Atherosclerosis remains a major cause of cardiovascular disease. It is well known that the cholesterol accumulated in the macrophage-derived foam cells is the major component of atherosclerotic plaque. However, the growing evidence suggests that about 40% of the total foam cells in the atherosclerotic plaque were vascular smooth muscle cells (VSMCs)-derived. VSMCs are the major cellular components of arterial wall and undergo phenotypic switching from a functional contractile phenotype to a synthetic proliferative phenotype during the development of atherosclerosis. In addition, the surrounding environment of VSMCs within vascular wall changes with alterations in extracellular matrix (ECM) stiffness and composition. The main goal of this study is to test hypothesis that VSMC mechanics undergoes significant changes in response to these surrounding microenvironment alteration in the progression of atherosclerosis. We employed an innovative approach integrating a series of novel experimental approaches and data-driven mathematical models to monitor the real time mechanics of VSMCs isolated from western diet fed apolipoprotein-E knockout (ApoE -/- ) and wild type (WT) mice. The results demonstrated significant differences in the actin cytoskeletal organization and cell mechanics between ApoE -/- VSMCs and WT cells, which may trigger the VSMC migration and contribute to the formation of the arterial plaque. These interesting finding will lead to a novel therapeutic strategy for the pharmaceutical treatment of atherosclerosis by interfering the alteration in VSMC mechanics.