Thromboembolic events secondary to rupture or erosion of advanced atherosclerotic plaques represent the leading cause of death worldwide. However, the mechanisms that regulate plaque stability are poorly understood. Human pathology studies show that lesions containing a high ratio of ACTA2+ to CD68+ cells and a thicker extracellular matrix (ECM)-rich fibrous cap are more stable, but there are major ambiguities regarding the origins and functions of ACTA2+ cells within lesions as well as the mechanisms that regulate their investment and/or retention in the protective fibrous cap. The overall hypothesis of our Leducq Fondation PlaqOmics TransAtlantic Network is that detrimental reprogramming of smooth muscle cells (SMC) and other ACTA2+ fibrous cap cells destabilizes atherosclerotic plaques and that there are critical genetic determinants of coronary artery disease (CAD) risk that act in part by impacting phenotypic transitions of fibrous cap cells. Our ultimate goals are to: 1) define distinct SMC phenotypes within human lesions and how these change as a function of lesion severity and vulnerability for rupture or erosion; and 2) to use complementary human and mouse studies to determine mechanisms by which these cells impact lesion pathogenesis and to identify novel therapeutic targets that promote beneficial (plaque stabilizing) changes in the phenotype of SMC and other ECM-producing lesion cells.
Keywords: animals; atherosclerosis; genetics; humans; mice; smooth muscle.