Skip to main content

Advertisement

Springer Nature Link
Log in

An update on the phenotypic switching of vascular smooth muscle cells in the pathogenesis of atherosclerosis

  • Review
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

Vascular smooth muscle cells (VSMCs) are involved in phenotypic switching in atherosclerosis. This switching is characterized by VSMC dedifferentiation, migration, and transdifferentiation into other cell types. VSMC phenotypic transitions have historically been considered bidirectional processes. Cells can adopt a physiological contraction phenotype or an alternative "synthetic" phenotype in response to injury. However, recent studies, including lineage tracing and single-cell sequencing studies, have shown that VSMCs downregulate contraction markers during atherosclerosis while adopting other phenotypes, including macrophage-like, foam cell, mesenchymal stem-like, myofibroblast-like, and osteochondral-like phenotypes. However, the molecular mechanism and processes regulating the switching of VSMCs at the onset of atherosclerosis are still unclear. This systematic review aims to review the critical outstanding challenges and issues that need further investigation and summarize the current knowledge in this field.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Explore related subjects

Discover the latest articles and news from researchers in related subjects, suggested using machine learning.

Availability of data and materials

Not applicable.

Code availability

Not applicable.

Consent for publication

Not applicable.

Consent to participate

Not applicable.

References

  1. Owens GK, Kumar MS, Wamhoff BR (2004) Molecular regulation of vascular smooth muscle cell differentiation in development and disease. Physiol Rev 84:767–801

    CAS  PubMed  Google Scholar 

  2. Wirka RC, Wagh D, Paik DT, Pjanic M, Nguyen T, Miller CL et al (2019) Atheroprotective roles of smooth muscle cell phenotypic modulation and the TCF21 disease gene as revealed by single-cell analysis. Nat Med 25:1280–1289

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Pan H, Xue C, Auerbach BJ, Fan J, Bashore AC, Cui J et al (2020) Single-cell genomics reveals a novel cell state during smooth muscle cell phenotypic switching and potential therapeutic targets for atherosclerosis in mouse and human. Circulation 142:2060–2075

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Rong JX, Shapiro M, Trogan E, Fisher EA (2003) Transdifferentiation of mouse aortic smooth muscle cells to a macrophage-like state after cholesterol loading. Proc Natl Acad Sci U S A 100:13531–13536

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Feil S, Fehrenbacher B, Lukowski R, Essmann F, Schulze-Osthoff K, Schaller M et al (2014) Transdifferentiation of vascular smooth muscle cells to macrophage-like cells during atherogenesis. Circ Res 115:662–667

    CAS  PubMed  Google Scholar 

  6. Shankman LS, Gomez D, Cherepanova OA, Salmon M, Alencar GF, Haskins RM et al (2015) KLF4-dependent phenotypic modulation of smooth muscle cells has a key role in atherosclerotic plaque pathogenesis. Nat Med 21:628–637

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Allahverdian S, Chehroudi AC, McManus BM, Abraham T, Francis GA (2014) Contribution of intimal smooth muscle cells to cholesterol accumulation and macrophage-like cells in human atherosclerosis. Circulation 129:1551–1559

    CAS  PubMed  Google Scholar 

  8. Vengrenyuk Y, Nishi H, Long X, Ouimet M, Savji N, Martinez FO et al (2015) Cholesterol loading reprograms the microRNA-143/145-myocardin axis to convert aortic smooth muscle cells to a dysfunctional macrophage-like phenotype. Arterioscler Thromb Vasc Biol 35:535–546

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Cochain C, Vafadarnejad E, Arampatzi P, Pelisek J, Winkels H, Ley K et al (2018) Single-cell RNA-seq reveals the transcriptional landscape and heterogeneity of aortic macrophages in murine atherosclerosis. Circ Res 122:1661–1674

    CAS  PubMed  Google Scholar 

  10. Berry DC, Jiang Y, Graff JM (2016) Mouse strains to study cold-inducible beige progenitors and beige adipocyte formation and function. Nat Commun 7:10184

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Long JZ, Svensson KJ, Tsai L, Zeng X, Roh HC, Kong X et al (2014) A smooth muscle-like origin for beige adipocytes. Cell Metab 19:810–820

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Bobryshev YV (2005) Transdifferentiation of smooth muscle cells into chondrocytes in atherosclerotic arteries in situ: implications for diffuse intimal calcification. J Pathol 205:641–650

    PubMed  Google Scholar 

  13. Speer MY, Yang HY, Brabb T, Leaf E, Look A, Lin WL et al (2009) Smooth muscle cells give rise to osteochondrogenic precursors and chondrocytes in calcifying arteries. Circ Res 104:733–741

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Chamley-Campbell J, Campbell GR, Ross R (1979) The smooth muscle cell in culture. Physiol Rev 59:1–61

    CAS  PubMed  Google Scholar 

  15. Bochaton-Piallat ML, Ropraz P, Gabbiani F, Gabbiani G (1996) Phenotypic heterogeneity of rat arterial smooth muscle cell clones. Implications for the development of experimental intimal thickening. Arterioscler Thromb Vasc Biol 16:815–820

    CAS  PubMed  Google Scholar 

  16. Wissler RW (1967) The arterial medial cell, smooth muscle, or multifunctional mesenchyme? Circulation 36:1–4

    CAS  PubMed  Google Scholar 

  17. Andreeva ER, Pugach IM, Orekhov AN (1997) Subendothelial smooth muscle cells of human aorta express macrophage antigen in situ and in vitro. Atherosclerosis 135:19–27

    CAS  PubMed  Google Scholar 

  18. Bobryshev YV, Killingsworth MC, Lord RS (2008) Spatial distribution of osteoblast-specific transcription factor Cbfa1 and bone formation in atherosclerotic arteries. Cell Tissue Res 333:225–235

    CAS  PubMed  Google Scholar 

  19. Jiang H, Lun Y, Wu X, Xia Q, Zhang X, Xin S et al (2014) Association between the hypomethylation of osteopontin and integrin beta3 promoters and vascular smooth muscle cell phenotype switching in great saphenous varicose veins. Int J Mol Sci 15:18747–18761

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Chamley JH, Groschel-Stewart U, Campbell GR, Burnstock G (1977) Distinction between smooth muscle, fibroblasts and endothelial cells in culture by the use of fluoresceinated antibodies against smooth muscle actin. Cell Tissue Res 177:445–457

    CAS  PubMed  Google Scholar 

  21. Skalli O, Ropraz P, Trzeciak A, Benzonana G, Gillessen D, Gabbiani G (1986) A monoclonal antibody against alpha-smooth muscle actin: a new probe for smooth muscle differentiation. J Cell Biol 103:2787–2796

    CAS  PubMed  Google Scholar 

  22. Wu SS, Lee JH, Koo BK (2019) Lineage tracing: computational reconstruction goes beyond the limit of imaging. Mol Cells 42:104–112

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Feil S, Hofmann F, Feil R (2004) SM22alpha modulates vascular smooth muscle cell phenotype during atherogenesis. Circ Res 94:863–865

    CAS  PubMed  Google Scholar 

  24. Gomez D, Shankman LS, Nguyen AT, Owens GK (2013) Detection of histone modifications at specific gene loci in single cells in histological sections. Nat Methods 10:171–177

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Albarrán-Juárez J, Kaur H, Grimm M, Offermanns S, Wettschureck N (2016) Lineage tracing of cells involved in atherosclerosis. Atherosclerosis 251:445–453

    PubMed  Google Scholar 

  26. Chappell J, Harman JL, Narasimhan VM, Yu H, Foote K, Simons BD et al (2016) Extensive proliferation of a subset of differentiated, yet plastic, medial vascular smooth muscle cells contributes to neointimal formation in mouse injury and atherosclerosis models. Circ Res 119:1313–1323

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Jacobsen K, Lund MB, Shim J, Gunnersen S, Füchtbauer EM, Kjolby M et al (2017) Diverse cellular architecture of atherosclerotic plaque derives from clonal expansion of a few medial SMCs. JCI Insight. https://doi.org/10.1172/jci.insight.95890

    Article  PubMed  PubMed Central  Google Scholar 

  28. Misra A, Feng Z, Chandran RR, Kabir I, Rotllan N, Aryal B et al (2018) Integrin beta3 regulates clonality and fate of smooth muscle-derived atherosclerotic plaque cells. Nat Commun 9:2073

    PubMed  PubMed Central  Google Scholar 

  29. Dobnikar L, Taylor AL, Chappell J, Oldach P, Harman JL, Oerton E et al (2018) Disease-relevant transcriptional signatures identified in individual smooth muscle cells from healthy mouse vessels. Nat Commun 9:4567

    PubMed  PubMed Central  Google Scholar 

  30. Bentzon JF, Sondergaard CS, Kassem M, Falk E (2007) Smooth muscle cells healing atherosclerotic plaque disruptions are of local, not blood, origin in apolipoprotein E knockout mice. Circulation 116:2053–2061

    CAS  PubMed  Google Scholar 

  31. Bentzon JF, Weile C, Sondergaard CS, Hindkjaer J, Kassem M, Falk E (2006) Smooth muscle cells in atherosclerosis originate from the local vessel wall and not circulating progenitor cells in ApoE knockout mice. Arterioscler Thromb Vasc Biol 26:2696–2702

    CAS  PubMed  Google Scholar 

  32. Yu H, Stoneman V, Clarke M, Figg N, Xin HB, Kotlikoff M et al (2011) Bone marrow-derived smooth muscle-like cells are infrequent in advanced primary atherosclerotic plaques but promote atherosclerosis. Arterioscler Thromb Vasc Biol 31:1291–1299

    CAS  PubMed  Google Scholar 

  33. Sata M, Saiura A, Kunisato A, Tojo A, Okada S, Tokuhisa T et al (2002) Hematopoietic stem cells differentiate into vascular cells that participate in the pathogenesis of atherosclerosis. Nat Med 8:403–409

    CAS  PubMed  Google Scholar 

  34. Caplice NM, Bunch TJ, Stalboerger PG, Wang S, Simper D, Miller DV et al (2003) Smooth muscle cells in human coronary atherosclerosis can originate from cells administered at marrow transplantation. Proc Natl Acad Sci U S A 100:4754–4759

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Naik V, Leaf EM, Hu JH, Yang HY, Nguyen NB, Giachelli CM et al (2012) Sources of cells that contribute to atherosclerotic intimal calcification: an in vivo genetic fate mapping study. Cardiovasc Res 94:545–554

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Speer MY, Li X, Hiremath PG, Giachelli CM (2010) Runx2/Cbfa1, but not loss of myocardin, is required for smooth muscle cell lineage reprogramming toward osteochondrogenesis. J Cell Biochem 110:935–947

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Durham AL, Speer MY, Scatena M, Giachelli CM, Shanahan CM (2018) Role of smooth muscle cells in vascular calcification: implications in atherosclerosis and arterial stiffness. Cardiovasc Res 114:590–600

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Kim JB, Zhao Q, Nguyen T, Pjanic M, Cheng P, Wirka R et al (2020) Environment-sensing aryl hydrocarbon receptor inhibits the chondrogenic fate of modulated smooth muscle cells in atherosclerotic lesions. Circulation 142:575–590

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Saliba AE, Westermann AJ, Gorski SA, Vogel J (2014) Single-cell RNA-seq: advances and future challenges. Nucleic Acids Res 42:8845–8860

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Kaur H, Carvalho J, Looso M, Singh P, Chennupati R, Preussner J et al (2017) Single-cell profiling reveals heterogeneity and functional patterning of GPCR expression in the vascular system. Nat Commun 8:15700

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Alencar GF, Owsiany KM, Karnewar S, Sukhavasi K, Mocci G, Nguyen AT et al (2020) Stem cell pluripotency genes Klf4 and Oct4 regulate complex SMC phenotypic changes critical in late-stage atherosclerotic lesion pathogenesis. Circulation 142:2045–2059

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Xie Y, Martin KA (2020) TCF21: flipping the phenotypic switch in SMC. Circ Res 126:530–532

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Kayashima Y, Maeda-Smithies N (2020) Atherosclerosis in different vascular locations unbiasedly approached with mouse genetics. Genes 11:1427

    CAS  PubMed Central  Google Scholar 

  44. Tang J, Wang H, Huang X, Li F, Zhu H, Li Y et al (2020) Arterial Sca1(+) vascular stem cells generate De Novo smooth muscle for artery repair and regeneration. Cell Stem Cell 26:81–96

    CAS  PubMed  Google Scholar 

  45. Dong X, Zhao B, Iacob RE, Zhu J, Koksal AC, Lu C et al (2017) Force interacts with macromolecular structure in activation of TGF-beta. Nature 542:55–59

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Wang X, Hu G, Betts C, Harmon EY, Keller RS, Van De Water L, et al (2011) Transforming growth factor-beta1-induced transcript 1 protein, a novel marker for smooth muscle contractile phenotype, is regulated by serum response factor/myocardin protein. J Biol Chem 286:4189–4199

    Google Scholar 

  47. Li HX, Han M, Bernier M, Zheng B, Sun SG, Su M et al (2010) Kruppel-like factor 4 promotes differentiation by transforming growth factor-beta receptor-mediated Smad and p38 MAPK signaling in vascular smooth muscle cells. J Biol Chem 285:17846–17856

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Zhang X, Xie H, Chang P, Zhao H, Xia Y, Zhang L et al (2019) Glycoprotein M6B interacts with TbetaRI to activate TGF-beta-Smad2/3 signaling and promote smooth muscle cell differentiation. Stem Cells 37:190–201

    CAS  PubMed  Google Scholar 

  49. Wang L, Han Y, Shen Y, Yan ZQ, Zhang P, Yao QP et al (2014) Endothelial insulin-like growth factor-1 modulates proliferation and phenotype of smooth muscle cells induced by low shear stress. Ann Biomed Eng 42:776–786

    PubMed  Google Scholar 

  50. Martin KA, Merenick BL, Ding M, Fetalvero KM, Rzucidlo EM, Kozul CD et al (2007) Rapamycin promotes vascular smooth muscle cell differentiation through insulin receptor substrate-1/phosphatidylinositol 3-kinase/Akt2 feedback signaling. J Biol Chem 282:36112–36120

    CAS  PubMed  Google Scholar 

  51. Lee CK, Lee HM, Kim HJ, Park HJ, Won KJ, Roh HY et al (2007) Syk contributes to PDGF-BB-mediated migration of rat aortic smooth muscle cells via MAPK pathways. Cardiovasc Res 74:159–168

    CAS  PubMed  Google Scholar 

  52. Wang H, Zhong B, Geng Y, Hao J, Jin Q, Zhang Y et al (2021) TIPE2 inhibits PDGF-BB-induced phenotype switching in airway smooth muscle cells through the PI3K/Akt signaling pathway. Respir Res 22:238

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Lu QB, Wan MY, Wang PY, Zhang CX, Xu DY, Liao X et al (2018) Chicoric acid prevents PDGF-BB-induced VSMC dedifferentiation, proliferation and migration by suppressing ROS/NFkappaB/mTOR/P70S6K signaling cascade. Redox Biol 14:656–668

    CAS  PubMed  Google Scholar 

  54. Yellaturu CR, Rao GN (2003) Cytosolic phospholipase A2 is an effector of Jak/STAT signaling and is involved in platelet-derived growth factor BB-induced growth in vascular smooth muscle cells. J Biol Chem 278:9986–9992

    CAS  PubMed  Google Scholar 

  55. Neeli I, Liu Z, Dronadula N, Ma ZA, Rao GN (2004) An essential role of the Jak-2/STAT-3/cytosolic phospholipase A(2) axis in platelet-derived growth factor BB-induced vascular smooth muscle cell motility. J Biol Chem 279:46122–46128

    CAS  PubMed  Google Scholar 

  56. Tang L, Dai F, Liu Y, Yu X, Huang C, Wang Y et al (2018) RhoA/ROCK signaling regulates smooth muscle phenotypic modulation and vascular remodeling via the JNK pathway and vimentin cytoskeleton. Pharmacol Res 133:201–212

    CAS  PubMed  Google Scholar 

  57. Qi Y, Liang X, Dai F, Guan H, Sun J, Yao W (2020) RhoA/ROCK pathway activation is regulated by AT1 receptor and participates in smooth muscle migration and dedifferentiation via promoting actin cytoskeleton polymerization. Int J Mol Sci 21:5398

    CAS  PubMed Central  Google Scholar 

  58. Chen PY, Qin L, Li G, Tellides G, Simons M (2016) Fibroblast growth factor (FGF) signaling regulates transforming growth factor beta (TGFβ)-dependent smooth muscle cell phenotype modulation. Sci Rep 6:33407

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Hynes RO (2002) Integrins: bidirectional, allosteric signaling machines. Cell 110:673–687

    CAS  PubMed  Google Scholar 

  60. Orr AW, Lee MY, Lemmon JA, Yurdagul AJ, Gomez MF, Bortz PD et al (2009) Molecular mechanisms of collagen isotype-specific modulation of smooth muscle cell phenotype. Arterioscler Thromb Vasc Biol 29:225–231

    CAS  PubMed  Google Scholar 

  61. Graf K, Kappert K, Stawowy P, Bokemeyer J, Blaschke F, Schmidt G et al (2003) Statins regulate alpha2beta1-integrin expression and collagen I-dependent functions in human vascular smooth muscle cells. J Cardiovasc Pharmacol 41:89–96

    CAS  PubMed  Google Scholar 

  62. Shi F, Long X, Hendershot A, Miano JM, Sottile J (2014) Fibronectin matrix polymerization regulates smooth muscle cell phenotype through a Rac1 dependent mechanism. PLoS ONE 9:e94988

    PubMed  PubMed Central  Google Scholar 

  63. Ikesue M, Matsui Y, Ohta D, Danzaki K, Ito K, Kanayama M et al (2011) Syndecan-4 deficiency limits neointimal formation after vascular injury by regulating vascular smooth muscle cell proliferation and vascular progenitor cell mobilization. Arterioscler Thromb Vasc Biol 31:1066–1074

    CAS  PubMed  Google Scholar 

  64. Mao C, Ma Z, Jia Y, Li W, Xie N, Zhao G et al (2021) Nidogen-2 maintains the contractile phenotype of vascular smooth muscle cells and prevents neointima formation via bridging Jagged1-Notch3 signaling. Circulation. https://doi.org/10.1161/CIRCULATIONAHA.120.053361

    Article  PubMed  Google Scholar 

  65. Obradovic M, Essack M, Zafirovic S, Sudar-Milovanovic E, Bajic VP, Van Neste C et al (2020) Redox control of vascular biology. BioFactors 46:246–262

    CAS  PubMed  Google Scholar 

  66. Bedard K, Krause KH (2007) The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol Rev 87:245–313

    CAS  PubMed  Google Scholar 

  67. Clempus RE, Griendling KK (2006) Reactive oxygen species signaling in vascular smooth muscle cells. Cardiovasc Res 71:216–225

    CAS  PubMed  Google Scholar 

  68. Lassegue B, Sorescu D, Szocs K, Yin Q, Akers M, Zhang Y et al (2001) Novel gp91(phox) homologues in vascular smooth muscle cells : nox1 mediates angiotensin II-induced superoxide formation and redox-sensitive signaling pathways. Circ Res 88:888–894

    CAS  PubMed  Google Scholar 

  69. Hilenski LL, Clempus RE, Quinn MT, Lambeth JD, Griendling KK (2004) Distinct subcellular localizations of Nox1 and Nox4 in vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 24:677–683

    CAS  PubMed  Google Scholar 

  70. Clempus RE, Sorescu D, Dikalova AE, Pounkova L, Jo P, Sorescu GP et al (2007) Nox4 is required for maintenance of the differentiated vascular smooth muscle cell phenotype. Arterioscler Thromb Vasc Biol 27:42–48

    CAS  PubMed  Google Scholar 

  71. Lee MY, San MA, Mehta PK, Dikalova AE, Garrido AM, Datla SR et al (2009) Mechanisms of vascular smooth muscle NADPH oxidase 1 (Nox1) contribution to injury-induced neointimal formation. Arterioscler Thromb Vasc Biol 29:480–487

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Schroder K, Helmcke I, Palfi K, Krause KH, Busse R, Brandes RP (2007) Nox1 mediates basic fibroblast growth factor-induced migration of vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 27:1736–1743

    PubMed  Google Scholar 

  73. Lyle AN, Deshpande NN, Taniyama Y, Seidel-Rogol B, Pounkova L, Du P et al (2009) Poldip2, a novel regulator of Nox4 and cytoskeletal integrity in vascular smooth muscle cells. Circ Res 105:249–259

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Lu X, Murphy TC, Nanes MS, Hart CM (2010) PPAR{gamma} regulates hypoxia-induced Nox4 expression in human pulmonary artery smooth muscle cells through NF-{kappa}B. Am J Physiol Lung Cell Mol Physiol 299:L559–L566

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Manea A, Tanase LI, Raicu M, Simionescu M (2010) Jak/STAT signaling pathway regulates nox1 and nox4-based NADPH oxidase in human aortic smooth muscle cells. Arterioscler Thromb Vasc Biol 30:105–112

    CAS  PubMed  Google Scholar 

  76. Zhang L, Sheppard OR, Shah AM, Brewer AC (2008) Positive regulation of the NADPH oxidase NOX4 promoter in vascular smooth muscle cells by E2F. Free Radic Biol Med 45:679–685

    CAS  PubMed  Google Scholar 

  77. Rodríguez AI, Csányi G, Ranayhossaini DJ, Feck DM, Blose KJ, Assatourian L et al (2015) MEF2B-Nox1 signaling is critical for stretch-induced phenotypic modulation of vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 35:430–438

    PubMed  Google Scholar 

  78. Shi ZD, Tarbell JM (2011) Fluid flow mechanotransduction in vascular smooth muscle cells and fibroblasts. Ann Biomed Eng 39:1608–1619

    PubMed  PubMed Central  Google Scholar 

  79. Hergenreider E, Heydt S, Treguer K, Boettger T, Horrevoets AJ, Zeiher AM et al (2012) Atheroprotective communication between endothelial cells and smooth muscle cells through miRNAs. Nat Cell Biol 14:249–256

    CAS  PubMed  Google Scholar 

  80. Nakashima Y, Wight TN, Sueishi K (2008) Early atherosclerosis in humans: role of diffuse intimal thickening and extracellular matrix proteoglycans. Cardiovasc Res 79:14–23

    CAS  PubMed  Google Scholar 

  81. Nakashima Y, Fujii H, Sumiyoshi S, Wight TN, Sueishi K (2007) Early human atherosclerosis: accumulation of lipid and proteoglycans in intimal thickenings followed by macrophage infiltration. Arterioscler Thromb Vasc Biol 27:1159–1165

    CAS  PubMed  Google Scholar 

  82. Wagsater D, Olofsson PS, Norgren L, Stenberg B, Sirsjo A (2004) The chemokine and scavenger receptor CXCL16/SR-PSOX is expressed in human vascular smooth muscle cells and is induced by interferon gamma. Biochem Biophys Res Commun 325:1187–1193

    PubMed  Google Scholar 

  83. Higashimori M, Tatro JB, Moore KJ, Mendelsohn ME, Galper JB, Beasley D (2011) Role of toll-like receptor 4 in intimal foam cell accumulation in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol 31:50–57

    CAS  PubMed  Google Scholar 

  84. Yin YW, Liao SQ, Zhang MJ, Liu Y, Li BH, Zhou Y et al (2014) TLR4-mediated inflammation promotes foam cell formation of vascular smooth muscle cell by upregulating ACAT1 expression. Cell Death Dis 5:e1574

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Chen Z, Xue Q, Cao L, Wang Y, Chen Y, Zhang X et al (2021) Toll-like receptor 4 mediated oxidized low-density lipoprotein-induced foam cell formation in vascular smooth muscle cells via Src and Sirt1/3 pathway. Mediators Inflamm 2021:6639252

    PubMed  PubMed Central  Google Scholar 

  86. Wang Y, Dubland JA, Allahverdian S, Asonye E, Sahin B, Jaw JE et al (2019) Smooth muscle cells contribute the majority of foam cells in ApoE (Apolipoprotein E)-deficient mouse atherosclerosis. Arterioscler Thromb Vasc Biol 39:876–887

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Fan Y, Zhang J, Chen CY, Xiao YB, Asico LD, Jose PA et al (2017) Macrophage migration inhibitory factor triggers vascular smooth muscle cell dedifferentiation by a p68-serum response factor axis. Cardiovasc Res 113:519–530

    CAS  PubMed  Google Scholar 

  88. Ruan XZ, Moorhead JF, Tao JL, Ma KL, Wheeler DC, Powis SH et al (2006) Mechanisms of dysregulation of low-density lipoprotein receptor expression in vascular smooth muscle cells by inflammatory cytokines. Arterioscler Thromb Vasc Biol 26:1150–1155

    CAS  PubMed  Google Scholar 

  89. Gabunia K, Herman AB, Ray M, Kelemen SE, England RN, DeLa CR et al (2017) Induction of MiR133a expression by IL-19 targets LDLRAP1 and reduces oxLDL uptake in VSMC. J Mol Cell Cardiol 105:38–48

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Sendra J, Llorente-Cortes V, Costales P, Huesca-Gomez C, Badimon L (2008) Angiotensin II upregulates LDL receptor-related protein (LRP1) expression in the vascular wall: a new pro-atherogenic mechanism of hypertension. Cardiovasc Res 78:581–589

    CAS  PubMed  Google Scholar 

  91. Giannotti KC, Weinert S, Viana MN, Leiguez E, Araujo T, Laurindo F et al (2019) A secreted phospholipase A2 induces formation of smooth muscle foam cells which transdifferentiate to macrophage-like state. Molecules 24:3244

    CAS  PubMed Central  Google Scholar 

  92. Vendrov AE, Sumida A, Canugovi C, Lozhkin A, Hayami T, Madamanchi NR et al (2019) NOXA1-dependent NADPH oxidase regulates redox signaling and phenotype of vascular smooth muscle cell during atherogenesis. Redox Biol 21:101063

    CAS  PubMed  Google Scholar 

  93. Bao Z, Li L, Geng Y, Yan J, Dai Z, Shao C et al (2020) Advanced glycation end products induce vascular smooth muscle cell-derived foam cell formation and transdifferentiate to a macrophage-like state. Mediators Inflamm 2020:6850187

    PubMed  PubMed Central  Google Scholar 

  94. Xue JH, Yuan Z, Wu Y, Liu Y, Zhao Y, Zhang WP et al (2010) High glucose promotes intracellular lipid accumulation in vascular smooth muscle cells by impairing cholesterol influx and efflux balance. Cardiovasc Res 86:141–150

    CAS  PubMed  Google Scholar 

  95. Wu JH, Zhang L, Nepliouev I, Brian L, Huang T, Snow KP et al (2021) Drebrin attenuates atherosclerosis by limiting smooth muscle cell transdifferentiation. Cardiovasc Res. https://doi.org/10.1093/cvr/cvab156

    Article  PubMed  PubMed Central  Google Scholar 

  96. Moe SM, Chen NX (2008) Mechanisms of vascular calcification in chronic kidney disease. J Am Soc Nephrol 19:213–216

    CAS  PubMed  Google Scholar 

  97. Shanahan CM (2005) Mechanisms of vascular calcification in renal disease. Clin Nephrol 63:146–157

    CAS  PubMed  Google Scholar 

  98. Shanahan CM, Crouthamel MH, Kapustin A, Giachelli CM (2011) Arterial calcification in chronic kidney disease: key roles for calcium and phosphate. Circ Res 109:697–711

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Ducy P, Zhang R, Geoffroy V, Ridall AL, Karsenty G (1997) Osf2/Cbfa1: a transcriptional activator of osteoblast differentiation. Cell 89:747–754

    CAS  PubMed  Google Scholar 

  100. Shroff RC, Shanahan CM (2007) The vascular biology of calcification. Semin Dial 20:103–109

    PubMed  Google Scholar 

  101. Tada Y, Yano S, Yamaguchi T, Okazaki K, Ogawa N, Morita M et al (2013) Advanced glycation end products-induced vascular calcification is mediated by oxidative stress: functional roles of NAD(P)H-oxidase. Horm Metab Res 45:267–272

    CAS  PubMed  Google Scholar 

  102. Byon CH, Javed A, Dai Q, Kappes JC, Clemens TL, Darley-Usmar VM et al (2008) Oxidative stress induces vascular calcification through modulation of the osteogenic transcription factor Runx2 by AKT signaling. J Biol Chem 283:15319–15327

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Murshed M, McKee MD (2010) Molecular determinants of extracellular matrix mineralization in bone and blood vessels. Curr Opin Nephrol Hypertens 19:359–365

    CAS  PubMed  Google Scholar 

  104. Takemura A, Iijima K, Ota H, Son BK, Ito Y, Ogawa S et al (2011) Sirtuin 1 retards hyperphosphatemia-induced calcification of vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 31:2054–2062

    CAS  PubMed  Google Scholar 

  105. Badi I, Mancinelli L, Polizzotto A, Ferri D, Zeni F, Burba I et al (2018) miR-34a promotes vascular smooth muscle cell calcification by downregulating SIRT1 (Sirtuin 1) and Axl (AXL Receptor Tyrosine Kinase). Arterioscler Thromb Vasc Biol 38:2079–2090

    CAS  PubMed  Google Scholar 

  106. Navas-Madronal M, Castelblanco E, Camacho M, Consegal M, Ramirez-Morros A, Sarrias MR et al (2020) Role of the scavenger receptor CD36 in accelerated diabetic atherosclerosis. Int J Mol Sci 21:7360

    CAS  PubMed Central  Google Scholar 

  107. Di Bartolo BA, Schoppet M, Mattar MZ, Rachner TD, Shanahan CM, Kavurma MM (2011) Calcium and osteoprotegerin regulate IGF1R expression to inhibit vascular calcification. Cardiovasc Res 91:537–545

    PubMed  Google Scholar 

  108. Kanno Y, Into T, Lowenstein CJ, Matsushita K (2008) Nitric oxide regulates vascular calcification by interfering with TGF- signalling. Cardiovasc Res 77:221–230

    CAS  PubMed  Google Scholar 

  109. Adijiang A, Goto S, Uramoto S, Nishijima F, Niwa T (2008) Indoxyl sulphate promotes aortic calcification with expression of osteoblast-specific proteins in hypertensive rats. Nephrol Dial Transplant 23:1892–1901

    CAS  PubMed  Google Scholar 

  110. Peng YQ, Xiong D, Lin X, Cui RR, Xu F, Zhong JY et al (2017) Oestrogen inhibits arterial calcification by promoting autophagy. Sci Rep 7:3549

    PubMed  PubMed Central  Google Scholar 

  111. Collin-Osdoby P (2004) Regulation of vascular calcification by osteoclast regulatory factors RANKL and osteoprotegerin. Circ Res 95:1046–1057

    CAS  PubMed  Google Scholar 

  112. Oh YJ, Kim H, Kim AJ, Ro H, Chang JH, Lee HH et al (2020) Reduction of secreted frizzled-related protein 5 drives vascular calcification through Wnt3a-mediated Rho/ROCK/JNK signaling in chronic kidney disease. Int J Mol Sci 21:3539

    CAS  PubMed Central  Google Scholar 

  113. Proudfoot D, Davies JD, Skepper JN, Weissberg PL, Shanahan CM (2002) Acetylated low-density lipoprotein stimulates human vascular smooth muscle cell calcification by promoting osteoblastic differentiation and inhibiting phagocytosis. Circulation 106:3044–3050

    CAS  PubMed  Google Scholar 

  114. Goettsch C, Rauner M, Hamann C, Sinningen K, Hempel U, Bornstein SR et al (2011) Nuclear factor of activated T cells mediates oxidised LDL-induced calcification of vascular smooth muscle cells. Diabetologia 54:2690–2701

    CAS  PubMed  Google Scholar 

  115. Cai Z, Ding Y, Zhang M, Lu Q, Wu S, Zhu H et al (2016) Ablation of adenosine monophosphate-activated protein kinase alpha1 in vascular smooth muscle cells promotes diet-induced atherosclerotic calcification in vivo. Circ Res 119:422–433

    CAS  PubMed  Google Scholar 

  116. Schiffrin EL, Lipman ML, Mann JF (2007) Chronic kidney disease: effects on the cardiovascular system. Circulation 116:85–97

    PubMed  Google Scholar 

  117. Parhami F, Basseri B, Hwang J, Tintut Y, Demer LL (2002) High-density lipoprotein regulates calcification of vascular cells. Circ Res 91:570–576

    CAS  PubMed  Google Scholar 

  118. Neven E, De Schutter TM, De Broe ME, D’Haese PC (2011) Cell biological and physicochemical aspects of arterial calcification. Kidney Int 79:1166–1177

    CAS  PubMed  Google Scholar 

  119. Chen PY, Qin L, Li G, Malagon-Lopez J, Wang Z, Bergaya S et al (2020) Smooth muscle cell reprogramming in aortic aneurysms. Cell Stem Cell 26:542–557

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Gudas LJ, Wagner JA (2011) Retinoids regulate stem cell differentiation. J Cell Physiol 226:322–330

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Streb JW, Long X, Lee TH, Sun Q, Kitchen CM, Georger MA et al (2011) Retinoid-induced expression and activity of an immediate early tumor suppressor gene in vascular smooth muscle cells. PLoS ONE 6:e18538

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Fujiu K, Manabe I, Ishihara A, Oishi Y, Iwata H, Nishimura G et al (2005) Synthetic retinoid Am 80 suppresses smooth muscle phenotypic modulation and in-stent neointima formation by inhibiting KLF5. Circ Res 97:1132–1141

    CAS  PubMed  Google Scholar 

  123. van der Loop FT, Gabbiani G, Kohnen G, Ramaekers FC, van Eys GJ (1997) Differentiation of smooth muscle cells in human blood vessels as defined by smoothelin, a novel marker for the contractile phenotype. Arterioscler Thromb Vasc Biol 17:665–671

    PubMed  Google Scholar 

  124. van der Loop FT, Schaart G, Timmer ED, Ramaekers FC, van Eys GJ (1996) Smoothelin, a novel cytoskeletal protein specific for smooth muscle cells. J Cell Biol 134:401–411

    PubMed  Google Scholar 

  125. Christen T, Verin V, Bochaton-Piallat M, Popowski Y, Ramaekers F, Debruyne P et al (2001) Mechanisms of neointima formation and remodeling in the porcine coronary artery. Circulation 103:882–888

    CAS  PubMed  Google Scholar 

  126. Zhao Y, Samal E, Srivastava D (2005) Serum response factor regulates a muscle-specific microRNA that targets Hand2 during cardiogenesis. Nature 436:214–220

    CAS  PubMed  Google Scholar 

  127. Ackers-Johnson M, Talasila A, Sage AP, Long X, Bot I, Morrell NW et al (2015) Myocardin regulates vascular smooth muscle cell inflammatory activation and disease. Arterioscler Thromb Vasc Biol 35:817–828

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Wang D, Chang PS, Wang Z, Sutherland L, Richardson JA, Small E et al (2001) Activation of cardiac gene expression by myocardin, a transcriptional cofactor for serum response factor. Cell 105:851–862

    CAS  PubMed  Google Scholar 

  129. Chen J, Kitchen CM, Streb JW, Miano JM (2002) Myocardin: a component of a molecular switch for smooth muscle differentiation. J Mol Cell Cardiol 34:1345–1356

    CAS  PubMed  Google Scholar 

  130. Qiu P, Ritchie RP, Fu Z, Cao D, Cumming J, Miano JM et al (2005) Myocardin enhances Smad3-mediated transforming growth factor-beta1 signaling in a CArG box-independent manner: Smad-binding element is an important cis element for SM22alpha transcription in vivo. Circ Res 97:983–991

    CAS  PubMed  Google Scholar 

  131. Wang Z, Wang DZ, Pipes GC, Olson EN (2003) Myocardin is a master regulator of smooth muscle gene expression. Proc Natl Acad Sci U S A 100:7129–7134

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Xia XD, Zhou Z, Yu XH, Zheng XL, Tang CK (2017) Myocardin: a novel player in atherosclerosis. Atherosclerosis 257:266–278

    CAS  PubMed  Google Scholar 

  133. Onuh JO, Qiu H (2021) Serum response factor-cofactor interactions and their implications in disease. FEBS J 288:3120–3134

    CAS  PubMed  Google Scholar 

  134. Liu Y, Sinha S, McDonald OG, Shang Y, Hoofnagle MH, Owens GK (2005) Kruppel-like factor 4 abrogates myocardin-induced activation of smooth muscle gene expression. J Biol Chem 280:9719–9727

    CAS  PubMed  Google Scholar 

  135. Horita H, Wysoczynski CL, Walker LA, Moulton KS, Li M, Ostriker A et al (2016) Nuclear PTEN functions as an essential regulator of SRF-dependent transcription to control smooth muscle differentiation. Nat Commun 7:10830

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Salmon M, Gomez D, Greene E, Shankman L, Owens GK (2012) Cooperative binding of KLF4, pELK-1, and HDAC2 to a G/C repressor element in the SM22α promoter mediates transcriptional silencing during SMC phenotypic switching in vivo. Circ Res 111:685–696

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Zheng JP, He X, Liu F, Yin S, Wu S, Yang M et al (2020) YY1 directly interacts with myocardin to repress the triad myocardin/SRF/CArG box-mediated smooth muscle gene transcription during smooth muscle phenotypic modulation. Sci Rep 10:21781

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Liu ZP, Wang Z, Yanagisawa H, Olson EN (2005) Phenotypic modulation of smooth muscle cells through interaction of Foxo4 and myocardin. Dev Cell 9:261–270

    PubMed  Google Scholar 

  139. Deaton RA, Gan Q, Owens GK (2009) Sp1-dependent activation of KLF4 is required for PDGF-BB-induced phenotypic modulation of smooth muscle. Am J Physiol Heart Circ Physiol 296:H1027–H1037

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Guo X, Shi N, Cui XB, Wang JN, Fukui Y, Chen SY (2015) Dedicator of cytokinesis 2, a novel regulator for smooth muscle phenotypic modulation and vascular remodeling. Circ Res 116:e71–e80

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Nagao M, Lyu Q, Zhao Q, Wirka RC, Bagga J, Nguyen T et al (2020) Coronary disease-associated gene TCF21 inhibits smooth muscle cell differentiation by blocking the myocardin-serum response factor pathway. Circ Res 126:517–529

    CAS  PubMed  Google Scholar 

  142. Bonasio R, Tu S, Reinberg D (2010) Molecular signals of epigenetic states. Science 330:612–616

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Jones PA, Takai D (2001) The role of DNA methylation in mammalian epigenetics. Science 293:1068–1070

    CAS  PubMed  Google Scholar 

  144. Laukkanen MO, Mannermaa S, Hiltunen MO, Aittomäki S, Airenne K, Jänne J et al (1999) Local hypomethylation in atherosclerosis found in rabbit ec-sod gene. Arterioscler Thromb Vasc Biol 19:2171–2178

    CAS  PubMed  Google Scholar 

  145. Liu R, Jin Y, Tang WH, Qin L, Zhang X, Tellides G et al (2013) Ten-eleven translocation-2 (TET2) is a master regulator of smooth muscle cell plasticity. Circulation 128:2047–2057

    PubMed  PubMed Central  Google Scholar 

  146. Zhuang J, Luan P, Li H, Wang K, Zhang P, Xu Y et al (2017) The Yin-Yang dynamics of DNA methylation is the key regulator for smooth muscle cell phenotype switch and vascular remodeling. Arterioscler Thromb Vasc Biol 37:84–97

    CAS  PubMed  Google Scholar 

  147. Hiltunen MO, Turunen MP, Häkkinen TP, Rutanen J, Hedman M, Mäkinen K et al (2002) DNA hypomethylation and methyltransferase expression in atherosclerotic lesions. Vasc Med 7:5–11

    PubMed  Google Scholar 

  148. Jiang JX, Aitken KJ, Sotiropoulos C, Kirwan T, Panchal T, Zhang N et al (2013) Phenotypic switching induced by damaged matrix is associated with DNA methyltransferase 3A (DNMT3A) activity and nuclear localization in smooth muscle cells (SMC). PLoS ONE 8:e69089

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Rozenberg JM, Tesfu DB, Musunuri S, Taylor JM, Mack CP (2014) DNA methylation of a GC repressor element in the smooth muscle myosin heavy chain promoter facilitates binding of the Notch-associated transcription factor, RBPJ/CSL1. Arterioscler Thromb Vasc Biol 34:2624–2631

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Wang YS, Chou WW, Chen KC, Cheng HY, Lin RT, Juo SH (2012) MicroRNA-152 mediates DNMT1-regulated DNA methylation in the estrogen receptor α gene. PLoS ONE 7:e30635

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Hu W, Wang M, Yin H, Yao C, He Q, Yin L et al (2015) MicroRNA-1298 is regulated by DNA methylation and affects vascular smooth muscle cell function by targeting connexin 43. Cardiovasc Res 107:534–545

    CAS  PubMed  Google Scholar 

  152. Ning Y, Huang H, Dong Y, Sun Q, Zhang W, Xu W et al (2013) 5-Aza-2’-deoxycytidine inhibited PDGF-induced rat airway smooth muscle cell phenotypic switching. Arch Toxicol 87:871–881

    CAS  PubMed  Google Scholar 

  153. Azechi T, Sato F, Sudo R, Wachi H (2014) 5-aza-2’-Deoxycytidine, a DNA methyltransferase inhibitor, facilitates the inorganic phosphorus-induced mineralization of vascular smooth muscle cells. J Atheroscler Thromb 21:463–476

    PubMed  Google Scholar 

  154. Raines EW (2000) The extracellular matrix can regulate vascular cell migration, proliferation, and survival: relationships to vascular disease. Int J Exp Pathol 81:173–182

    CAS  PubMed  PubMed Central  Google Scholar 

  155. Connelly JJ, Cherepanova OA, Doss JF, Karaoli T, Lillard TS, Markunas CA et al (2013) Epigenetic regulation of COL15A1 in smooth muscle cell replicative aging and atherosclerosis. Hum Mol Genet 22:5107–5120

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Xie SA, Zhang T, Wang J, Zhao F, Zhang YP, Yao WJ et al (2018) Matrix stiffness determines the phenotype of vascular smooth muscle cell in vitro and in vivo: Role of DNA methyltransferase 1. Biomaterials 155:203–216

    CAS  PubMed  Google Scholar 

  157. Manabe I, Owens GK (2001) Recruitment of serum response factor and hyperacetylation of histones at smooth muscle-specific regulatory regions during differentiation of a novel P19-derived in vitro smooth muscle differentiation system. Circ Res 88:1127–1134

    CAS  PubMed  Google Scholar 

  158. Qiu P, Li L (2002) Histone acetylation and recruitment of serum responsive factor and CREB-binding protein onto SM22 promoter during SM22 gene expression. Circ Res 90:858–865

    CAS  PubMed  Google Scholar 

  159. Kee HJ, Kwon JS, Shin S, Ahn Y, Jeong MH, Kook H (2011) Trichostatin A prevents neointimal hyperplasia via activation of Krüppel like factor 4. Vascul Pharmacol 55:127–134

    CAS  PubMed  Google Scholar 

  160. McDonald OG, Wamhoff BR, Hoofnagle MH, Owens GK (2006) Control of SRF binding to CArG box chromatin regulates smooth muscle gene expression in vivo. J Clin Invest 116:36–48

    CAS  PubMed  PubMed Central  Google Scholar 

  161. Qiu P, Ritchie RP, Gong XQ, Hamamori Y, Li L (2006) Dynamic changes in chromatin acetylation and the expression of histone acetyltransferases and histone deacetylases regulate the SM22alpha transcription in response to Smad3-mediated TGFbeta1 signaling. Biochem Biophys Res Commun 348:351–358

    CAS  PubMed  Google Scholar 

  162. Yoshida T, Gan Q, Shang Y, Owens GK (2007) Platelet-derived growth factor-BB represses smooth muscle cell marker genes via changes in binding of MKL factors and histone deacetylases to their promoters. Am J Physiol Cell Physiol 292:C886–C895

    CAS  PubMed  Google Scholar 

  163. Usui T, Morita T, Okada M, Yamawaki H (2014) Histone deacetylase 4 controls neointimal hyperplasia via stimulating proliferation and migration of vascular smooth muscle cells. Hypertension 63:397–403

    CAS  PubMed  Google Scholar 

  164. Yoshida T, Gan Q, Owens GK (2008) Kruppel-like factor 4, Elk-1, and histone deacetylases cooperatively suppress smooth muscle cell differentiation markers in response to oxidized phospholipids. Am J Physiol Cell Physiol 295:C1175–C1182

    CAS  PubMed  PubMed Central  Google Scholar 

  165. Liu M, Espinosa-Diez C, Mahan S, Du M, Nguyen AT, Hahn S et al (2021) H3K4 di-methylation governs smooth muscle lineage identity and promotes vascular homeostasis by restraining plasticity. Dev Cell 56:2765–2782

    CAS  PubMed  Google Scholar 

  166. Lino CC, Kessinger CW, Cheng Y, MacDonald C, MacGillivray T, Ghoshhajra B et al (2018) An HDAC9-MALAT1-BRG1 complex mediates smooth muscle dysfunction in thoracic aortic aneurysm. Nat Commun 9:1009

    Google Scholar 

  167. Albinsson S, Suarez Y, Skoura A, Offermanns S, Miano JM, Sessa WC (2010) MicroRNAs are necessary for vascular smooth muscle growth, differentiation, and function. Arterioscler Thromb Vasc Biol 30:1118–1126

    CAS  PubMed  PubMed Central  Google Scholar 

  168. Cheng Y, Liu X, Yang J, Lin Y, Xu DZ, Lu Q et al (2009) MicroRNA-145, a novel smooth muscle cell phenotypic marker and modulator, controls vascular neointimal lesion formation. Circ Res 105:158–166

    CAS  PubMed  PubMed Central  Google Scholar 

  169. Cordes KR, Sheehy NT, White MP, Berry EC, Morton SU, Muth AN et al (2009) miR-145 and miR-143 regulate smooth muscle cell fate and plasticity. Nature 460:705–710

    CAS  PubMed  PubMed Central  Google Scholar 

  170. Farina FM, Hall IF, Serio S, Zani S, Climent M, Salvarani N et al (2020) miR-128-3p is a novel regulator of vascular smooth muscle cell phenotypic switch and vascular diseases. Circ Res 126:e120–e135

    CAS  PubMed  Google Scholar 

  171. Yang F, Chen Q, He S, Yang M, Maguire EM, An W et al (2018) miR-22 is a novel mediator of vascular smooth muscle cell phenotypic modulation and neointima formation. Circulation 137:1824–1841

    CAS  PubMed  PubMed Central  Google Scholar 

  172. Yang K, Ren J, Li X, Wang Z, Xue L, Cui S et al (2020) Prevention of aortic dissection and aneurysm via an ALDH2-mediated switch in vascular smooth muscle cell phenotype. Eur Heart J 41:2442–2453

    CAS  PubMed  Google Scholar 

  173. Zeng Z, Xia L, Fan X, Ostriker AC, Yarovinsky T, Su M et al (2019) Platelet-derived miR-223 promotes a phenotypic switch in arterial injury repair. J Clin Invest 129:1372–1386

    PubMed  PubMed Central  Google Scholar 

  174. Quinn JJ, Chang HY (2016) Unique features of long non-coding RNA biogenesis and function. Nat Rev Genet 17:47–62

    CAS  PubMed  Google Scholar 

  175. Michalik KM, You X, Manavski Y, Doddaballapur A, Zörnig M, Braun T et al (2014) Long noncoding RNA MALAT1 regulates endothelial cell function and vessel growth. Circ Res 114:1389–1397

    CAS  PubMed  Google Scholar 

  176. Zhao J, Zhang W, Lin M, Wu W, Jiang P, Tou E et al (2016) MYOSLID is a novel serum response factor-dependent long noncoding RNA that amplifies the vascular smooth muscle differentiation program. Arterioscler Thromb Vasc Biol 36:2088–2099

    CAS  PubMed  PubMed Central  Google Scholar 

  177. Ahmed A, Dong K, Liu J, Wen T, Yu L, Xu F et al (2018) Long noncoding RNA NEAT1 (nuclear paraspeckle assembly transcript 1) is critical for phenotypic switching of vascular smooth muscle cells. Proc Natl Acad Sci U S A 115:E8660–E8667

    PubMed  PubMed Central  Google Scholar 

  178. Bell RD, Long X, Lin M, Bergmann JH, Nanda V, Cowan SL et al (2014) Identification and initial functional characterization of a human vascular cell-enriched long noncoding RNA. Arterioscler Thromb Vasc Biol 34:1249–1259

    CAS  PubMed  PubMed Central  Google Scholar 

  179. Wang YN, Shan K, Yao MD, Yao J, Wang JJ, Li X et al (2016) Long noncoding RNA-GAS5: a novel regulator of hypertension-induced vascular remodeling. Hypertension 68:736–748

    CAS  PubMed  Google Scholar 

  180. Choi M, Lu YW, Zhao J, Wu M, Zhang W, Long X (2020) Transcriptional control of a novel long noncoding RNA Mymsl in smooth muscle cells by a single Cis-element and its initial functional characterization in vessels. J Mol Cell Cardiol 138:147–157

    CAS  PubMed  Google Scholar 

  181. Zhang C, Ge S, Gong W, Xu J, Guo Z, Liu Z et al (2020) LncRNA ANRIL acts as a modular scaffold of WDR5 and HDAC3 complexes and promotes alteration of the vascular smooth muscle cell phenotype. Cell Death Dis 11:435

    CAS  PubMed  PubMed Central  Google Scholar 

  182. Kristensen LS, Andersen MS, Stagsted L, Ebbesen KK, Hansen TB, Kjems J (2019) The biogenesis, biology and characterization of circular RNAs. Nat Rev Genet 20:675–691

    CAS  PubMed  Google Scholar 

  183. Hall IF, Climent M, Quintavalle M, Farina FM, Schorn T, Zani S et al (2019) Circ_Lrp6, a circular RNA enriched in vascular smooth muscle cells, acts as a sponge regulating miRNA-145 function. Circ Res 124:498–510

    CAS  PubMed  Google Scholar 

  184. Zeng Z, Xia L, Fan S, Zheng J, Qin J, Fan X et al (2021) Circular RNA CircMAP3K5 Acts as a MicroRNA-22-3p sponge to promote resolution of intimal hyperplasia via TET2-mediated smooth muscle cell differentiation. Circulation 143:354–371

    CAS  PubMed  Google Scholar 

  185. Xu JY, Chang NB, Rong ZH, Li T, Xiao L, Yao QP et al (2019) circDiaph3 regulates rat vascular smooth muscle cell differentiation, proliferation, and migration. FASEB J 33:2659–2668

    CAS  PubMed  Google Scholar 

  186. Mao YY, Wang JQ, Guo XX, Bi Y, Wang CX (2018) Circ-SATB2 upregulates STIM1 expression and regulates vascular smooth muscle cell proliferation and differentiation through miR-939. Biochem Biophys Res Commun 505:119–125

    CAS  PubMed  Google Scholar 

  187. Yang L, Yang F, Zhao H, Wang M, Zhang Y (2019) Circular RNA circCHFR facilitates the proliferation and migration of vascular smooth muscle via miR-370/FOXO1/Cyclin D1 pathway. Mol Ther Nucleic Acids 16:434–441

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This work was supported by the National Natural Science Foundation of China (No. 81974182 and No. 82171325 to LM, No. 81771249 to YPX).

Author information

Author notes

  1. Feng Zhang and Xiaoqing Guo contributed equally to this work.

Authors and Affiliations

  1. Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China

    Feng Zhang, Xiaoqing Guo, Yuanpeng Xia & Ling Mao

Authors
  1. Feng Zhang
    View author publications

    Search author on:PubMed Google Scholar

  2. Xiaoqing Guo
    View author publications

    Search author on:PubMed Google Scholar

  3. Yuanpeng Xia
    View author publications

    Search author on:PubMed Google Scholar

  4. Ling Mao
    View author publications

    Search author on:PubMed Google Scholar

Contributions

FZ and XG wrote this manuscript. LM and YX designed the review and approved this manuscript.

Corresponding authors

Correspondence to Yuanpeng Xia or Ling Mao.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest.

Ethical approval

Not applicable.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, F., Guo, X., Xia, Y. et al. An update on the phenotypic switching of vascular smooth muscle cells in the pathogenesis of atherosclerosis. Cell. Mol. Life Sci. 79, 6 (2022). https://doi.org/10.1007/s00018-021-04079-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s00018-021-04079-z

Keywords