ADAMTS7 Promotes Smooth Muscle Cell Foam Cell Expansion in Atherosclerosis

Human genetic studies have repeatedly associated SNPs near the gene ADAMTS7 with atherosclerotic cardiovascular disease. Subsequent investigations in mice demonstrated that ADAMTS7 is proatherogenic, induced in response to vascular injury, and alters smooth muscle cell function. However, the mechanisms governing this function and its relationship to atherosclerosis remain unclear. Here, we report the first conditional Adamts7 transgenic mouse in which the gene can be conditionally overexpressed in smooth muscle cells, mimicking its induction in atherosclerosis. We observed that smooth muscle cell Adamts7 overexpression results in a 3.5-fold increase in peripheral atherosclerosis, coinciding with an expansion of smooth muscle foam cells. RNA sequencing of Adamts7 overexpressed primary smooth muscle cells revealed an upregulation in the expression of lipid uptake genes. Subsequent experiments in primary smooth muscle cells demonstrated that increased Spi1 and Cd36 expression leads to increased smooth muscle cell oxLDL uptake. To uncover ADAMTS7 expression in human disease, we have interrogated the largest scRNA-seq dataset of human carotid atherosclerosis. This analysis discovered that endothelial cells had the highest expression level of ADAMTS7 with lesser expression in smooth muscle cells, fibroblasts, and mast cells. Subsequent conditional knockout studies in smooth muscle cells surprisingly showed no change in atherosclerosis, suggesting redundant expression of this secreted factor in the vessel wall. Finally, mice overexpressing Adamts7 in endothelial cells also exhibit increased atherosclerosis, suggesting that multiple vascular cell types can contribute to ADAMTS7-mediated foam cell expansion. In summary, Adamts7 is expressed by multiple vascular cell types in atherosclerosis, and ADAMTS7 promotes oxLDL uptake in smooth muscle cells, increasing smooth muscle foam cell formation and peripheral atherosclerosis in mice.