Smad3 regulates smooth muscle cell fate and mediates adverse remodeling and calcification of the atherosclerotic plaque

Atherosclerotic plaques consist mostly of smooth muscle cells (SMCs), and genes that influence SMC phenotype can modulate coronary artery disease (CAD) risk. Allelic variation at 15q22.33 has been identified by genome-wide association studies to modify the risk of CAD and is associated with the expression of SMAD3 in SMCs. However, the mechanism by which this gene modifies CAD risk remains poorly understood. Here we show that SMC-specific deletion of Smad3 in a murine atherosclerosis model resulted in greater plaque burden, more outward remodeling and increased vascular calcification. Single-cell transcriptomic analyses revealed that loss of Smad3 altered SMC transition cell state toward two fates: an SMC phenotype that governs both vascular remodeling and recruitment of inflammatory cells as well as a chondromyocyte fate. Together, the findings reveal that Smad3 expression in SMCs inhibits the emergence of specific SMC phenotypic transition cells that mediate adverse plaque features, including outward remodeling, monocyte recruitment and vascular calcification. Cheng et al. show that smooth muscle cell (SMC)-specific deletion of Smad3 influences the fate of de-differentiated SMCs in atherosclerotic plaques in vivo, promoting both a pro-remodeling SMC transition phenotype and expansion of the SMC-derived chondromyocyte population. These cellular changes are associated with increased outward remodeling and plaque calcification.