Smooth Muscle Cell Dynamics in Atherosclerosis

Atherosclerosis is a chronic arterial disease marked by lipid deposition, inflammation and extracellular matrix remodelling. Vascular smooth muscle cells (SMCs) are central actors in both plaque formation and stability. In healthy vessels, SMCs exhibit a contractile phenotype, regulating vascular tone through expression of markers such as α-smooth muscle actin. Under atherogenic stimuli—including oxidised lipids, cytokines and disturbed flow—SMCs undergo phenotypic switching to synthetic, osteogenic, fibroblast-like or macrophage-like states. This plasticity enables intimal migration, proliferation and secretion of matrix components that form the fibrous cap. While controlled SMC activity fortifies plaques, maladaptive transitions can weaken the cap, promote calcification or fuel inflammation. Single-cell analyses have uncovered multiple SMC subpopulations within lesions, each driven by transcriptional regulators such as KLF4 or TEAD1 and influenced by intercellular signals like IL-1β. Given the global burden of cardiovascular disease, targeting SMC dynamics offers promise for stabilising vulnerable plaques and reducing adverse events.

Research from Nature Portfolio

Recent studies have exploited single-cell transcriptomics and lineage tracing to delineate SMC heterogeneity in human and murine atherosclerosis. One investigation demonstrated that a few medial SMC progenitors clonally expand to populate developing plaques, with integrin β3 deficiency enhancing TLR4-driven conversion into macrophage-like cells—unveiling cell-autonomous control of phenotypic fate. Another work mapped macrophage-like SMC subsets in carotid lesions and identified IL-1β/STAT3 crosstalk as a driver of SMC inflammation, adhesion and apoptosis. These findings clarify how SMC-macrophage interactions shape plaque progression and pinpoint molecular pathways amenable to therapeutic modulation.

Smooth Muscle Cell Dynamics in Atherosclerosis publication trend

The graph below shows the total number of articles in smooth muscle cell dynamics in atherosclerosis across all publications each year (not limited to Nature Index journals).

Technical terms

Phenotypic switching: The ability of SMCs to change from a contractile state to alternative functional states under pathological stimuli.

Transdifferentiation: Direct conversion of one differentiated cell type into another, for example SMCs to macrophage-like cells.

Single-cell RNA sequencing: A technique analysing gene expression in individual cells to reveal cellular diversity within tissues.

Lineage tracing: A method that labels and tracks the progeny of specific cells to determine their fate over time.

Fibrous cap: A collagen-rich SMC-and matrix-derived layer that overlies the lipid core of an atherosclerotic plaque, preventing rupture.

Extracellular matrix: A complex network of proteins and polysaccharides that provides structural support and signalling cues to cells.

Macrophage-like phenotype: A state in which SMCs adopt features of macrophages, including surface markers and pro-inflammatory functions.

References

1. Translatome profiling reveals Itih4 as a novel smooth muscle cell–specific gene in atherosclerosis. Cardiovascular Research (2024).
2. ANGPTL4 stabilizes atherosclerotic plaques and modulates the phenotypic transition of vascular smooth muscle cells through KLF4 downregulation. Experimental & Molecular Medicine (2023).
3. TEAD1‐Mediated Trans‐Differentiation of Vascular Smooth Muscle Cells into Fibroblast‐Like Cells Contributes to the Stabilization and Repair of Disrupted Atherosclerotic Plaques. Advanced Science (2024).
4. Integrin beta3 regulates clonality and fate of smooth muscle-derived atherosclerotic plaque cells. Nature Communications (2018).
5. Macrophages regulate vascular smooth muscle cell function during atherosclerosis progression through IL-1β/STAT3 signaling. Communications Biology (2022).