How lipoproteins shape smooth muscle plasticity and cell state trajectories in atherosclerosis

PURPOSE OF REVIEW: Arterial smooth muscle cells (SMCs) can develop inflammatory and lipid-laden phenotypes during atherogenesis. The SMC lineage also undergoes extensive state transitions that lead to fibromyocyte and osteochondrogenic phenotypes with distinct effects on plaque biology. We review emerging evidence that different lipoprotein populations shape SMC plasticity and cell state trajectories. RECENT FINDINGS: Lowering apolipoprotein B (APOB)-containing lipoproteins (triglyceride-rich lipoproteins, remnant lipoproteins, and LDL) suppresses inflammatory programs in SMCs and selectively depletes fibromyocytes and chondromyocytes while preserving fibrous cap SMCs, whereas aggregated LDL induces a fibromyocyte-derived SMC lipid-laden program. HDL can suppress the SMC lipid-laden transcriptomic program in a mouse model of lesion regression. High levels of triglyceride-rich lipoproteins and their remnants in mouse models of diabetes increase arterial free cholesterol accumulation and broad SMC inflammatory/stress programs that are largely prevented by silencing hepatic apolipoprotein C3 (APOC3). Importantly, specific smooth muscle-lineage cells can be targeted by immunotherapy in a mouse model, reducing atherosclerosis. SUMMARY: Lipoproteins modulate SMC inflammatory and lipid-laden phenotypes and shape cell state trajectories, linking lipoprotein metabolism to SMC remodeling and potential opportunities for smooth muscle-lineage-directed imaging and therapy. Future research is needed to address the clinical implications of this new area of research.