Vascular aging-driven tumor-like transformation of vascular smooth muscle cells in atherosclerotic cardiovascular disease: Mechanisms and therapeutic targets.

Atherosclerotic cardiovascular disease (ASCVD) remains a leading cause of morbidity and mortality, with substantial residual risk persisting despite contemporary lipid-lowering, antithrombotic, and anti-inflammatory therapies. Increasing evidence indicates that vascular smooth muscle cells (VSMCs) actively shape plaque composition, progression, and stability through cellular programs that partially resemble those involved in tumor evolution. Within this framework, tumor-like transformation refers to the convergence of selected pathological features, including genomic instability, clonal selection, phenotypic plasticity, non-mutational state reprogramming, inflammatory microenvironmental remodeling, and pathological angiogenesis, rather than malignant transformation in the strict sense. This review examines vascular aging as an overarching factor that promotes these processes by impairing genomic and epigenetic homeostasis, altering extracellular matrix and mechanical cues, inducing cellular senescence(definition) and senescence-associated secretory activity, and reshaping local selective niches. We then discuss four interconnected mechanisms underlying VSMC tumor-like remodeling: DNA damage accumulation and repair imbalance, epigenetic reprogramming, clonal expansion coupled with multilineage phenotypic plasticity, and pathological microvascular remodeling within the plaque microenvironment. Therapeutic opportunities are considered along three corresponding axes: preservation of DNA damage response and genomic stability, promotion of fibrous cap-associated protective states while restricting harmful clonal and phenotypic trajectories, and lesion-targeted inhibition of intraplaque neovascularization. Although these strategies provide a mechanistic basis for precision plaque stabilization, most supporting evidence remains preclinical. Future studies should define stage- and state-specific therapeutic windows and develop targeted, spatially restricted interventions that account for the cellular and regional heterogeneity of atherosclerotic plaques.