Atherosclerosis is a major constraint to living long and healthy lives in modern societies. It is a chronic disease caused by the accumulation of low-density lipoproteins (LDLs) in the arterial intima, which induces plaque development with progressive accumulation of macrophages, smooth muscle cells (SMCs), fibrous tissue, calcifications, and necrotic debris. After decades of silent development, plaques with necrosis that reach the luminal surface may suddenly rupture, precipitate thrombosis, and cause heart attack or stroke. These complications underlie almost 1/3 of all deaths in the world, and this number is projected to increase as increasing life span puts larger parts of the global population at risk.
Current therapies against atherosclerosis lower LDL and blood pressure, but even optimal current medical therapy is insufficient to completely halt the disease. There is therefore an urgent need to identify alternative targets for anti-atherosclerotic therapy.
In EXPLOSIA, we explore disease mechanisms carried by smooth muscle cells (SMCs) in atherosclerosis. We and others have uncovered a large population of SMCs in plaques, which has escaped detection because the cells completely lose the conventional SMC phenotype. Strikingly, we have found that the entire plaque SMC population derives from only a few founder SMCs that undergo massive clonal expansion and phenotypic modulation during lesion formation. We hypothesize that the balance between the different modulated SMC subtypes and the functions they carry are central to lesion progression.
We address this hypothesis in 3 steps. First, we determine links between SMC subtypes, their gene expression programs, and atherosclerotic disease activity by combining single-cell transcriptomics with novel techniques to alter atherosclerotic disease activity in gene-modified mice and minipigs. Second, we will develop techniques for manipulating genes in modulated plaque SMCs and test the causal role of perturbing SMC subtypes and function for lesion progression. Third, we conduct a comparative analysis of clonal structure in mice, minipigs, and humans.
