Jarad Suha, Gill Govind, Amadi Peter, Gu Hong-Mei, Zhang Da-Wei
The Department of Biochemistry and Group on the Molecular and Cell Biology of Lipids, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.
The Department of Pediatrics and Group on the Molecular and Cell Biology of Lipids, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.
Pharmacol Res. 2025 Aug;218:107833. doi: 10.1016/j.phrs.2025.107833. Epub 2025 Jun 20.
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.
动脉粥样硬化性心血管疾病（ASCVD）是全球死亡和发病的主要原因之一。降脂药物，如他汀类药物和前蛋白转化酶枯草溶菌素/克新9型抑制剂，可有效降低血浆低密度脂蛋白胆固醇水平和ASCVD风险。然而，ASCVD的残余风险仍然很高。因此，迫切需要治疗ASCVD的新策略。血管平滑肌细胞（VSMC）是动脉粥样硬化发生和发展的重要促成因素，超过50%的动脉粥样硬化泡沫细胞起源于VSMC。VSMC的特点是具有可塑性，并能根据动脉粥样硬化病变不断变化的环境改变表型，从内膜增厚的早期阶段到最晚期的动脉粥样硬化病变。然而，VSMC并非独立发挥作用，它们与相邻细胞相互作用，并通过调节蛋白质表达和改变表型来响应周围的生长因子和细胞因子。因此，VSMC在动脉粥样硬化中的主要功能将受到影响，包括细胞外基质（ECM）蛋白的产生和动脉粥样硬化斑块稳定性的维持。在本综述中，我们总结了目前对VSMC在动脉粥样硬化中的认识，重点关注其起源、可塑性、表型转换以及在动脉粥样硬化不同阶段的作用。此外，我们强调了生长因子和细胞因子对动脉粥样硬化中VSMC行为的影响，并讨论了ECM重塑，特别是整合素和基质金属蛋白酶对动脉粥样硬化中VSMC的作用。最后，我们重点介绍了目前针对动脉粥样硬化管理中VSMC的治疗策略和选择。
