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A multiphase model of growth factor-regulated atherosclerotic cap formation

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Abstract

Atherosclerosis is characterised by the growth of fatty plaques in the inner artery wall. In mature plaques, vascular smooth muscle cells (SMCs) are recruited from adjacent tissue to deposit a collagenous cap over the fatty plaque core. This cap isolates the thrombogenic plaque content from the bloodstream and prevents the clotting cascade that leads to myocardial infarction or stroke. Despite the protective role of the cap, the mechanisms that regulate cap formation and maintenance are not well understood. It remains unclear why some caps become stable, while others become vulnerable to rupture. We develop a multiphase PDE model with non-standard boundary conditions to investigate collagen cap formation by SMCs in response to diffusible growth factor signals from the endothelium. Platelet-derived growth factor stimulates SMC migration, proliferation and collagen degradation, while transforming growth factor (TGF)-\(\beta \) stimulates SMC collagen synthesis and inhibits collagen degradation. The model SMCs respond haptotactically to gradients in the collagen phase and have reduced rates of migration and proliferation in dense collagenous tissue. The model, which is parameterised using in vivo and in vitro experimental data, reproduces several observations from plaque growth in mice. Numerical and analytical results demonstrate that a stable cap can be formed by a relatively small SMC population and emphasise the critical role of TGF-\(\beta \) in effective cap formation. These findings provide unique insight into the mechanisms that may lead to plaque destabilisation and rupture. This work represents an important step towards the development of a comprehensive in silico plaque model.

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  1. School of Mathematics and Statistics, University of Sydney, Sydney, Australia

    Michael G. Watson, Charlie Macaskill & Mary R. Myerscough

  2. Wolfson Centre for Mathematical Biology, Mathematical Institute, University of Oxford, Oxford, UK

    Helen M. Byrne

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  1. Michael G. Watson
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Michael G. Watson, Charlie Macaskill and Mary R. Myerscough acknowledge funding from an Australian Research Council Discovery Grant (DP160104685).

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Watson, M.G., Byrne, H.M., Macaskill, C. et al. A multiphase model of growth factor-regulated atherosclerotic cap formation. J. Math. Biol. 81, 725–767 (2020). https://doi.org/10.1007/s00285-020-01526-6

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