Molecular imaging of platelet-endothelial interactions and endothelial von Willebrand factor in early and mid-stage atherosclerosis

Chi Young Shim, Ya Ni Liu, Tamara Atkinson, Aris Xie, Ted Foster, Brian P. Davidson, Mackenzie Treible, Yue Qi, José A. López, Adam Munday, Zaverio Ruggeri, Jonathan R. Lindner

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Abstract

Background: Nonthrombotic platelet-endothelial interactions may contribute to atherosclerotic plaque development, although in vivo studies examining mechanism without platelet preactivation are lacking. Using in vivo molecular imaging at various stages of atherosclerosis, we quantified platelet-endothelial interactions and evaluated the contribution of major adhesion pathways. Methods and Results: Mice deficient for the low-density lipoprotein receptor and Apobec-1 were studied as an agedependent model of atherosclerosis at 10, 20, 30, and 40 weeks of age, which provided progressive increase in stage from early fatty streak (10 weeks) to large complex plaques without rupture (40 weeks). Platelet-targeted contrast ultrasound molecular imaging of the thoracic aorta performed with microbubbles targeted to GPIbá demonstrated selective signal enhancement as early as 10 weeks of age. This signal increased progressively with age (almost 8-fold increase from 10 to 40 weeks, analysis of variance P<0.001). Specificity for platelet targeting was confirmed by the reduction in platelettargeted signal commensurate with the decrease in platelet count after immunodepletion with anti-GPIb or anti-CD41 antibody. Inhibition of P-selectin in 20 and 40 weeks atherosclerotic mice resulted in a small (15% to 30%) reduction in platelet signal. Molecular imaging with microbubbles targeted to the A1 domain of von Willebrand factor demonstrated selective signal enhancement at all time points, which did not significantly increase with age. Treatment of 20 and 40 week mice with recombinant ADAMTS13 eliminated platelet and von Willebrand factor molecular imaging signal. Conclusions: Platelet-endothelial interactions occur in early atherosclerosis. These interactions are in part caused by endothelial von Willebrand factor large multimers, which can be reversed with exogenous ADAMTS13.

Original languageEnglish
Article numbere002765
JournalCirculation: Cardiovascular Imaging
Volume8
Issue number7
DOIs
Publication statusPublished - 2015 May 1

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All Science Journal Classification (ASJC) codes

  • Radiology Nuclear Medicine and imaging
  • Cardiology and Cardiovascular Medicine

Cite this

Shim, C. Y., Liu, Y. N., Atkinson, T., Xie, A., Foster, T., Davidson, B. P., Treible, M., Qi, Y., López, J. A., Munday, A., Ruggeri, Z., & Lindner, J. R. (2015). Molecular imaging of platelet-endothelial interactions and endothelial von Willebrand factor in early and mid-stage atherosclerosis. Circulation: Cardiovascular Imaging, 8(7), [e002765]. https://doi.org/10.1161/CIRCIMAGING.114.002765