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Inflammation Drives Stiffness Mediated Uptake of Lipoproteins in Primary Human Macrophages and Foam Cell Proliferation

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Abstract

Macrophage to foam cell transition and their accumulation in the arterial intima are the key events that trigger atherosclerosis, a multifactorial inflammatory disease. Previous studies have linked arterial stiffness and cardiovascular disease and have highlighted the use of arterial stiffness as a potential early-stage marker. Yet the relationship between arterial stiffness and atherosclerosis in terms of macrophage function is poorly understood. Thus, it is pertinent to understand the mechanobiology of macrophages to clarify their role in plaque advancement. We explore how substrate stiffness affects proliferation of macrophages and foam cells, traction forces exerted by macrophages and uptake of native and oxidized low-density lipoproteins. We demonstrate that stiffness influences foam cell proliferation under both naïve and inflammatory conditions. Naïve foam cells proliferated faster on the 4 kPa polyacrylamide gel and glass whereas under inflammatory conditions, maximum proliferation was recorded on glass. Macrophage and foam cell traction forces were positively correlated to the substrate stiffness. Furthermore, the influence of stiffness was demonstrated on the uptake of lipoproteins on macrophages treated with lipopolysaccharide + interferon gamma. Cells on softer 1 kPa substrates had a significantly higher uptake of low-density lipoproteins and oxidized low-density lipoproteins compared to stiffer substrates. The results herein indicate that macrophage function is modulated by stiffness and help better understand ways in which macrophages and foam cells could contribute to the development and progression of atherosclerotic plaque.

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Acknowledgments

The authors thank laboratory members Maziyar Keshavarzian, Alyssa Lamberti, Kaylie Kruppa, Dhivya Addula, Julia Mach for their assistance in imaging and FACS experimentation and analysis. We also thank Jacob Henderson from the Flow cytometry Core for helping with the FACS experiments. Lastly, we are extremely grateful to Dr. Adam J. Engler and Jaimie Mayner for providing us with the TimelapseTFMcode for the traction force data analysis.

Funding

This work was supported by the National Heart, Lung, And Blood Institute of the National Institutes of Health (NIH) under award number R01HL136776, and American Heart Association (AHA) under Award No. 17SDG33400239. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or AHA.

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The authors have no conflicts of interest to declare.

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  1. Department of Biomedical Engineering, University of Texas at Dallas, BSB 12.826, 800 W Campbell Road, Richardson, TX, 75080, USA

    Manasvini Ammanamanchi & Heather N. Hayenga

  2. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, 14850, USA

    Melanie Maurer

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Ammanamanchi, M., Maurer, M. & Hayenga, H.N. Inflammation Drives Stiffness Mediated Uptake of Lipoproteins in Primary Human Macrophages and Foam Cell Proliferation. Ann Biomed Eng 49, 3425–3437 (2021). https://doi.org/10.1007/s10439-021-02881-1

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