Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

MiRNAs, lncRNAs, and circular RNAs as mediators in hypertension-related vascular smooth muscle cell dysfunction

Abstract

Hypertension is a multifactorial disorder that involves complex genetic and environmental factors. Vascular smooth muscle cells (VSMCs) are important components of blood vessels, and their dysregulation has been shown to be involved in vascular remodeling during the development of systemic hypertension and pulmonary arterial hypertension (PAH) via multiple mechanisms, such as aberrant apoptosis, phenotype conversion, proliferation, and migration of VSMCs. With increasing advances in microarrays and next-generation sequencing, nonprotein-coding RNAs (ncRNAs) have attracted much attention due to their numerous functions in health and diseases. Among ncRNAs, microRNAs (miRNAs), long noncoding RNAs (lncRNAs), and circular RNAs are emerging as novel modulators in the biological behaviors of VSMCs, especially in systemic hypertension and PAH. Studies have recommended miRNAs, lncRNAs, and circular RNAs as predictive biomarkers and therapeutic targets for systemic hypertension and PAH. In this review, we summarize the current studies focusing on the roles of VSMC-derived miRNAs, lncRNAs and circular RNAs in the pathologies of systemic hypertension and PAH. MiRNAs, lncRNAs, and circular RNAs might serve as attractive targets for the prevention and treatment of VSMC dysfunction-linked systemic hypertension and PAH.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    Chow CK, Teo KK, Rangarajan S, Islam S, Gupta R, Avezum A, et al. Prevalence, awareness, treatment, and control of hypertension in rural and urban communities in high-, middle-, and low-income countries. JAMA.2013;310:959–68.

    CAS  PubMed  Google Scholar 

  2. 2.

    Basu S, Millett C. Social epidemiology of hypertension in middle-income countries: determinants of prevalence, diagnosis, treatment, and control in the WHO SAGE study. Hypertension. 2013;62:18–26.

    CAS  PubMed  Google Scholar 

  3. 3.

    Costache II, Miron A, Hancianu M, Aursulesei V, Costache AD, Aprotosoaie AC. Pharmacokinetic interactions between cardiovascular medicines and plant products. Cardiovasc Ther. 2019;2019:9402781.

    PubMed  PubMed Central  Google Scholar 

  4. 4.

    Li X, Chang P, Wang Q. Effects of angiotensin-converting enzyme inhibitors on arterial stiffness: a systematic review and meta-analysis of randomized controlled trials. Cardiovasc Ther. 2020;2020:7056184.

    PubMed  PubMed Central  Google Scholar 

  5. 5.

    Mills KT, Bundy JD, Kelly TN, Reed JE, Kearney PM, Reynolds K, et al. Global disparities of hypertension prevalence and control: a systematic analysis of population-based studies from 90 countries. Circulation. 2016;134:441–50.

    PubMed  PubMed Central  Google Scholar 

  6. 6.

    Rosendorff C, Lackland DT, Allison M, Aronow WS, Black HR, Blumenthal RS, et al. Treatment of hypertension in patients with coronary artery disease: a scientific statement from the American Heart Association, American College of Cardiology, and American Society of Hypertension. Circulation. 2015;131:e435–70.

    PubMed  Google Scholar 

  7. 7.

    Whelton PK, Carey RM, Aronow WS, Casey DE Jr., Collins KJ, Dennison Himmelfarb C, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2018;138:e484–594.

    PubMed  Google Scholar 

  8. 8.

    Whelton PK, Carey RM, Aronow WS, Casey DE Jr., Collins KJ, Dennison Himmelfarb C, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension. 2018;71:1269–324.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Carretero OA, Oparil S. Essential hypertension. Part I: definition and etiology. Circulation. 2000;101:329–35.

    CAS  PubMed  Google Scholar 

  10. 10.

    Poulter NR, Prabhakaran D, Caulfield M. Hypertension. Lancet. 2015;386:801–12.

    PubMed  Google Scholar 

  11. 11.

    Parikh V, Bhardwaj A, Nair A. Pharmacotherapy for pulmonary arterial hypertension. J Thorac Dis. 2019;11 Suppl 14:S1767–81.

    Google Scholar 

  12. 12.

    Taichman DB, Mandel J. Epidemiology of pulmonary arterial hypertension. Clin Chest Med. 2013;34:619–37.

    PubMed  Google Scholar 

  13. 13.

    Jin Q, Zhao Z, Zhao Q, Yu X, Yan L, Zhang Y., et al. Long noncoding RNAs: emerging roles in pulmonary hypertension. Heart Fail Rev. 2019. https://doi.org/10.1007/s10741-019-09866-2.

  14. 14.

    Levy E, Spahis S, Bigras JL, Delvin E, Borys JM. The epigenetic machinery in vascular dysfunction and hypertension. Curr Hypertension Rep. 2017;19:52.

    Google Scholar 

  15. 15.

    Bavishi C, Bangalore S, Messerli FH. Outcomes of intensive blood pressure lowering in older hypertensive patients. J Am Coll Cardiol. 2017;69:486–93.

    PubMed  Google Scholar 

  16. 16.

    Cordina R, Celermajer D. Late-onset pulmonary arterial hypertension after a successful atrial or arterial switch procedure for transposition of the great arteries. Pediatr Cardiol. 2010;31:238–41.

    PubMed  Google Scholar 

  17. 17.

    Sun HJ, Ren XS, Xiong XQ, Chen YZ, Zhao MX, Wang JJ, et al. NLRP3 inflammasome activation contributes to VSMC phenotypic transformation and proliferation in hypertension. Cell Death Dis. 2017;8:e3074.

    PubMed  PubMed Central  Google Scholar 

  18. 18.

    Lacolley P, Regnault V, Avolio AP. Smooth muscle cell and arterial aging: basic and clinical aspects. Cardiovasc Res. 2018;114:513–28.

    CAS  PubMed  Google Scholar 

  19. 19.

    Chi C, Li DJ, Jiang YJ, Tong J, Fu H, Wu YH, et al. Vascular smooth muscle cell senescence and age-related diseases: State of the art. Biochim Biophys Acta Mol Basis Dis. 2019;1865:1810–21.

    CAS  PubMed  Google Scholar 

  20. 20.

    Thompson AAR, Lawrie A. Targeting vascular remodeling to treat pulmonary arterial hypertension. Trends Mol Med. 2017;23:31–45.

    CAS  PubMed  Google Scholar 

  21. 21.

    Gollasch M, Welsh DG. Perivascular adipose tissue and the dynamic regulation of Kv 7 and Kir channels: implications for resistant hypertension. Microcirculation. 2018;25:e12434.

    Google Scholar 

  22. 22.

    Dai Z, Zhu MM, Peng Y, Machireddy N, Evans CE, Machado R, et al. Therapeutic targeting of vascular remodeling and right heart failure in pulmonary arterial hypertension with a HIF-2alpha inhibitor. Am J Respir Crit Care Med. 2018;198:1423–34.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Lu QB, Wang HP, Tang ZH, Cheng H, Du Q, Wang YB, et al. Nesfatin-1 functions as a switch for phenotype transformation and proliferation of VSMCs in hypertensive vascular remodeling. Biochim Biophys Acta Mol Basis Dis. 2018;1864:2154–68.

    CAS  PubMed  Google Scholar 

  24. 24.

    Egom EE. Pulmonary arterial hypertension due to NPR-C mutation: a novel paradigm for normal and pathologic remodeling? Int J Mol Sci. 2019;20:3063.

    CAS  PubMed Central  Google Scholar 

  25. 25.

    Sun HJ, Hou B, Wang X, Zhu XX, Li KX, Qiu LY. Endothelial dysfunction and cardiometabolic diseases: Role of long non-coding RNAs. Life Sci. 2016;167:6–11.

    CAS  PubMed  Google Scholar 

  26. 26.

    Simion V, Haemmig S, Feinberg MW. LncRNAs in vascular biology and disease. Vasc Pharmacol. 2019;114:145–56.

    CAS  Google Scholar 

  27. 27.

    Tang N, Jiang S, Yang Y, Liu S, Ponnusamy M, Xin H, et al. Noncoding RNAs as therapeutic targets in atherosclerosis with diabetes mellitus. Cardiovasc Ther. 2018;36:e12436.

    PubMed  Google Scholar 

  28. 28.

    Cheng X, Wang Y, Du L. Epigenetic modulation in the initiation and progression of pulmonary hypertension. Hypertension. 2019;74:733–9.

    CAS  PubMed  Google Scholar 

  29. 29.

    Leimena C, Qiu H. Non-coding RNA in the pathogenesis, progression and treatment of hypertension. Int J Mol Sci. 2018;19:927.

    PubMed Central  Google Scholar 

  30. 30.

    Murakami K. Non-coding RNAs and hypertension-unveiling unexpected mechanisms of hypertension by the dark matter of the genome. Curr Hypertens Rev. 2015;11:80–90.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Zaiou M. Circular RNAs in hypertension: challenges and clinical promise. Hypertens Res. 2019;42:1653–63.

    PubMed  Google Scholar 

  32. 32.

    Wang Y, Song X, Li Z, Liu B. Long non-coding RNAs in coronary atherosclerosis. Life Sci. 2018;211:189–97.

    CAS  PubMed  Google Scholar 

  33. 33.

    Sun Y, Yang Z, Zheng B, Zhang XH, Zhang ML, Zhao XS, et al. A novel regulatory mechanism of smooth muscle alpha-actin expression by NRG-1/circACTA2/miR-548f-5p axis. Circul Res. 2017;121:628–35.

    CAS  Google Scholar 

  34. 34.

    Birney E, Stamatoyannopoulos JA, Dutta A, Guigo R, Gingeras TR, Margulies EH, et al. Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. Nature. 2007;447:799–816.

    CAS  PubMed  Google Scholar 

  35. 35.

    Thurman RE, Rynes E, Humbert R, Vierstra J, Maurano MT, Haugen E, et al. The accessible chromatin landscape of the human genome. Nature. 2012;489:75–82.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Njock MS, Fish JE. Endothelial miRNAs as cellular messengers in cardiometabolic diseases. Trends Endocrinol Metab. 2017;28:237–46.

    CAS  PubMed  Google Scholar 

  37. 37.

    Araldi E, Suarez Y. MicroRNAs as regulators of endothelial cell functions in cardiometabolic diseases. Biochim Biophys Acta. 2016;1861:2094–103.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Fernandez-Hernando C, Suarez Y. MicroRNAs in endothelial cell homeostasis and vascular disease. Curr Opin Hematol. 2018;25:227–36.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Ebert MS, Sharp PA. Roles for microRNAs in conferring robustness to biological processes. Cell 2012;149:515–24.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40.

    K RB, Tay Y. The Yin-Yang regulation of reactive oxygen species and MicroRNAs in cancer. Int J Mol Sci. 2019;20:5335.

    Google Scholar 

  41. 41.

    Angelucci F, Cechova K, Valis M, Kuca K, Zhang B, Hort J. MicroRNAs in Alzheimer’s disease: diagnostic markers or therapeutic agents? Front Pharmacol. 2019;10:665.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Zitzer NC, Garzon R, Ranganathan P. Toll-like receptor stimulation by MicroRNAs in acute graft-vs.-host disease. Front Immunol. 2018;9:2561.

    PubMed  PubMed Central  Google Scholar 

  43. 43.

    Uszczynska-Ratajczak B, Lagarde J. Towards a complete map of the human long non-coding RNA transcriptome. Nat Rev Genet. 2018;19:535–48.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Ingolia NT, Brar GA, Stern-Ginossar N, Harris MS, Talhouarne GJ, Jackson SE, et al. Ribosome profiling reveals pervasive translation outside of annotated protein-coding genes. Cell Rep. 2014;8:1365–79.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Brown CJ, Hendrich BD, Rupert JL, Lafreniere RG, Xing Y, Lawrence J, et al. The human XIST gene: analysis of a 17 kb inactive X-specific RNA that contains conserved repeats and is highly localized within the nucleus. Cell. 1992;71:527–42.

    CAS  PubMed  Google Scholar 

  46. 46.

    Brockdorff N, Ashworth A, Kay GF, McCabe VM, Norris DP, Cooper PJ, et al. The product of the mouse Xist gene is a 15 kb inactive X-specific transcript containing no conserved ORF and located in the nucleus. Cell. 1992;71:515–26.

    CAS  PubMed  Google Scholar 

  47. 47.

    Brannan CI, Dees EC, Ingram RS, Tilghman SM. The product of the H19 gene may function as an RNA. Mol Cell Biol. 1990;10:28–36.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Greco S, Cardinali B. Circular RNAs in muscle function and disease. Int J Mol Sci. 2018;19:3454.

    PubMed Central  Google Scholar 

  49. 49.

    Zhou MY, Yang JM, Xiong XD. The emerging landscape of circular RNA in cardiovascular diseases. J Mol Cell Cardiol. 2018;122:134–9.

    CAS  PubMed  Google Scholar 

  50. 50.

    Chen Y, Lin Y, Shu Y, He J, Gao W. Interaction between N(6)-methyladenosine (m(6)A) modification and noncoding RNAs in cancer. Mol Cancer. 2020;19:94.

    PubMed  PubMed Central  Google Scholar 

  51. 51.

    Wang T, Pan W, Hu J, Zhang Z, Li G, Liang Y. Circular RNAs in metabolic diseases. Adv Exp Med Biol. 2018;1087:275–85.

    CAS  PubMed  Google Scholar 

  52. 52.

    Vasu S, Kumano K, Darden CM, Rahman I, Lawrence MC, Naziruddin B. MicroRNA signatures as future biomarkers for diagnosis of diabetes states. Cells. 2019;8:1533.

    CAS  PubMed Central  Google Scholar 

  53. 53.

    Khalili N, Nouri-Vaskeh M, Segherlou ZH, Baghbanzadeh A, Halimi M, Rezaee H., et al. Diagnostic, prognostic, and therapeutic significance of miR-139-5p in cancers. Life Sci. 2020:117865. https://doi.org/10.1016/j.lfs.2020.117865.

  54. 54.

    Farina FM, Hall IF, Serio S, Zani S, Climent M, Salvarani N, et al. miR-128-3p is a novel regulator of vascular smooth muscle cell phenotypic switch and vascular diseases. Circul Res. 2020;126:e120–35

    CAS  Google Scholar 

  55. 55.

    Mahmoud AD, Ballantyne MD, Miscianinov V, Pinel K, Hung J, Scanlon JP, et al. The human-specific and smooth muscle cell-enriched LncRNA smilr promotes proliferation by regulating mitotic CENPF mRNA and drives cell-cycle progression which can be targeted to limit vascular remodeling. Circul Res. 2019;125:535–51.

    CAS  Google Scholar 

  56. 56.

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

    CAS  Google Scholar 

  57. 57.

    Lu D, Thum T. RNA-based diagnostic and therapeutic strategies for cardiovascular disease. Nat Rev Cardiol. 2019;16:661–74.

    PubMed  Google Scholar 

  58. 58.

    Bei Y, Yang T, Wang L, Holvoet P, Das S, Sluijter JPG, et al. Circular RNAs as potential theranostics in the cardiovascular system. Mol Ther Nucleic Acids. 2018;13:407–18.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 59.

    Zhang CY, Liu M, Wan JM, Gao MQ, Zhang Y, Soyan M, et al. Role of noncoding RNA in pulmonary arterial hypertension and potential drug therapeutic target. Curr Top Med Chem. 2018;18:975–86.

    CAS  PubMed  Google Scholar 

  60. 60.

    Grootaert MOJ, Moulis M, Roth L, Martinet W, Vindis C, Bennett MR, et al. Vascular smooth muscle cell death, autophagy and senescence in atherosclerosis. Cardiovasc Res. 2018;114:622–34.

    CAS  PubMed  Google Scholar 

  61. 61.

    Shi N, Chen SY. Mechanisms simultaneously regulate smooth muscle proliferation and differentiation. J Biomed Res. 2014;28:40–6.

    CAS  PubMed  Google Scholar 

  62. 62.

    Saboor F, Reckmann AN, Tomczyk CU, Peters DM, Weissmann N, Kaschtanow A, et al. Nestin-expressing vascular wall cells drive development of pulmonary hypertension. Eur Respir J. 2016;47:876–88.

    CAS  PubMed  Google Scholar 

  63. 63.

    Liu J, Huang Y. Role of endogenous sulfur dioxide in regulating vascular structural remodeling in hypertension. Oxid Med Cell Longev. 2016;2016:4529060.

    PubMed  PubMed Central  Google Scholar 

  64. 64.

    Watanabe T, Arita S, Shiraishi Y, Suguro T, Sakai T, Hongo S, et al. Human urotensin II promotes hypertension and atherosclerotic cardiovascular diseases. Curr Med Chem. 2009;16:550–63.

    CAS  PubMed  Google Scholar 

  65. 65.

    Fang YC, Yeh CH. Role of microRNAs in vascular remodeling. Curr Mol Med. 2015;15:684–96.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66.

    Li FJ, Zhang CL, Luo XJ, Peng J, Yang TL. Involvement of the MiR-181b-5p/HMGB1 pathway in Ang II-induced phenotypic transformation of smooth muscle cells in hypertension. Aging Dis. 2019;10:231–48.

    PubMed  PubMed Central  Google Scholar 

  67. 67.

    Coll-Bonfill N, de la Cruz-Thea B, Pisano MV, Musri MM. Noncoding RNAs in smooth muscle cell homeostasis: implications in phenotypic switch and vascular disorders. Pflug Arch: Eur J Physiol. 2016;468:1071–87.

    CAS  Google Scholar 

  68. 68.

    Montezano AC, Zimmerman D, Yusuf H, Burger D, Chignalia AZ, Wadhera V, et al. Vascular smooth muscle cell differentiation to an osteogenic phenotype involves TRPM7 modulation by magnesium. Hypertension. 2010;56:453–62.

    CAS  PubMed  Google Scholar 

  69. 69.

    Zhang R, Sui L, Hong X, Yang M, Li W. MiR-448 promotes vascular smooth muscle cell proliferation and migration in through directly targeting MEF2C. Environ Sci Pollut Res Int. 2017;24:22294–300.

    PubMed  Google Scholar 

  70. 70.

    Xu D, Liao R, Wang XX, Cheng Z. Effects of miR-155 on hypertensive rats via regulating vascular mesangial hyperplasia. Eur Rev Med Pharmacol Sci. 2018;22:7431–8.

    CAS  PubMed  Google Scholar 

  71. 71.

    Liu K, Ying Z, Qi X, Shi Y, Tang Q. MicroRNA-1 regulates the proliferation of vascular smooth muscle cells by targeting insulin-like growth factor 1. Int J Mol Med. 2015;36:817–24.

    CAS  PubMed  Google Scholar 

  72. 72.

    Ren XS, Tong Y, Ling L, Chen D, Sun HJ, Zhou H, et al. NLRP3 gene deletion attenuates angiotensin II-induced phenotypic transformation of vascular smooth muscle cells and vascular remodeling. Cell Physiol Biochem: Int J Exp Cell Physiol Biochem Pharmacol. 2017;44:2269–80.

    CAS  Google Scholar 

  73. 73.

    Yang J, Chen L, Ding J, Fan Z, Li S, Wu H, et al. MicroRNA-24 inhibits high glucose-induced vascular smooth muscle cell proliferation and migration by targeting HMGB1. Gene. 2016;586:268–73.

    CAS  PubMed  Google Scholar 

  74. 74.

    Zhang L, Yang F, Yan Q. Candesartan ameliorates vascular smooth muscle cell proliferation via regulating miR-301b/STAT3 axis. Hum Cell. 2020. https://doi.org/10.1007/s13577-020-00333-x.

  75. 75.

    Tian L, Cai D, Zhuang D, Wang W, Wang X, Bian X, et al. miR-96-5p regulates proliferation, migration, and apoptosis of vascular smooth muscle cell induced by angiotensin II via targeting NFAT5. J Vasc Res. 2020;57:86–96.

    CAS  PubMed  Google Scholar 

  76. 76.

    Gu Q, Zhao G, Wang Y, Xu B, Yue J. Silencing miR-16 expression promotes angiotensin II stimulated vascular smooth muscle cell growth. Cell Dev Biol. 2017;6:1.

    Google Scholar 

  77. 77.

    Wang S, Tang L, Zhou Q, Lu D, Duan W, Chen C, et al. miR-185/P2Y6 axis inhibits angiotensin II-induced human aortic vascular smooth muscle cell proliferation. DNA Cell Biol. 2017;36:377–85.

    PubMed  Google Scholar 

  78. 78.

    Zahid KR, Raza U, Chen J, Raj JU, Gou D. Pathobiology of pulmonary artery hypertension: role of lncRNAs. Cardiovasc Res. 2020. https://doi.org/10.1093/cvr/cvaa050.

  79. 79.

    Zhou G, Chen T, Raj JU. MicroRNAs in pulmonary arterial hypertension. Am J Respir Cell Mol Biol. 2015;52:139–51.

    PubMed  PubMed Central  Google Scholar 

  80. 80.

    Courboulin A, Paulin R, Giguère NJ, Saksouk N, Perreault T, Meloche J, et al. Role for miR-204 in human pulmonary arterial hypertension. J Exp Med. 2011;208:535–48.

    CAS  PubMed  PubMed Central  Google Scholar 

  81. 81.

    Rhodes CJ, Wharton J, Boon RA, Roexe T, Tsang H, Wojciak-Stothard B, et al. Reduced microRNA-150 is associated with poor survival in pulmonary arterial hypertension. Am J Respir Crit Care Med. 2013;187:294–302.

    CAS  PubMed  Google Scholar 

  82. 82.

    Chen M, Shen C, Zhang Y, Shu H. MicroRNA-150 attenuates hypoxia-induced excessive proliferation and migration of pulmonary arterial smooth muscle cells through reducing HIF-1α expression. Biomed Pharmacother. 2017;93:861–8.

    CAS  PubMed  Google Scholar 

  83. 83.

    Pullamsetti SS, Doebele C, Fischer A, Savai R, Kojonazarov B, Dahal BK, et al. Inhibition of microRNA-17 improves lung and heart function in experimental pulmonary hypertension. Am J Respir Crit Care Med. 2012;185:409–19.

    CAS  PubMed  Google Scholar 

  84. 84.

    Caruso P, MacLean MR, Khanin R, McClure J, Soon E, Southgate M, et al. Dynamic changes in lung microRNA profiles during the development of pulmonary hypertension due to chronic hypoxia and monocrotaline. Arterioscler Thromb Vasc Biol. 2010;30:716–23.

    CAS  PubMed  Google Scholar 

  85. 85.

    Drake KM, Zygmunt D, Mavrakis L, Harbor P, Wang L, Comhair SA, et al. Altered MicroRNA processing in heritable pulmonary arterial hypertension: an important role for Smad-8. Am J Respir Crit Care Med. 2011;184:1400–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86.

    Caruso P, Dempsie Y, Stevens HC, McDonald RA, Long L, Lu R. et al. A role for miR-145 in pulmonary arterial hypertension: evidence from mouse models and patient samples. Circul Res. 2012;111:290–300.

    CAS  Google Scholar 

  87. 87.

    Yang S, Banerjee S, Freitas A, Cui H, Xie N, Abraham E, et al. miR-21 regulates chronic hypoxia-induced pulmonary vascular remodeling. Am J Physiol Lung Cell Mol Physiol. 2012;302:L521–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  88. 88.

    Chen W, Li S. Circulating microRNA as a novel biomarker for pulmonary arterial hypertension due to congenital heart disease. Pediatr Cardiol. 2017;38:86–94.

    CAS  PubMed  Google Scholar 

  89. 89.

    Bertero T, Lu Y, Annis S, Hale A, Bhat B, Saggar R. et al. Systems-level regulation of microRNA networks by miR-130/301 promotes pulmonary hypertension. J Clin Investig. 2014;124:3514–28.

    CAS  PubMed  Google Scholar 

  90. 90.

    Tanzer A, Stadler PF. Molecular evolution of a microRNA cluster. J Mol Biol. 2004;339:327–35.

    CAS  PubMed  Google Scholar 

  91. 91.

    Bienertova-Vasku J, Novak J, Vasku A. MicroRNAs in pulmonary arterial hypertension: pathogenesis, diagnosis and treatment. J Am Soc Hypertens. 2015;9:221–34.

    CAS  PubMed  Google Scholar 

  92. 92.

    Chen T, Zhou G, Zhou Q, Tang H, Ibe JC, Cheng H, et al. Loss of microRNA-1792 in smooth muscle cells attenuates experimental pulmonary hypertension via induction of PDZ and LIM domain 5. Am J Respir Crit Care Med. 2015;191:678–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93.

    Sarkar J, Gou D, Turaka P, Viktorova E, Ramchandran R, Raj JU. MicroRNA-21 plays a role in hypoxia-mediated pulmonary artery smooth muscle cell proliferation and migration. Am J Physiol Lung Cell Mol Physiol. 2010;299:L861–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  94. 94.

    Kang K, Peng X, Zhang X, Wang Y, Zhang L, Gao L, et al. MicroRNA-124 suppresses the transactivation of nuclear factor of activated T cells by targeting multiple genes and inhibits the proliferation of pulmonary artery smooth muscle cells. J Biol Chem. 2013;288:25414–27.

    CAS  PubMed  PubMed Central  Google Scholar 

  95. 95.

    Lee C, Mitsialis SA, Aslam M, Vitali SH, Vergadi E, Konstantinou G, et al. Exosomes mediate the cytoprotective action of mesenchymal stromal cells on hypoxia-induced pulmonary hypertension. Circulation. 2012;126:2601–11.

    CAS  PubMed  PubMed Central  Google Scholar 

  96. 96.

    Gou D, Ramchandran R, Peng X, Yao L, Kang K, Sarkar J, et al. miR-210 has an antiapoptotic effect in pulmonary artery smooth muscle cells during hypoxia. Am J Physiol Lung Cell Mol Physiol. 2012;303:L682–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  97. 97.

    Cordes KR, Sheehy NT, White MP, Berry EC, Morton SU, Muth AN, et al. miR-145 and miR-143 regulate smooth muscle cell fate and plasticity. Nature. 2009;460:705–10.

    CAS  PubMed  PubMed Central  Google Scholar 

  98. 98.

    Boettger T, Beetz N, Kostin S, Schneider J, Krüger M, Hein L, et al. Acquisition of the contractile phenotype by murine arterial smooth muscle cells depends on the Mir143/145 gene cluster. J Clin Investig. 2009;119:2634–47.

    CAS  PubMed  Google Scholar 

  99. 99.

    Davis-Dusenbery BN, Chan MC, Reno KE, Weisman AS, Layne MD, Lagna G, et al. down-regulation of Kruppel-like factor-4 (KLF4) by microRNA-143/145 is critical for modulation of vascular smooth muscle cell phenotype by transforming growth factor-beta and bone morphogenetic protein 4. J Biol Chem. 2011;286:28097–110.

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100.

    Xing XQ, Li B, Xu SL, Liu J, Zhang CF, Yang J. MicroRNA-214-3p regulates hypoxia-mediated pulmonary artery smooth muscle cell proliferation and migration by targeting ARHGEF12. Med Sci Monit: Int Med J Exp Clin Res. 2019;25:5738–46.

    CAS  Google Scholar 

  101. 101.

    Lee J, Kang H. Hypoxia promotes vascular smooth muscle cell proliferation through microRNA-mediated suppression of cyclin-dependent kinase inhibitors. Cells. 2019;8:802.

    CAS  PubMed Central  Google Scholar 

  102. 102.

    Liu G, Hao P, Xu J, Wang L, Wang Y, Han R, et al. Upregulation of microRNA-17-5p contributes to hypoxia-induced proliferation in human pulmonary artery smooth muscle cells through modulation of p21 and PTEN. Respir Res. 2018;19:200.

    CAS  PubMed  PubMed Central  Google Scholar 

  103. 103.

    Mondejar-Parreño G, Callejo M, Barreira B, Morales-Cano D. miR-1 is increased in pulmonary hypertension and downregulates Kv1.5 channels in rat pulmonary arteries. J Physiol. 2019;597:1185–97.

    PubMed  Google Scholar 

  104. 104.

    Wang CC, Ying L, Barnes EA, Adams ES, Kim FY, Engel KW, et al. Pulmonary artery smooth muscle cell HIF-1α regulates endothelin expression via microRNA-543. Am J Physiol Lung Cell Mol Physiol. 2018;315:L422–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  105. 105.

    Zhang X, Shao R, Gao W, Sun G, Liu Y, Fa X. Inhibition of miR-361-5p suppressed pulmonary artery smooth muscle cell survival and migration by targeting ABCA1 and inhibiting the JAK2/STAT3 pathway. Exp Cell Res. 2018;363:255–61.

    CAS  PubMed  Google Scholar 

  106. 106.

    Ma C, Zhang C, Ma M, Zhang L, Zhang L, Zhang F, et al. MiR-125a regulates mitochondrial homeostasis through targeting mitofusin 1 to control hypoxic pulmonary vascular remodeling. J Mol Med. 2017;95:977–93.

    CAS  PubMed  Google Scholar 

  107. 107.

    Hong Z, Chen KH, DasGupta A, Potus F, Dunham-Snary K, Bonnet S, et al. MicroRNA-138 and MicroRNA-25 down-regulate mitochondrial calcium uniporter, causing the pulmonary arterial hypertension cancer phenotype. Am J Respir Crit Care Med. 2017;195:515–29.

    CAS  PubMed  PubMed Central  Google Scholar 

  108. 108.

    Xu Y, Bei Y, Shen S, Zhang J, Lu Y, Xiao J, et al. MicroRNA-222 promotes the proliferation of pulmonary arterial smooth muscle cells by targeting P27 and TIMP3. Cell Physiol Biochem: Int J Exp Cell Physiol Biochem Pharmacol. 2017;43:282–92.

    CAS  Google Scholar 

  109. 109.

    Sahoo S, Meijles DN, Al Ghouleh I, Tandon M, Cifuentes-Pagano E, Sembrat J, et al. MEF2C-MYOCD and Leiomodin1 suppression by miRNA-214 promotes smooth muscle cell phenotype switching in pulmonary arterial hypertension. PLoS One. 2016;11:e0153780.

    PubMed  PubMed Central  Google Scholar 

  110. 110.

    Brock M, Haider TJ, Vogel J, Gassmann M, Speich R, Trenkmann M, et al. The hypoxia-induced microRNA-130a controls pulmonary smooth muscle cell proliferation by directly targeting CDKN1A. Int J Biochem Cell Biol. 2015;61:129–37.

    CAS  PubMed  Google Scholar 

  111. 111.

    Jin Y, Pang T, Nelin LD, Wang W, Wang Y, Yan J, et al. MKP-1 is a target of miR-210 and mediate the negative regulation of miR-210 inhibitor on hypoxic hPASMC proliferation. Cell Biol Int. 2015;39:113–20.

    CAS  PubMed  Google Scholar 

  112. 112.

    Tao W, Sun W, Zhu H, Zhang J. miR-205-5p suppresses pulmonary vascular smooth muscle cell proliferation by targeting MICAL2-mediated Erk1/2 signaling. Microvasc Res. 2019;124:43–50.

    CAS  PubMed  Google Scholar 

  113. 113.

    Zhang C, Ma C, Zhang L, Zhang L, Zhang F, Ma M, et al. MiR-449a-5p mediates mitochondrial dysfunction and phenotypic transition by targeting Myc in pulmonary arterial smooth muscle cells. J Mol Med. 2019;97:409–22.

    CAS  PubMed  Google Scholar 

  114. 114.

    Liu A, Liu Y, Li B, Yang M, Liu Y, Su J. Role of miR-223-3p in pulmonary arterial hypertension via targeting ITGB3 in the ECM pathway. Cell Prolif. 2019;52:e12550.

    PubMed  Google Scholar 

  115. 115.

    Yang YZ, Zhang YF, Yang L, Xu J, Mo XM, Peng W. miR‑760 mediates hypoxia-induced proliferation and apoptosis of human pulmonary artery smooth muscle cells via targeting TLR4. Int J Mol Med. 2018;42:2437–46.

    CAS  PubMed  PubMed Central  Google Scholar 

  116. 116.

    Chen J, Cui X, Li L, Qu J, Raj JU, Gou D. MiR-339 inhibits proliferation of pulmonary artery smooth muscle cell by targeting FGF signaling. Physiol Rep. 2017;5:e13441.

    PubMed  PubMed Central  Google Scholar 

  117. 117.

    Rothman AM, Arnold ND, Pickworth JA, Iremonger J, Ciuclan L, Allen RM, et al. MicroRNA-140-5p and SMURF1 regulate pulmonary arterial hypertension. J Clin Investig. 2016;126:2495–508.

    PubMed  Google Scholar 

  118. 118.

    Wallace E, Morrell NW, Yang XD, Long L, Stevens H, Nilsen M, et al. A sex-specific MicroRNA-96/5-hydroxytryptamine 1B axis influences development of pulmonary hypertension. Am J Respir Crit Care Med. 2015;191:1432–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  119. 119.

    Jin L, Lin X, Yang L, Fan X, Wang W, Li S, et al. AK098656, a novel vascular smooth muscle cell-dominant long noncoding RNA, promotes hypertension. Hypertension. 2018;71:262–72.

    CAS  PubMed  Google Scholar 

  120. 120.

    Fang G, Qi J, Huang L, Zhao X. LncRNA MRAK048635_P1 is critical for vascular smooth muscle cell function and phenotypic switching in essential hypertension. Biosci Rep. 2019;39:BSR20182229.

    CAS  PubMed  PubMed Central  Google Scholar 

  121. 121.

    Tan J, Xie Y, Yao A, Qin Y, Li L, Shen L, et al. Long noncoding RNA-dependent regulation of vascular smooth muscle cell proliferation and migration in hypertension. Int J Biochem Cell Biol. 2020;118:105653.

    CAS  PubMed  Google Scholar 

  122. 122.

    Liu K, Liu C, Zhang Z. lncRNA GAS5 acts as a ceRNA for miR-21 in suppressing PDGF-bb-induced proliferation and migration in vascular smooth muscle cells. J Cell Biochem. 2019;120:15233–40.

    CAS  PubMed  Google Scholar 

  123. 123.

    Shi L, Tian C, Sun L, Cao F, Meng Z. The lncRNA TUG1/miR-145-5p/FGF10 regulates proliferation and migration in VSMCs of hypertension. Biochem Biophys Res Commun. 2018;501:688–95.

    CAS  PubMed  Google Scholar 

  124. 124.

    Masi S, Uliana M, Virdis A. Angiotensin II and vascular damage in hypertension: role of oxidative stress and sympathetic activation. Vasc Pharmacol. 2019;115:13–7.

    CAS  Google Scholar 

  125. 125.

    Virdis A, Duranti E, Taddei S. Oxidative stress and vascular damage in hypertension: role of angiotensin II. Int J Hypertens. 2011;2011:916310.

    PubMed  PubMed Central  Google Scholar 

  126. 126.

    Das S, Zhang E, Senapati P, Amaram V, Reddy MA, Stapleton K, et al. A novel angiotensin II-induced long noncoding RNA giver regulates oxidative stress, inflammation, and proliferation in vascular smooth muscle cells. Circul Res. 2018;123:1298–312.

    CAS  Google Scholar 

  127. 127.

    Leung A, Trac C, Jin W, Lanting L, Akbany A, Saetrom P, et al. Novel long noncoding RNAs are regulated by angiotensin II in vascular smooth muscle cells. Circul Res. 2013;113:266–78.

    CAS  Google Scholar 

  128. 128.

    Ando J, Yamamoto K. Flow detection and calcium signalling in vascular endothelial cells. Cardiovasc Res. 2013;99:260–8.

    CAS  PubMed  Google Scholar 

  129. 129.

    Ando J, Yamamoto K. Effects of shear stress and stretch on endothelial function. Antioxid Redox Signal. 2011;15:1389–403.

    CAS  PubMed  Google Scholar 

  130. 130.

    Mantella LE, Singh KK, Sandhu P, Kantores C, Ramadan A, Khyzha N, et al. Fingerprint of long non-coding RNA regulated by cyclic mechanical stretch in human aortic smooth muscle cells: implications for hypertension. Mol Cell Biochem. 2017;435:163–73.

    CAS  PubMed  Google Scholar 

  131. 131.

    Yao QP, Xie ZW, Wang KX, Zhang P, Han Y, Qi YX, et al. Profiles of long noncoding RNAs in hypertensive rats: long noncoding RNA XR007793 regulates cyclic strain-induced proliferation and migration of vascular smooth muscle cells. J Hypertens. 2017;35:1195–203.

    CAS  PubMed  Google Scholar 

  132. 132.

    Song X, Shan D, Chen J, Jing Q. miRNAs and lncRNAs in vascular injury and remodeling. Sci China Life Sci. 2014;57:826–35.

    CAS  PubMed  Google Scholar 

  133. 133.

    Ding S, Zhu Y, Liang Y, Huang H, Xu Y, Zhong C. Circular RNAs in vascular functions and diseases. Adv Exp Med Biol. 2018;1087:287–97.

    CAS  PubMed  Google Scholar 

  134. 134.

    Wang X, Yan C, Xu X, Dong L, Su H, Hu Y, et al. Long noncoding RNA expression profiles of hypoxic pulmonary hypertension rat model. Gene. 2016;579:23–8.

    CAS  PubMed  Google Scholar 

  135. 135.

    Sun Z, Liu Y, Yu F, Xu Y, Yanli L, Liu N. Long non-coding RNA and mRNA profile analysis of metformin to reverse the pulmonary hypertension vascular remodeling induced by monocrotaline. Biomed Pharmacother. 2019;115:108933.

    CAS  PubMed  Google Scholar 

  136. 136.

    Jiang X, Lei R, Ning Q. Circulating long noncoding RNAs as novel biomarkers of human diseases. Biomark Med. 2016;10:757–69.

    CAS  PubMed  Google Scholar 

  137. 137.

    Shi Q, Yang X. Circulating MicroRNA and long noncoding RNA as biomarkers of cardiovascular diseases. J Cell Physiol. 2016;231:751–5.

    CAS  PubMed  Google Scholar 

  138. 138.

    Jiang X, Ning Q. Long noncoding RNAs as novel players in the pathogenesis of hypertension. Hypertens Res. 2020. https://doi.org/10.1038/s41440-020-0408-2.

  139. 139.

    Sun Z, Nie X, Sun S, Dong S, Yuan C, Li Y, et al. Long non-coding RNA MEG3 downregulation triggers human pulmonary artery smooth muscle cell proliferation and migration via the p53 signaling pathway. Cell Physiol Biochem: Int J Exp Cell Physiol Biochem Pharmacol. 2017;42:2569–81.

    CAS  Google Scholar 

  140. 140.

    Xing Y, Zheng X, Fu Y, Qi J, Li M, Ma M, et al. Long noncoding RNA-maternally expressed gene 3 contributes to hypoxic pulmonary hypertension. Mol Ther: J Am Soc Gene Ther. 2019;27:2166–81.

    CAS  Google Scholar 

  141. 141.

    Zhuo Y, Zeng Q, Zhang P, Li G, Xie Q, Cheng Y. Functional polymorphism of lncRNA MALAT1 contributes to pulmonary arterial hypertension susceptibility in Chinese people. Clin Chem Lab Med. 2017;55:38–46.

    CAS  PubMed  Google Scholar 

  142. 142.

    Leisegang MS, Fork C, Josipovic I, Richter FM, Preussner J, Hu J, et al. Long noncoding RNA MANTIS facilitates endothelial angiogenic function. Circulation. 2017;136:65–79.

    CAS  PubMed  PubMed Central  Google Scholar 

  143. 143.

    Zhu TT, Sun RL, Yin YL, Quan JP, Song P, Xu J, et al. Long noncoding RNA UCA1 promotes the proliferation of hypoxic human pulmonary artery smooth muscle cells. Pflug Arch. 2019;471:347–55.

    CAS  Google Scholar 

  144. 144.

    Jandl K, Thekkekara Puthenparampil H, Marsh LM, Hoffmann J, Wilhelm J, Veith C, et al. Long non-coding RNAs influence the transcriptome in pulmonary arterial hypertension: the role of PAXIP1-AS1. J Pathol. 2019;247:357–70.

    CAS  PubMed  PubMed Central  Google Scholar 

  145. 145.

    Zhang Z, Li Z, Wang Y, Wei L, Chen H. Overexpressed long noncoding RNA CPS1-IT alleviates pulmonary arterial hypertension in obstructive sleep apnea by reducing interleukin-1beta expression via HIF1 transcriptional activity. J Cell Physiol. 2019;234:19715–27.

    CAS  PubMed  Google Scholar 

  146. 146.

    Wang S, Zhang C, Zhang X. Downregulation of long noncoding RNA ANRIL promotes proliferation and migration in hypoxic human pulmonary artery smooth muscle cells. Mol Med Rep. 2020;21:589–96.

    CAS  PubMed  Google Scholar 

  147. 147.

    Schlosser K, Hanson J, Villeneuve PJ, Dimitroulakos J, McIntyre L, Pilote L, et al. Assessment of circulating LncRNAs under physiologic and pathologic conditions in humans reveals potential limitations as biomarkers. Sci Rep. 2016;6:36596.

    CAS  PubMed  PubMed Central  Google Scholar 

  148. 148.

    Zhang H, Liu Y, Yan L, Wang S, Zhang M, Ma C, et al. Long noncoding RNA Hoxaas3 contributes to hypoxia-induced pulmonary artery smooth muscle cell proliferation. Cardiovasc Res. 2019;115:647–57.

    CAS  PubMed  Google Scholar 

  149. 149.

    Wang H, Qin R, Cheng Y. LncRNA-Ang362 promotes pulmonary arterial hypertension by regulating miR-221 and miR-222. Shock. 2019. https://doi.org/10.1097/shk.0000000000001410.

  150. 150.

    Su H, Xu X, Yan C, Shi Y, Hu Y, Dong L, et al. LncRNA H19 promotes the proliferation of pulmonary artery smooth muscle cells through AT1R via sponging let-7b in monocrotaline-induced pulmonary arterial hypertension. Respir Res. 2018;19:254.

    CAS  PubMed  PubMed Central  Google Scholar 

  151. 151.

    Wang S, Cao W, Gao S, Nie X, Zheng X, Xing Y, et al. TUG1 regulates pulmonary arterial smooth muscle cell proliferation in pulmonary arterial hypertension. Can J Cardiol. 2019;35:1534–45.

    PubMed  Google Scholar 

  152. 152.

    Bonnet S, Boucherat O, Provencher S, Paulin R. Early evidence for the role of lncRNA TUG1 in vascular remodelling in pulmonary hypertension. Can J Cardiol. 2019;35:1433–4.

    PubMed  Google Scholar 

  153. 153.

    Yang L, Liang H, Shen L, Guan Z, Meng X. LncRNA Tug1 involves in the pulmonary vascular remodeling in mice with hypoxic pulmonary hypertension via the microRNA-374c-mediated Foxc1. Life Sci. 2019;237:116769.

    CAS  PubMed  Google Scholar 

  154. 154.

    Zhu B, Gong Y, Yan G, Wang D, Qiao Y, Wang Q, et al. Down-regulation of lncRNA MEG3 promotes hypoxia-induced human pulmonary artery smooth muscle cell proliferation and migration via repressing PTEN by sponging miR-21. Biochem Biophys Res Commun. 2018;495:2125–32.

    CAS  PubMed  Google Scholar 

  155. 155.

    Chen J, Guo J, Cui X, Dai Y, Tang Z, Qu J, et al. The long noncoding RNA LnRPT is regulated by PDGF-BB and modulates the proliferation of pulmonary artery smooth muscle cells. Am J Respir Cell Mol Biol. 2018;58:181–93.

    CAS  PubMed  Google Scholar 

  156. 156.

    Liu Y, Sun Z, Zhu J, Xiao B, Dong J, Li X. LncRNA-TCONS_00034812 in cell proliferation and apoptosis of pulmonary artery smooth muscle cells and its mechanism. J Cell Physiol. 2018;233:4801–14.

    CAS  PubMed  Google Scholar 

  157. 157.

    Gong J, Chen Z, Chen Y, Lv H, Lu H, Yan F, et al. Long non-coding RNA CASC2 suppresses pulmonary artery smooth muscle cell proliferation and phenotypic switch in hypoxia-induced pulmonary hypertension. Respir Res. 2019;20:53.

    PubMed  PubMed Central  Google Scholar 

  158. 158.

    Bao X, Zheng S, Mao S, Gu T, Liu S, Sun J, et al. A potential risk factor of essential hypertension in case-control study: circular RNA hsa_circ_0037911. Biochem Biophys Res Commun. 2018;498:789–94.

    CAS  PubMed  Google Scholar 

  159. 159.

    Wu N, Jin L, Cai J. Profiling and bioinformatics analyses reveal differential circular RNA expression in hypertensive patients. Clin Exp Hypertens. 2017;39:454–9.

    CAS  PubMed  Google Scholar 

  160. 160.

    Zheng S, Gu T, Bao X, Sun J, Zhao J, Zhang T, et al. Circular RNA hsa_circ_0014243 may serve as a diagnostic biomarker for essential hypertension. Exp Ther Med. 2019;17:1728–36.

    CAS  PubMed  Google Scholar 

  161. 161.

    Liu L, Gu T, Bao X, Zheng S, Zhao J, Zhang L. Microarray profiling of circular RNA identifies hsa_circ_0126991 as a potential risk factor for essential hypertension. Cytogenet Genome Res. 2019;157:203–12.

    CAS  PubMed  Google Scholar 

  162. 162.

    Bao X, He X, Zheng S, Sun J, Luo Y, Tan R, et al. Up-regulation of circular RNA hsa_circ_0037909 promotes essential hypertension. J Clin Lab Anal. 2019;33:e22853.

    PubMed  PubMed Central  Google Scholar 

  163. 163.

    Cheng X, Joe B. Circular RNAs in rat models of cardiovascular and renal diseases. Physiol Genom. 2017;49:484–90.

    Google Scholar 

  164. 164.

    Murphy S, Krainock R, Tham M. Neuregulin signaling via erbB receptor assemblies in the nervous system. Mol Neurobiol. 2002;25:67–77.

    CAS  PubMed  Google Scholar 

  165. 165.

    Montero JC, Yuste L, Diaz-Rodriguez E, Esparis-Ogando A, Pandiella A. Differential shedding of transmembrane neuregulin isoforms by the tumor necrosis factor-alpha-converting enzyme. Mol Cell Neurosci. 2000;16:631–48.

    CAS  PubMed  Google Scholar 

  166. 166.

    Montero JC, Rodriguez-Barrueco R, Yuste L, Juanes PP, Borges J, Esparis-Ogando A, et al. The extracellular linker of pro-neuregulin-alpha2c is required for efficient sorting and juxtacrine function. Mol Biol Cell. 2007;18:380–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  167. 167.

    Mao YY, Wang JQ, Guo XX, Bi Y, Wang CX. Circ-SATB2 upregulates STIM1 expression and regulates vascular smooth muscle cell proliferation and differentiation through miR-939. Biochem Biophys Res Commun. 2018;505:119–25.

    CAS  PubMed  Google Scholar 

  168. 168.

    Xu JY, Chang NB, Rong ZH, Li T, Xiao L, Yao QP, et al. circDiaph3 regulates rat vascular smooth muscle cell differentiation, proliferation, and migration. FASEB J. 2019;33:2659–68.

    CAS  PubMed  Google Scholar 

  169. 169.

    Heumuller AW, Dimmeler S. Circular RNA control of vascular smooth muscle cell functions. Circul Res. 2019;124:456–8.

    Google Scholar 

  170. 170.

    Rong ZH, Chang NB, Yao QP, Li T, Zhu XL, Cao Y, et al. Suppression of circDcbld1 alleviates intimal hyperplasia in rat carotid artery by targeting miR-145-3p/Neuropilin-1. Mol Ther Nucleic Acids. 2019;18:999–1008.

    CAS  PubMed  PubMed Central  Google Scholar 

  171. 171.

    Wang J, Zhu M, Pan J, Chen C, Xia S, Song Y. Circular RNAs: a rising star in respiratory diseases. Respir Res. 2019;20:3.

    PubMed  PubMed Central  Google Scholar 

  172. 172.

    Miao R, Wang Y, Wan J, Leng D, Gong J, Li J, et al. Microarray expression profile of circular RNAs in chronic thromboembolic pulmonary hypertension. Medicine. 2017;96:e7354.

    CAS  PubMed  PubMed Central  Google Scholar 

  173. 173.

    Wang J, Zhu MC, Kalionis B, Wu JZ, Wang LL, Ge HY, et al. Characteristics of circular RNA expression in lung tissues from mice with hypoxiainduced pulmonary hypertension. Int J Mol Med. 2018;42:1353–66.

    CAS  PubMed  PubMed Central  Google Scholar 

  174. 174.

    Miao R, Gong J, Zhang C, Wang Y, Guo X, Li J, et al. Hsa_circ_0046159 is involved in the development of chronic thromboembolic pulmonary hypertension. J Thromb Thrombolysis. 2020;49:386–94.

    CAS  PubMed  Google Scholar 

  175. 175.

    Zhou S, Jiang H, Li M, Wu P, Sun L, Liu Y, et al. Circular RNA hsa_circ_0016070 is associated with pulmonary arterial hypertension by promoting PASMC proliferation. Mol Ther Nucleic Acids. 2019;18:275–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  176. 176.

    Zhang J, Li Y, Qi J, Yu X, Ren H, Zhao X., et al. Circ-calm4 serves as an miR-337-3p sponge to regulate Myo10 (Myosin 10) and promote pulmonary artery smooth muscle proliferation. Hypertension. 2020. https://doi.org/10.1161/hypertensionaha.119.13715.

  177. 177.

    Lin Q, Fan C, Gomez-Arroyo J, Van Raemdonck K, Meuchel LW, Skinner JT, et al. HIMF (hypoxia-induced mitogenic factor) signaling mediates the HMGB1 (high mobility group box 1)—dependent endothelial and smooth muscle cell crosstalk in pulmonary hypertension. Arterioscler Thromb Vasc Biol. 2019;39:2505–19.

    CAS  PubMed  PubMed Central  Google Scholar 

  178. 178.

    Wang YN, Shan K, Yao MD, Yao J, Wang JJ, Li X, et al. Long noncoding RNA-GAS5: a novel regulator of hypertension-induced vascular remodeling. Hypertension. 2016;68:736–48.

    CAS  PubMed  Google Scholar 

  179. 179.

    Ren XS, Tong Y, Qiu Y, Ye C, Wu N, Xiong XQ, et al. MiR155-5p in adventitial fibroblasts-derived extracellular vesicles inhibits vascular smooth muscle cell proliferation via suppressing angiotensin-converting enzyme expression. J Extracell Vesicles. 2020;9:1698795.

    CAS  PubMed  Google Scholar 

  180. 180.

    Vanhaverbeke M, Gal D, Holvoet P. Functional role of cardiovascular exosomes in myocardial injury and atherosclerosis. Adv Exp Med Biol. 2017;998:45–58.

    CAS  PubMed  Google Scholar 

  181. 181.

    Sun HJ, Zhu XX, Cai WW, Qiu LY. Functional roles of exosomes in cardiovascular disorders: a systematic review. Eur Rev Med Pharmacol Sci. 2017;21:5197–206.

    PubMed  Google Scholar 

  182. 182.

    Leung A, Stapleton K, Natarajan R. Functional long non-coding RNAs in vascular smooth muscle cells. Curr Top Microbiol Immunol. 2016;394:127–41.

    PubMed  Google Scholar 

  183. 183.

    Guo Y, Yang X, He J, Liu J, Yang S, Dong H. Important roles of the Ca(2+)-sensing receptor in vascular health and disease. Life Sci. 2018;209:217–27.

    CAS  PubMed  Google Scholar 

  184. 184.

    Lopez-Crisosto C, Pennanen C, Vasquez-Trincado C, Morales PE, Bravo-Sagua R, Quest AFG, et al. Sarcoplasmic reticulum-mitochondria communication in cardiovascular pathophysiology. Nat Rev Cardiol. 2017;14:342–60.

    CAS  PubMed  Google Scholar 

  185. 185.

    Bourgeois A, Lambert C, Habbout K, Ranchoux B, Paquet-Marceau S, Trinh I, et al. FOXM1 promotes pulmonary artery smooth muscle cell expansion in pulmonary arterial hypertension. J Mol Med. 2018;96:223–35.

    CAS  PubMed  Google Scholar 

  186. 186.

    Wang H, Qin R, Cheng Y. LncRNA-Ang362 promotes pulmonary arterial hypertension by regulating miR-221 and miR-222. Shock. 2020;53:723–9.

    CAS  PubMed  Google Scholar 

  187. 187.

    Wang S, Zhang C, Zhang X. Downregulation of long non‑coding RNA ANRIL promotes proliferation and migration in hypoxic human pulmonary artery smooth muscle cells. Mol Med Rep. 2020;21:589–96.

    CAS  PubMed  Google Scholar 

  188. 188.

    Zhang Z, Li Z, Wang Y, Wei L, Chen H. Overexpressed long noncoding RNA CPS1-IT alleviates pulmonary arterial hypertension in obstructive sleep apnea by reducing interleukin-1β expression via HIF1 transcriptional activity. J Cell Physiol. 2019;234:19715–27.

    CAS  PubMed  Google Scholar 

  189. 189.

    Su H, Xu X, Yan C, Shi Y, Hu Y, Dong L, et al. LncRNA H19 promotes the proliferation of pulmonary artery smooth muscle cells through AT(1)R via sponging let-7b in monocrotaline-induced pulmonary arterial hypertension. Respir Res. 2018;19:254.

    CAS  PubMed  PubMed Central  Google Scholar 

  190. 190.

    Zhang J, Li Y, Qi J, Yu X, Ren H, Zhao X, et al. Circ-calm4 serves as an miR-337-3p sponge to regulate Myo10 (Myosin 10) and promote pulmonary artery smooth muscle proliferation. Hypertension. 2020;75:668–79.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the Fund of the National Natural Science Foundation of China (81700364), Jiangsu Natural Science Foundation (BK20170179 and BK20191138), Jiangsu Province Department of Science and Technology (BE2020634), Key Young Medical Talent Project of Jiangsu Health Commission (QNRC2016158), Project funded by China Postdoctoral Science Foundation (2017M611688), and Project funded by Jiangsu Postdoctoral Science Foundation (1701062C).

Author information

Affiliations

Authors

Corresponding author

Correspondence to Hai-Jian Sun.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

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

Verify currency and authenticity via CrossMark

Cite this article

Zhang, JR., Sun, HJ. MiRNAs, lncRNAs, and circular RNAs as mediators in hypertension-related vascular smooth muscle cell dysfunction. Hypertens Res 44, 129–146 (2021). https://doi.org/10.1038/s41440-020-00553-6

Download citation

Key words

  • Long noncoding RNAs
  • miRNAs
  • Circular RNAs
  • Hypertension
  • Vascular smooth muscle cells

Search

Quick links