The Transformation of Vascular Smooth Muscle into Macrophages in Atherosclerotic Plaques
Atherosclerosis, the growth of fatty plaques in blood vessel walls, is the largest cause of human mortality. Unstable plaques rupture to block blood vessels to cause a heart attack or stroke, while the narrowing of arteries by plaque contributes to heart failure, dementia, and other conditions. A plaque is in essence a growing macrophage graveyard. Macrophage cells of the innate immune system constantly arrive from the bloodstream, drawn to the plaque, and attempt to repair it. The macrophages are instead overwhelmed by the toxic plaque environment, become inflammatory to call in more macrophages, and die to add their mass to the plaque. The largest plaques also distort the biochemistry of the smooth muscle surrounding blood vessels, and smooth muscle cells transform into macrophages to further accelerate the process of plaque growth - almost a cancer-like mechanism of growth.
Atherosclerosis, the fundamental pathological basis of most cardiovascular diseases which remain the leading cause of global mortality, is driven by both lipid accumulation and dynamic cellular reprogramming within the vessel wall. Central to this process is the remarkable phenotypic plasticity of vascular smooth muscle cells (VSMCs). Far from being terminally differentiated, VSMCs undergo profound transitions from a contractile state to diverse states, including synthetic, macrophage-like, foam cell-like, and fibroblast-like states, which critically influence plaque formation, stability, and rupture.
This review synthesizes the multilayered molecular mechanisms governing VSMC plasticity, encompassing transcriptional networks, epigenetic reprogramming, and microenvironmental cues. Moreover, this review highlights recent breakthroughs enabled by single-cell omics and lineage tracing, that have revealed unprecedented heterogeneity and clonal expansion of VSMCs within atherosclerotic lesions. Furthermore, we explore the translational potential of targeting VSMC plasticity, and discuss emerging strategies, including phenotype-specific modulation, immunotherapy, nanomedicine, and senotherapeutics.
Finally, we outline future directions focused on dynamic regulatory networks, spatial pathophysiology, and the integration of aging biology to advance precision medicine in atherosclerosis. In summary, VSMC phenotypic plasticity is a core mechanism underlying the initiation and progression of atherosclerosis. Precise modulation of this process holds promise for overcoming current therapeutic limitations and driving a paradigm shift toward mechanism-guided personalized therapy for cardiovascular diseases.