Premature cell senescence promotes vascular smooth muscle cell phenotypic modulation in atherosclerosis and after injury

Human atherosclerotic plaque cells display DNA damage that can promote premature cell senescence. Vascular smooth muscle cells (VSMCs) predisposed to senescence promote atherogenesis and features of unstable plaques, and increase injury-induced neointima formation. However, how premature senescence promotes vascular disease is unknown. Two independent in vitro models of VSMC senescence induced a range of modulated VSMC phenotype markers, whose expression domains overlapped with senescence markers in atherosclerotic plaque scRNA-seq datasets of human and mouse VSMCs. Mice expressing a VSMC-restricted mutant telomere protein (TRF2T188A) increased expression of multiple de-differentiation genes in vivo in atherosclerosis and after injury, and pathways associated with extracellular matrix organisation, inflammation and Tgfb response. Trf2T188A VSMCs had defective Tgfb signaling and were resistant to Tgfb-induced re-differentiation. Our results suggest that VSMC senescence promotes atherosclerosis and neointima formation in part by driving inflammation and inhibiting re-differentiation of VSMCs.