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.

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.

Rapamycin (mTOR inhibitor) failed to reverse these changes, indicating a potential role between impaired autophagy mediated by the KLF4-dependent mTOR signaling pathway and the VSMC phenotypic remodeling . Leucine supplementation activates the SIRT1-Foxo1 pathway through the Slc3a2/Slc7a5 transporter, inhibiting the transformation of VSMC to a synthetic phenotype, vascular inflammatory response, and ROS generation during aging . At the same time, single-cell RNA sequencing and microarray analysis found that glutamate metabolism-related enzymes Glutamate-Ammonia Ligase and Glutaminase (GLS) and glutamate receptor subunits GRIA1 and GRIA2 were highly expressed in VSMCs. The latest study found that glutamine and serine as anaplerosis of the TCA cycle increased in unstable plaques . Adipokine stimulation upregulates CD36, a key fatty acid transporter in VSMCs, resulting in enhanced fatty acid uptake and lipid deposition, ERK pathway activation, and subsequent VSMC proliferation and inflammatory responses .

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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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It's time to get truckin' in our range of free truck-driving games! The cookie is updated every time data is sent to the Google Analytics server. Used to determine whether a user is included in an A / B or Multivariate test. This cookie is updated every time new data is sent to the Google Analytics server. Vascular smooth muscle cell metabolic reprogramming and phenotypic remodeling in atherosclerosis. The connection between cellular metabolism and VSMC phenotype presents potential opportunities for therapeutic intervention. The Itga8-Cre/Itga8-CreERT2 model avoids myeloid cell leakage and does not induce the lethal visceral myopathy commonly seen in Myh11-driven models, making it an ideal tool for studying VSMC sex differences and remodeling processes 238, 239. Tagln-Cre and its knock-in variant Tagln-CreKI have been used to study VSMC aging, proliferation, and calcification.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). 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. All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. This approach offers the potential for sustained inhibition and even regression of IH. This shift provides a scientific basis for the advancement of cardiovascular disease therapies. Currently, the primary pharmacological agents include microtubule stabilizers (e.g., paclitaxel-based drugs) and mTOR signaling inhibitors (e.g., rapamycin-based drugs). EDIs, which are buffer solutions developed based on the GALA formula (containing reduced glutathione, L-ascorbic acid, and L-arginine), exhibit antioxidant properties, scavenge free radicals, and support eNOS activity (95, 96).

Macrophage-like Smooth Muscle Cells In Atherosclerosis

PDGF-BB, a key member of the PDGF family, is a peptide growth factor with diverse biological functions. In vitro studies have demonstrated that venous VSMCs are smaller, spindle-shaped, and exhibit enhanced proliferative and migratory potential. Commonly used vascular grafts in CABG include the left internal mammary artery (LIMA), radial artery (RA), and great saphenous vein (GSV). Check if you have access through your login credentials or your institution to get full access on this article. If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Authors of the article cited in the comment will be invited to reply, as appropriate. ELetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Expression and promoter analysis of a highly restricted integrin alpha gene in vascular smooth muscle.

Another significant structural change of vascular aging is the calcification of tunica intima and tunica media. All of them significantly reduced VSMCs stiffness in vivo and in vitro, confirming the possibility of targeting cytoskeletal protein junctions for the treatment of vascular sclerosis . At the same time, ECM degradation also facilitated VSMCs migration and neointimal formation. Contractile VSMCs spontaneously modify their phenotype instantaneously to synthetic phenotype when vascular damage occurs. The interaction between VSMCs and other cell types (such as endothelial cells, macrophages, and lymphocytes) in the complex environment of vascular diseases may involve Notch pathway to regulate VSMCs phenotype, which needs to be further investigated. Given the diversity of miRNAs involved in VSMCs phenotype regulation, we believe that manifold miRNAs that potentially regulate VSMCs phenotype switching remain undiscovered. In general, miRNAs that inhibit VSMCs ossification include miR-542-3p , miR-133a , miR-135a miR-204 , and miR-223-3p , all of which regulate osteogenic switching of VSMCs by directly binding to osteogenic genes or related transcription factors. Early studies have established the importance of miRNAs in vascular calcification, and miRNAs can serve as vascular calcification markers .

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The Landscape Of Vsmcs Phenotypes

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 ooosch slots 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).