VSMCs in atherosclerosis: Implications on the role of inflammation and extracellular matrix remodelling

Atherosclerotic cardiovascular disease (ASCVD) is one of the leading causes of mortality and morbidity worldwide. Lipid-lowering drugs, such as statins and proprotein convertase subtilisin/kexin type 9 inhibitors, are effective in reducing plasma low-density lipoprotein cholesterol levels and the risk of ASCVD. However, the residual risk of ASCVD remains very high. Therefore, new strategies to treat ASCVD are urgently needed. Vascular smooth muscle cells (VSMCs) are essential contributors to atherosclerosis development and progression, with more than 50 % of atherosclerotic foam cells originating from VSMCs. VSMCs are characterized by their plasticity and ability to switch phenotype in response to the changing environment of atherosclerotic lesions, starting from the early stage of intimal thickening to the most advanced atherosclerotic lesions. However, VSMCs do not act independently, they interact with neighbouring cells and respond to the surrounding growth factors and cytokines by modulating their protein expression and changing their phenotype. Therefore, the main functions of VSMCs in atherosclerosis will be influenced, including the production of extracellular matrix (ECM) proteins and the maintenance of atherosclerotic plaque stability. In this review, we summarize the current understanding of VSMCs in atherosclerosis, focusing on their origin, plasticity, phenotype switching, and role at different stages of atherosclerosis. Furthermore, we highlight the influence of growth factors and cytokines on VSMC behaviour in atherosclerosis and discuss the role of ECM remodelling, specifically by integrins and matrix metalloproteinases, on VSMCs in atherosclerosis. Finally, we focus on current therapeutic strategies and options to target VSMCs in atherosclerosis management.