Department of Biomedical Engineering, University of Texas at Dallas, BSB 12.826, 800 W Campbell Road, Richardson, TX, 75080, USA.
Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, 14850, USA.
Ann Biomed Eng. 2021 Dec;49(12):3425-3437. doi: 10.1007/s10439-021-02881-1. Epub 2021 Nov 3.
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.
巨噬细胞向泡沫细胞的转化及其在动脉内膜中的积累是引发动脉粥样硬化这一多因素炎症性疾病的关键事件。先前的研究将动脉僵硬度与心血管疾病联系起来，并强调了动脉僵硬度作为潜在的早期标志物的应用。然而，就巨噬细胞功能而言，动脉僵硬度与动脉粥样硬化之间的关系尚未得到充分理解。因此，了解巨噬细胞的机械生物学对于阐明其在斑块进展中的作用至关重要。我们探讨了基质硬度如何影响巨噬细胞和泡沫细胞的增殖、巨噬细胞施加的牵引力以及天然和氧化低密度脂蛋白的摄取。结果表明，在初始状态和炎症状态下，硬度都会影响泡沫细胞的增殖。在初始状态下，泡沫细胞在 4 kPa 的聚丙烯酰胺凝胶和玻璃上的增殖速度更快，而在炎症状态下，在玻璃上的增殖速度最快。巨噬细胞和泡沫细胞的牵引力与基质硬度呈正相关。此外，还在经脂多糖+干扰素γ处理的巨噬细胞上对脂蛋白的摄取进行了硬度影响的研究。与较硬的基质相比，在较软的 1 kPa 基质上的细胞对低密度脂蛋白和氧化低密度脂蛋白的摄取明显更高。本研究结果表明，巨噬细胞功能受硬度调节，并有助于更好地理解巨噬细胞和泡沫细胞如何促进动脉粥样硬化斑块的发生和发展。
