Role of vascular smooth muscle cell phenotypic switching in plaque progression: A hybrid modeling study

Growing genetic lineage mapping experiments have definitively shown a wide-ranging plasticity of vascular smooth muscle cells (VSMCs) in atherosclerotic plaque and suggested that VSMCs can modulate their phenotypes in response to plaque microenvironment. Here, a multiscale hybrid discrete-continuous (HDC) modeling system is established to investigate the complex role of VSMC phenotypic switching within atherosclerotic lesions. The cellular behaviors of VSMCs and macrophages, including proliferation, migration, phenotypic transformation and necrosis, are determined by cellular automata (CA) rules in discrete model. While the dynamics of plaque microenvironmental factors, such as lipid, extracellular matrix (ECM) and chemokines, are described by continuous reaction-diffusion equations in macroscopy. The simulation results demonstrate how the VSMC activities change the extracellular microenvironment and consequently affect the plaque morphology and stability. The regulation of VSMC phenotypes can affect not only the plaque morphology (necrotic core size and fibrous cap thickness) but also the deposition and distribution of microenvironmental factors (lipoprotein, ECM, and chemokines). In addition, it is found that plaque vulnerability can be inhibited by blocking VSMC transdifferentiation to a macrophage-like state and promoting it to a myofibroblastic phenotype, which suggests that targeting VSMC phenotypic switching could be a potential and promising therapeutic strategy for atherosclerosis.