conclusions:

  • ADAMTS13 influences inflammatory plaque progression in hypercholesterolemic mice through a mechanism dependent on VWF.
  • These findings highlight the critical role of the ADAMTS13/VWF axis in the pathophysiology of atherosclerosis.
  • The study provides strong evidence for VWF as a key mediator in ADAMTS13's atheroprotective effects.
Keywords:
ADAMTS13 proteinatherosclerosisinflammationneutrophilsthrombosisvon Willebrand Factor

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