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Phenotypic modulation of intima and media smooth muscle cells in fatal cases of coronary artery lesion. CARMN loss regulates smooth muscle cells and accelerates atherosclerosis in mice. Cholesterol loading reprograms the microRNA‐143/145‐myocardin axis to convert aortic smooth muscle cells to a dysfunctional macrophage‐like phenotype. Fasolo F, Paloschi V, Maegdefessel L. Long non‐coding RNAs at the crossroad of vascular smooth muscle cell phenotypic modulation in atherosclerosis and neointimal formation. Activation of the pluripotency factor OCT4 in smooth muscle cells is atheroprotective.

Zhang P, Guan Y, Chen J, Li X, McConnell BK, Zhou W, Boini KM, Zhang Y. Contribution of p62/SQSTM1 to PDGF‐BB‐induced myofibroblast‐like phenotypic transition in vascular smooth muscle cells lacking Smpd1 gene. Adipocytic differentiation and liver x receptor pathways regulate the accumulation of triacylglycerols in human vascular smooth muscle cells. Feil S, Fehrenbacher B, Lukowski R, Essmann F, Schulze‐Osthoff K, Schaller M, Feil R. Transdifferentiation of vascular smooth muscle cells to macrophage‐like cells during atherogenesis. Extensive proliferation of a subset of differentiated, yet plastic, medial vascular smooth muscle cells contributes to neointimal formation in mouse injury and atherosclerosis models. KLF4‐dependent phenotypic modulation of smooth muscle cells has a key role in atherosclerotic plaque pathogenesis. Regulation of differentiation of vascular smooth muscle cells.

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.

A Standardized Approach For The Isolation Of Vascular Smooth Muscle Cells From Carotid Atherosclerotic Plaques

In recent years, the rapid advancement of single-cell and spatial transcriptomics technologies has provided unprecedented spatiotemporal resolution oosch casino for deciphering the dedifferentiation trajectories of VSMCs. These findings highlight the potential of folic acid and β‑aminoisobutyric acid to regulate VSMC phenotype by balancing amino acid metabolism and inflammation. Folic acid is a key regulator of nucleotide synthesis and methylation reactions. As atherosclerotic plaque formation and lipid deposition intensify, lipid abnormalities progressively emerge as key regulators of mid-to-late-stage phenotypic remodeling. Concurrently, glycolytic byproduct lactate promotes VSMC dedifferentiation by stabilizing HIF-1α, reinforcing the synthetic phenotype. Enhanced glucose metabolism promotes lipid synthesis and activates amino acid metabolism; disrupted lipid metabolism, in turn, negatively regulates glycolysis and amino acid utilization via ROS and ER stress, while amino acid metabolism provides compensatory substrates for impaired glucose and lipid metabolism during energy deficiency.

Adipocyte‐derived factors regulate vascular smooth muscle cells through mineralocorticoid and glucocorticoid receptors. Zhang F, Guo X, Xia Y, Mao L. An update on the phenotypic switching of vascular smooth muscle cells in the pathogenesis of atherosclerosis. Yoshida T, Yamashita M, Hayashi M. Kruppel‐like factor 4 contributes to high phosphate‐induced phenotypic switching of vascular smooth muscle cells into osteogenic cells. Nakahara T, Kawai‐Kowase K, Matsui H, Sunaga H, Utsugi T, Iso T, Arai M, Tomono S, Kurabayashi M. Fibroblast growth factor 23 inhibits osteoblastic gene expression and induces osteoprotegerin in vascular smooth muscle cells. Toll‐like receptor 4 mediated oxidized low‐density lipoprotein‐induced foam cell formation in vascular smooth muscle cells via Src and Sirt1/3 pathway. Burger F, Baptista D, Roth A, da Silva RF, Montecucco F, Mach F, Brandt KJ, Miteva K. NLRP3 inflammasome activation controls vascular smooth muscle cells phenotypic switch in atherosclerosis. Zhang Z, Huang J, Wang Y, Shen W. Transcriptome analysis revealed a two‐step transformation of vascular smooth muscle cells to macrophage‐like cells.

Buffer solutions—such as the University of Wisconsin solution, TiProtec, and He solution—can better maintain ion homeostasis and physiological pH. These solutions provide superior protection of endothelial structure and function compared to AWB and normal saline (93). The proposed protective mechanisms include the preservation of eNOS activity, which is abundantly expressed in the adventitia, and the retention of perivascular adipose tissue markers such as leptin and adiponectin (85, 86). These approaches provide a diversified portfolio for improving vein graft patency. Further elucidation of their roles may not only deepen our understanding of IH but also provide theoretical foundations and therapeutic targets for developing effective intervention strategies. To facilitate comparison and provide an integrated overview of the evidence discussed above, representative studies describing non-coding RNAs-mediated regulation of VSMCs phenotypic switching, including molecular targets and functional consequences, are summarized in Table 2. These molecules participate in the regulation of VSMCs phenotypic switching through intricate molecular mechanisms and play essential roles in the onset and progression of cardiovascular diseases (Figure 2).

Several mouse lines for cell lineage tracing have been developed and used for studying VSMC phenotypic switching. In vitro studies have shown that VSMCs can be de‐differentiated to a myofibroblast‐like VSMC state by stimulating VSMCs with platelet‐derived growth factor and transforming growth factor‐β.21, 54 In vivo studies have suggested that myofibroblast‐like VSMCs are derived from a subset of tenascin C VSMCs recruited from the tunica media.55 Hao et al found a subpopulation of VSMCs in the intima of human atherosclerotic lesions that had reduced or completely lost expression of MYH11 and SMTN, and displayed characteristics of myofibroblasts.50 The myofibroblast cell is phenotypically intermediate between fibroblasts and VSMCs.51 Mechanistically, the study of Pan et al14 suggests that cellular retinoic acid binding protein 2, a transducer of retinoic acid signaling, is a master regulator of vascular cell adhesion molecule 1 and lymphocyte antigen 6 family member C1. Mechanistically, studies have suggested that during atherogenesis, KLF4 mediates VSMC transition from the contractile phenotype to mesenchymal‐like phenotype cells.8, 13, 44 KLF4 inhibits the expression of sex‐determining region Y‐box 9, transient receptor potential cation channel subfamily V member 4, and S100 calcium‐binding protein B. Markers of the contractile phenotype include MYH11 (also known as smooth muscle myosin heavy chain 11), calponin, transgelin (also known as SM22α), myocardin, and α‐smooth muscle actin.11

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.