Role of Cell and Extracellular Matrix Stiffness in Atherosclerosis: Relevance in Lipid Transportation and Metabolism.

The developing process of atherosclerosis is characterized by disordered lipid transportation and metabolism, which exert detrimental functions in cellular cholesterol homeostasis. With the accumulation of lipids, atherosclerotic plaques exhibit a range of stiffness variations, including soft lipid cores and stiff calcification and fibrous caps. These altered biomechanical environments in arteries give rise to changes in cellular behaviors, such as endocytosis, inflammation, lipid balance, and so on. In addition, the cellular cholesterol concentration also regulates membrane stiffness, resulting in the disrupted lysosomal exocytosis and vesicle trafficking that is closely related to lipid deposition in the plaque. Importantly, the soft area of atherosclerotic plaque, such as lipid core, is crucial for the formation of foam cells and further induces death in surrounding cells, thereby necrotic core and plaque instability. Meanwhile, calcification as the stiff area in advanced atherosclerotic plaque will trigger cholesterol accumulation in vascular smooth muscle cells and increase cell stiffness. This review focuses on the changing landscape of cell and matrix stiffness on vascular cell lipid metabolism and their contribution to the structure and mechanical properties of atherosclerotic plaque.