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.
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 .
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 .
2 Intimal Hyperplasia
Hu CT, Shao YD, Liu YZ, Xiao X, Cheng ZB, Qu SL, Huang L, Zhang C. Oxidative stress in vascular calcification. Epigenetic control of smooth muscle cell differentiation and phenotypic switching in vascular development and disease. Atheroprotective roles of smooth muscle cell phenotypic modulation and the TCF21 disease gene as revealed by single‐cell analysis. Plaque evaluation by ultrasound and transcriptomics reveals BCLAF1 as a regulator of smooth muscle cell lipid transdifferentiation in atherosclerosis. Dichotomous roles of smooth muscle cell‐derived MCP1 (monocyte chemoattractant protein 1) in development of atherosclerosis. Ten‐eleven translocation‐2 (TET2) is a master regulator of smooth muscle cell plasticity.
Malonyl-CoA decarboxylase (MCD) is an endogenous inhibitor of CPT1 and a key regulatory enzyme of FAO . As a result, FAO is suppressed, causing accumulation of intracellular long-chain fatty acids and reduced palmitate oxidation activity, ultimately enhancing VSMC proliferation and migration . In Elovl6-/- mice, the formation of new intima is significantly reduced, the number of Ki-67-positive cells and the expression of α-SMA and SM22α are reduced. The latest study found that Elovl6 co-localizes with α-SMA -positive cells during vascular injury. The energy produced by aerobic glycolysis can be provided by FAO, and the activity of glycolysis is regulated by the feedback of FAO metabolites . In TRAP1-knockout rats, acetyl-CoA and citrate were increased, and the expression levels of senescence markers (P53, P21, and P16) and H4K12la in VSMCs were decreased, while lipid accumulation, plaque area, and necrotic core size in the aorta were reduced . In addition, SM22α can synergistically enhance G6PD activity, stimulate the PPP to increase NADPH production, maintain GSH homeostasis, and promote VSMC proliferation and migration . Immunoprecipitation revealed that the N-terminal domain of G6PD interacts with VDAC1 and competes with ooosch casino ireland Bax for binding to VDAC1, alleviating VSMC apoptosis by reducing VDAC1 oligomerization and maintaining the synthetic phenotype of VSMC .
Additionally, high homoarginine reinforces VSMCs osteogenic transition and vascular calcification given the background of hyperphosphatemia . Whereas, a recent study found that adventitial VSCs did not differentiate into the pathogenic VSMCs in atherosclerosis . Earlier studies believed that tunica adventitia derived mesenchymal-like VSMCs contribute to atherosclerotic plaque growth and CKD-induced vascular calcification . Once vascular injury occurred, VSCs migrate to the tunica media and differentiate into mesenchymal-like VSMCs for repairing . In addition to deriving from contractile VSMCs, Mesenchymal-like VSMCs can also derive from SCA1+ vascular stem cells (VSCs) originally located in the tunica adventitia. The potential plasticity shown by VSMCs is comprehensive and inherent, since VSMCs necessitate high abilities of proliferation, migration, and ECM secretion (such as collagen and elastin) in response to vascular morphogenesis and frequent vascular injury. Whereas, contractile VSMCs spontaneously modify their phenotype instantaneously to a highly synthetic phenotype when the vessel is physically or chemically damaged. In healthy adults, the vast majority of VSMCs are located in tunica media and represent quiescent contractile phenotype.
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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).
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.
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.
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