Yap C, Mieremet A, de Vries CJM, Micha D, de Waard V. Six shades of vascular smooth muscle cells illuminated by KLF4 (Kruppel‐like factor 4). In addition, this article summarizes several methodologies that have been developed and used to study VSMC phenotypic switching and discusses their respective advantages and limitations. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. Upregulation of key enzymes like GLUT1, HK2, and PFKFB3 provides abundant ATP and metabolic intermediates, supporting migration, proliferation, and ECM synthesis in synthetic VSMCs. These findings suggest that targeting the miR-145/miR-143 axis may provide a potential strategy to prevent Hcy-induced VSMC phenotypic remodeling. In addition, Hcy activated the PI3K/AKT/mTOR signaling pathway by inhibiting miR-145 expression, inducing VSMC proliferation, migration, and transformation to a synthetic phenotype. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

Sorry, a shareable link is not currently available for this article. Changes in the retardation of cells treated with contraction and relaxation chemicals against controls were evaluated at each time point using Steel’s test. At each time point, the cell area, ACell, was measured by manually outlining the shape of the VSMCs in the phase contrast images. Because the retardation in background areas changed with time, a background image was taken just before imaging a cell. Retardations of passage 2 and 12 cells were compared because lower passage VSMCs have a contractile phenotype, while higher passage VSMCs dedifferentiate towards the synthetic phenotype39. VSMCs with the contractile phenotype show a higher retardation than those with the synthetic phenotype, suggesting that retardation can be used to evaluate VSMC phenotype.

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Cholesterol‐induced phenotypic modulation of smooth muscle cells to macrophage/fibroblast‐like cells is driven by an unfolded protein response. Transdifferentiation of mouse aortic smooth muscle cells to a macrophage‐like state after cholesterol loading. Low LAL (lysosomal acid lipase) expression by smooth muscle cells relative to macrophages as a mechanism for arterial foam cell formation. Contribution of intimal smooth muscle cells to cholesterol accumulation and macrophage‐like cells in human atherosclerosis. BMAL1 modulates smooth muscle cells phenotypic switch towards fibroblast‐like cells and stabilizes atherosclerotic plaques by upregulating YAP1.

Synthetic Vsmcs

Furthermore, the contribution of endogenous progenitor cells in the tunica media or adventitia remains to be further verified. In addition, VSMCs are thought to achieve phenotype switching through selective expression of marker genes. In ApoE−/− mice, NFATc1 deletion reduced CD137L-induced neointima formation . Chappell et al. showed that VSMCs-derived cells in the neointima of AS were usually formed by clonal expansion of a few VSMCs in tunica media . Another study showed that VSMC-derived foam cells carried a higher cholesterol burden than leukocyte derived foam cells . A recent study showed that in advanced coronary atherosclerotic plaque, 50% of foam cells express the VSMCs marker ACTA2. A recent lineage tracing experiment exploring the origin of foam cells in AS showed that manifold VSMCs, which should be quiescent in the tunica media, migrated to tunica intima and transform to macrophage-like VSMCs . Since vascular calcification occurs only in arteries but not in veins, it suggests that VSMCs, the specific component of arteries, play an irreplaceable role in arterial calcification.

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This value is larger than the cell retardation measured in the current study, approximately 0.3 nm (Fig. 4h), implying that changes in cell retardation would not be detected in aortic tissue. According to our previous study31, the retardation of aortic tissue with a thickness of 100 µm is approximately 30 nm. This study demonstrates that retardation measurement is useful for evaluating the cell phenotype in VSMCs. Generally, SFs in cells dynamically change their position and structure on this time scale. Figure 2b of the present study shows that retardation increased mainly in the central region upon calyculin A application, implying that retardation is increased by SF contraction. (d–f) Changes in (d) cell retardation, RetCell; (e) cell area, ACell; and (f) total cell retardation, RetCellTotal, with time. (a–c) Typical time-lapse images of retardation of single cells after application of (a) DMEM (control), (b) calyculin A, and (c) Y solution.

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Changes in retardation with time when the chemical reagent was applied to the cell to alter the cellular contraction state. Under the assumption that the refractive index stays constant, retardation measurements provide information on the mechanical state. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice.

A more complete understanding of the role of VSMC phenotype transition and the relative contributions of the different VSMC phenotypes can potentially aid the identification of new therapeutic targets and the development of new drugs that can modulate VSMC phenotypes and inhibit atherosclerosis progression. Studies to date have provided substantial insights into VSMC plasticity and phenotypic switching, and its roles in atherosclerosis. The single‐cell RNA sequencing technique provides transcriptomic data of individual cells and therefore can be applied to identify VSMCs of different types according to their gene expression profiles. In response to the nonspecific expression of Cre recombinase, He et al reported a dual recombinase‐mediated genetic lineage tracing technique.92 The combination of the Dre‐rox recombination system permits rigorous control of potential unintentional Cre‐loxP recombination, effectively improving the accuracy of the traditional Cre‐loxP approach in lineage tracing. The Myh11 transgene is located on the Y chromosome and so this line is unsuitable for studying female mice.

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Shi J, Yang Y, Cheng A, Xu G, He F. Metabolism of vascular smooth muscle cells in vascular diseases. Atherosclerotic plaques are characterized by the accumulation of cholesterol crystals in the arterial wall, a fibrous cap rich in extracellular matrix produced by vascular smooth muscle cells (VSMCs) and infiltration of immune cells (such as monocytes-macrophages, T cells, and mast cells) ooosch casino bonus 3, 4. Photoelasticity-based evaluation of cellular contractile force for phenotypic discrimination of vascular smooth muscle cells. Photoelasticity-based evaluation of cellular contractile force for phenotypic discrimination of vascular smooth muscle cells Coronary artery bypass grafting, intimal hyperplasia, phenotypic switching, vascular smooth muscle cells, vein graft failure Zargham R, Touyz RM, Thibault G. Alpha 8 integrin overexpression in de‐differentiated vascular smooth muscle cells attenuates migratory activity and restores the characteristics of the differentiated phenotype. Generation and comparative analysis of an Itga8‐CreER (T2) mouse with preferential activity in vascular smooth muscle cells. Shioi A, Nishizawa Y, Jono S, Koyama H, Hosoi M, Morii H. Beta‐glycerophosphate accelerates calcification in cultured bovine vascular smooth muscle cells.

Non-coding RNAs, important epigenetic regulators, primarily include microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs). Targeting key molecules within the NF-κB pathway—such as circACTA2 and HMGB1/2—may help preserve the contractile phenotype of VSMCs and offers promising therapeutic strategies for vascular remodeling–related diseases. A variety of stimuli can activate this pathway in VSMCs, promoting their transition to a synthetic phenotype and accelerating pathological remodeling. Elucidating its molecular mechanisms not only enhances our understanding of vascular remodeling but also provides a promising foundation for the development of targeted therapeutic strategies aimed at preventing vascular graft failure and related pathologies. It involves the integration of multiple signaling pathways (MAPK, mTOR, NF-κB, TGF-β) and a complex network of non-coding RNAs (miRNAs, lncRNAs, circRNAs), which collectively orchestrate the transition from a contractile to a synthetic phenotype. The mechanism is initiated by endothelial dysfunction and amplified by the key driver PDGF-BB. A thorough understanding of PDGF-BB–mediated signaling pathways may provide essential theoretical support for the development of targeted therapies to prevent VGF.