A rare pre-existing progenitor-like Primed SMC compartment is the dominant inferred source of SMC-derived cellularity in vascular injury and atherosclerosis

Abstract

The contribution of pre-existing smooth muscle cell (SMC) states to vascular lesions remains unresolved. Here we identify a rare, progenitor-like Primed SMC compartment before lesion formation in sham-operated carotid arteries and across Myh11-lineage marked mouse aortic datasets, with a Primed-like counterpart in non-diseased human aorta. Primed SMCs retain SMC identity while combining attenuated contractile programmes with conserved niche-associated (Cd34, Fst, Tnfrsf11b) and matricellular (Vcam1, Thbs1, Timp1) cores, overlaid by vessel-specific developmental signatures (Nrn1, Gdf10, Scx). After carotid ligation and during high-fat diet-induced atherosclerosis in Ldlr-/- and Apoe-/- mice, disease-associated Primed, cycling and fibrochondrocyte populations preferentially map to baseline Primed SMCs, whereas contractile SMCs are depleted as inferred feeder sources. Concordant trajectory, graph-based and cross-dataset analyses support a model in which this pre-existing compartment is the dominant inferred source of SMC-derived lesional cellularity. These findings favour expansion and diversification of the Primed compartment over widespread phenotypic switching of contractile SMCs.