Skip to main content

Advertisement

SpringerLink
Log in

The Epigenetic Machinery in Vascular Dysfunction and Hypertension

  • Hypertension and Metabolic Syndrome (J Sperati, Section Editor)
  • Published:
Current Hypertension Reports Aims and scope Submit manuscript

Abstract

Hypertension (HT) is among the major components of the metabolic syndrome, i.e., obesity, dyslipidemia, and hyperglycemia/insulin resistance. It represents a significant health problem with foremost risks for chronic cardiovascular disease and a significant cause of morbidity and mortality worldwide. Therefore, it is not surprising that this disorder constitutes a serious public health concern. Although multiple studies have stressed the multifactorial nature of HT, the pathogenesis remains largely unknown. However, if we want to reduce the global prevalence of HT, restrain the number of deaths (currently 9.4 million/year in the world), and alleviate the socio-economic burden, a deeper insight into the mechanisms is urgently needed in order to define new meaningful therapeutic targets. Recently, the role of epigenetics in the development of various complex diseases has attracted much attention. In the present review, we provide a critical update on the available literature and ongoing research regarding the epigenetic modifications of genes involved in several pathways of elevated blood pressure, especially those linked to the vascular epithelium. This review also focuses on the role of microRNA (miRNA) in the regulation of gene expression associated with HT and of fetal programming mediating susceptibility to HT in adulthood.

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

Access this article

Log in via an institution

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

Similar content being viewed by others

Abbreviations

ACE:

Angiotensin-converting enzyme

AGTR1:

Angiotensin II receptor type 1

Ang:

Angiotensin

CMV:

Cytomegalovirus

CNS:

Central nervous system

Dot-1:

Disruptor of telomere silencing 1

ENaC:

Epithelial of sodium channel

eNOS:

Endothelial nitric oxide synthase

H3K4:

Histone H3 lysine 4

HT:

Hypertension

miRNA:

MicroRNA

NET:

Noradrenaline transporter

OxS:

Oxidative stress

RAAS:

Renin–angiotensin–aldosterone system

ROS:

Reactive oxygen species

SMC:

Smooth muscle cells

SNP:

Single nucleotide polymorphism

SOD:

Superoxide dismutase

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Carretero OA, Oparil S. Essential hypertension. Circulation. 2000;101(3):329–35.

    Article  CAS  PubMed  Google Scholar 

  2. Simon PH, Sylvestre M-P, Tremblay J, Hamet P. Key considerations and methods in the study of gene–environment interactions. Am J Hypertens. 2016;29(8):891–9.

    Article  PubMed  Google Scholar 

  3. Cat AND, Montezano AC, Touyz RM. Renin–angiotensin–aldosterone system: new concepts. Hypertension. 2013:84–100.

  4. Wei LK, Au A, Teh LK, Lye HS. Recent advances in the genetics of hypertension. 2016.

  5. • Baubec T, Schübeler D. Genomic patterns and context specific interpretation of DNA methylation. Curr Opin Genet Dev. 2014;25:85–92. The review focuses on the link between DNA methylation and the potential function of epigenetics.

    Article  CAS  PubMed  Google Scholar 

  6. Arnsdorf EJ, Tummala P, Castillo AB, Zhang F, Jacobs CR. The epigenetic mechanism of mechanically induced osteogenic differentiation. J Biomech. 2010;43(15):2881–6.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Lee RC, Ambros V. An extensive class of small RNAs in Caenorhabditis elegans. Science. 2001;294(5543):862–4.

    Article  CAS  PubMed  Google Scholar 

  8. Yoo AS, Staahl BT, Chen L, Crabtree GR. MicroRNA-mediated switching of chromatin-remodelling complexes in neural development. Nature. 2009;460(7255):642–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Floren M, Bonani W, Dharmarajan A, Motta A, Migliaresi C, Tan W. Human mesenchymal stem cells cultured on silk hydrogels with variable stiffness and growth factor differentiate into mature smooth muscle cell phenotype. Acta Biomater. 2016;31:156–66. doi:10.1016/j.actbio.2015.11.051.

    Article  CAS  PubMed  Google Scholar 

  10. Byon CH, Heath JM, Chen Y. Redox signaling in cardiovascular pathophysiology: a focus on hydrogen peroxide and vascular smooth muscle cells. Redox Biol. 2016;9:244–53. doi:10.1016/j.redox.2016.08.015.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. • Liu R, Leslie KL, Martin KA. Epigenetic regulation of smooth muscle cell plasticity. Biochimica et Biophysica Acta (BBA)-Gene Regulatory Mechanisms. 2015;1849(4):448–53. The review highlights the importance of how the smooth muscle cells can be affected by the epigenetic changes across the genome.

    Article  CAS  Google Scholar 

  12. •• Manabe I, Owens GK. 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. 2001;88(11):1127–34. In vitro studies on mechanisms controlling SMC differentiation marker genes within chromatin.

    Article  CAS  PubMed  Google Scholar 

  13. Cao D, Wang Z, Zhang C-L, Oh J, Xing W, Li S, et al. Modulation of smooth muscle gene expression by association of histone acetyltransferases and deacetylases with myocardin. Mol Cell Biol. 2005;25(1):364–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Misárková E, Behuliak M, Bencze M, Zicha J. Excitation-contraction coupling and excitation-transcription coupling in blood vessels: their possible interactions in hypertensive vascular remodeling. Physiol Res. 2016;65(2):173.

    PubMed  Google Scholar 

  15. Qin X, Wang X, Wang Y, Tang Z, Cui Q, Xi J, et al. MicroRNA-19a mediates the suppressive effect of laminar flow on cyclin D1 expression in human umbilical vein endothelial cells. Proc Natl Acad Sci U S A. 2010;107(7):3240–4. doi:10.1073/pnas.0914882107.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Kohlstedt K, Trouvain C, Boettger T, Shi L, Fisslthaler B, Fleming I. AMP-activated protein kinase regulates endothelial cell angiotensin-converting enzyme expression via p53 and the post-transcriptional regulation of microRNA-143/145. Circ Res. 2013;112(8):1150–8. doi:10.1161/CIRCRESAHA.113.301282.

    Article  CAS  PubMed  Google Scholar 

  17. Davies PF, Manduchi E, Stoeckert CJ, Jiménez JM, Jiang Y-Z. Emerging topic: flow-related epigenetic regulation of endothelial phenotype through DNA methylation. Vasc Pharmacol. 2014;62(2):88–93.

    Article  CAS  Google Scholar 

  18. Guay SP, Brisson D, Lamarche B, Biron S, Lescelleur O, Biertho L, et al. ADRB3 gene promoter DNA methylation in blood and visceral adipose tissue is associated with metabolic disturbances in men. Epigenomics. 2014;6(1):33–43. doi:10.2217/epi.13.82.

    Article  CAS  PubMed  Google Scholar 

  19. Wang F, Demura M, Cheng Y, Zhu A, Karashima S, Yoneda T, et al. Dynamic CCAAT/enhancer binding protein-associated changes of DNA methylation in the angiotensinogen gene. Hypertension. 2014;63(2):281–8. doi:10.1161/HYPERTENSIONAHA.113.02303.

    Article  CAS  PubMed  Google Scholar 

  20. Campion J, Milagro FI, Martinez JA. Individuality and epigenetics in obesity. Obes Rev. 2009;10(4):383–92. doi:10.1111/j.1467-789X.2009.00595.x.

    Article  CAS  PubMed  Google Scholar 

  21. • Coats A, Jain S. Protective effects of nebivolol from oxidative stress to prevent hypertension-related target organ damage. J Hum Hypertens. 2017; doi:10.1038/jhh.2017.8. Development of targeted therapies related to oxidative stress in hypertensive patients.

    PubMed  PubMed Central  Google Scholar 

  22. Ilatovskaya DV, Pavlov TS, Levchenko V, Staruschenko A. ROS production as a common mechanism of ENaC regulation by EGF, insulin, and IGF-1. Am J Physiol Cell Physiol. 2013;304(1):C102–11. doi:10.1152/ajpcell.00231.2012.

    Article  CAS  PubMed  Google Scholar 

  23. Chia N, Wang L, Lu X, Senut MC, Brenner C, Ruden DM. Hypothesis: environmental regulation of 5-hydroxymethylcytosine by oxidative stress. Epigenetics. 2011;6(7):853–6.

    Article  PubMed  CAS  Google Scholar 

  24. Archer SL. Acquired mitochondrial abnormalities, including epigenetic inhibition of superoxide dismutase 2, in pulmonary hypertension and cancer: therapeutic implications. Adv Exp Med Biol. 2016;903:29–53. doi:10.1007/978-1-4899-7678-9_3.

    Article  PubMed  Google Scholar 

  25. Nozik-Grayck E, Woods C, Stearman RS, Venkataraman S, Ferguson BS, Swain K, et al. Histone deacetylation contributes to low extracellular superoxide dismutase expression in human idiopathic pulmonary arterial hypertension. Am J Physiol Lung Cell Mol Physiol. 2016;311(1):L124–34. doi:10.1152/ajplung.00263.2015.

    Article  PubMed  Google Scholar 

  26. • Hirooka Y, Kishi T, Ito K, Sunagawa K. Potential clinical application of recently discovered brain mechanisms involved in hypertension. Hypertension. 2013;62(6):995–1002. doi:10.1161/HYPERTENSIONAHA.113.00801. The review highlights a better knowledge on the sympathetic nervous system in hypertension.

    Article  CAS  PubMed  Google Scholar 

  27. Esler M, Alvarenga M, Pier C, Richards J, El-Osta A, Barton D, et al. The neuronal noradrenaline transporter, anxiety and cardiovascular disease. J Psychopharmacol. 2006;20(4 Suppl):60–6. doi:10.1177/1359786806066055.

    Article  PubMed  Google Scholar 

  28. Esler M, Eikelis N, Schlaich M, Lambert G, Alvarenga M, Kaye D, et al. Human sympathetic nerve biology: parallel influences of stress and epigenetics in essential hypertension and panic disorder. Ann N Y Acad Sci. 2008;1148:338–48. doi:10.1196/annals.1410.064.

    Article  CAS  PubMed  Google Scholar 

  29. Marques FZ, Campain AE, Tomaszewski M, Zukowska-Szczechowska E, Yang YH, Charchar FJ, et al. Gene expression profiling reveals renin mRNA overexpression in human hypertensive kidneys and a role for microRNAs. Hypertension. 2011;58(6):1093–8. doi:10.1161/HYPERTENSIONAHA.111.180729.

    Article  CAS  PubMed  Google Scholar 

  30. Hultstrom M. Development of structural kidney damage in spontaneously hypertensive rats. J Hypertens. 2012;30(6):1087–91. doi:10.1097/HJH.0b013e328352b89a.

    Article  PubMed  CAS  Google Scholar 

  31. Dobrian AD, Schriver SD, Prewitt RL. Role of angiotensin II and free radicals in blood pressure regulation in a rat model of renal hypertension. Hypertension. 2001;38(3):361–6.

    Article  CAS  PubMed  Google Scholar 

  32. Zhang D, Yu ZY, Cruz P, Kong Q, Li S, Kone BC. Epigenetics and the control of epithelial sodium channel expression in collecting duct. Kidney Int. 2009;75(3):260–7. doi:10.1038/ki.2008.475.

    Article  CAS  PubMed  Google Scholar 

  33. Nishimoto M, Fujita T. Renal mechanisms of salt-sensitive hypertension: contribution of two steroid receptor-associated pathways. Am J Physiol Renal Physiol. 2015;308(5):F377–87. doi:10.1152/ajprenal.00477.2013.

    Article  CAS  PubMed  Google Scholar 

  34. Oudit GY, Penninger JM. Cardiac regulation by phosphoinositide 3-kinases and PTEN. Cardiovasc Res. 2009;82(2):250–60. doi:10.1093/cvr/cvp014.

    Article  CAS  PubMed  Google Scholar 

  35. Kang H, Chang W, Hurley M, Vignery A, Wu D. Important roles of PI3Kgamma in osteoclastogenesis and bone homeostasis. Proc Natl Acad Sci U S A. 2010;107(29):12901–6. doi:10.1073/pnas.1001499107.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Benigni A, Cassis P, Remuzzi G. Angiotensin II revisited: new roles in inflammation, immunology and aging. EMBO Mol Med. 2010;2(7):247–57. doi:10.1002/emmm.201000080.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Weber G, Pushpakumar S, Sen U. Hydrogen sulfide alleviates hypertensive kidney dysfunction through an epigenetic mechanism. Am J Physiol Heart Circ Physiol. 2017; doi:10.1152/ajpheart.00637.2016.

    PubMed  Google Scholar 

  38. Arpon A, Riezu-Boj JI, Milagro FI, Razquin C, Martinez-Gonzalez MA, Corella D, et al. Adherence to Mediterranean diet is associated with methylation changes in inflammation-related genes in peripheral blood cells. J Physiol Biochem. 2017; doi:10.1007/s13105-017-0552-6.

    PubMed  Google Scholar 

  39. Chung AS, Lee J, Ferrara N. Targeting the tumour vasculature: insights from physiological angiogenesis. Nat Rev Cancer. 2010;10(7):505–14. doi:10.1038/nrc2868.

    Article  CAS  PubMed  Google Scholar 

  40. •• Henning RJ. Therapeutic angiogenesis: angiogenic growth factors for ischemic heart disease. Futur Cardiol. 2016;12(5):585–99. doi:10.2217/fca-2016-0006. A better knowledge on therapeutic angiogenesis.

    Article  CAS  Google Scholar 

  41. Marek-Trzonkowska N, Kwieczynska A, Reiwer-Gostomska M, Kolinski T, Molisz A, Siebert J. Arterial hypertension is characterized by imbalance of pro-angiogenic versus anti-angiogenic factors. PLoS One. 2015;10(5):e0126190. doi:10.1371/journal.pone.0126190.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Kontaraki JE, Marketou ME, Zacharis EA, Parthenakis FI, Vardas PE. MicroRNA-9 and microRNA-126 expression levels in patients with essential hypertension: potential markers of target-organ damage. J Am Soc Hypertens. 2014;8(6):368–75. doi:10.1016/j.jash.2014.03.324.

    Article  CAS  PubMed  Google Scholar 

  43. Li S, Zhu J, Zhang W, Chen Y, Zhang K, Popescu LM, et al. Signature microRNA expression profile of essential hypertension and its novel link to human cytomegalovirus infection. Circulation. 2011;124(2):175–84. doi:10.1161/CIRCULATIONAHA.110.012237.

    Article  CAS  PubMed  Google Scholar 

  44. • Kontaraki JE, Marketou ME, Parthenakis FI, Maragkoudakis S, Zacharis EA, Petousis S, et al. Hypertrophic and antihypertrophic microRNA levels in peripheral blood mononuclear cells and their relationship to left ventricular hypertrophy in patients with essential hypertension. J Am Soc Hypertens. 2015;9(10):802–10. doi:10.1016/j.jash.2015.07.013. MicroRNAs regulate several pathophysiological cardiovascular diseases promoting beneficial therapeutic strategies.

    Article  CAS  PubMed  Google Scholar 

  45. •• Kontaraki JE, Marketou ME, Zacharis EA, Parthenakis FI, Vardas PE. Differential expression of vascular smooth muscle-modulating microRNAs in human peripheral blood mononuclear cells: novel targets in essential hypertension. J Hum Hypertens. 2014;28(8):510–6. doi:10.1038/jhh.2013.117. MicroRNAs regulating hypertension in vascular smooth muscle

    Article  CAS  PubMed  Google Scholar 

  46. 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(3):294–302. doi:10.1164/rccm.201205-0839OC.

    Article  CAS  PubMed  Google Scholar 

  47. Courboulin A, Paulin R, Giguere NJ, Saksouk N, Perreault T, Meloche J, et al. Role for miR-204 in human pulmonary arterial hypertension. J Exp Med. 2011;208(3):535–48. doi:10.1084/jem.20101812.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Zhu N, Zhang D, Chen S, Liu X, Lin L, Huang X, et al. Endothelial enriched microRNAs regulate angiotensin II-induced endothelial inflammation and migration. Atherosclerosis. 2011;215(2):286–93. doi:10.1016/j.atherosclerosis.2010.12.024.

    Article  CAS  PubMed  Google Scholar 

  49. Eskildsen TV, Jeppesen PL, Schneider M, Nossent AY, Sandberg MB, Hansen PB, et al. Angiotensin II regulates microRNA-132/-212 in hypertensive rats and humans. Int J Mol Sci. 2013;14(6):11190–207. doi:10.3390/ijms140611190.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Kumar S, Kim CW, Simmons RD, Jo H. Role of flow-sensitive microRNAs in endothelial dysfunction and atherosclerosis: mechanosensitive athero-miRs. Arterioscler Thromb Vasc Biol. 2014;34(10):2206–16. doi:10.1161/ATVBAHA.114.303425.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Harris TA, Yamakuchi M, Kondo M, Oettgen P, Lowenstein CJ. Ets-1 and Ets-2 regulate the expression of microRNA-126 in endothelial cells. Arterioscler Thromb Vasc Biol. 2010;30(10):1990–7. doi:10.1161/ATVBAHA.110.211706.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Cheng HS, Sivachandran N, Lau A, Boudreau E, Zhao JL, Baltimore D, et al. MicroRNA-146 represses endothelial activation by inhibiting pro-inflammatory pathways. EMBO Mol Med. 2013;5(7):1017–34. doi:10.1002/emmm.201202318.

    Article  PubMed  CAS  Google Scholar 

  53. Yang Y, Zhou Y, Cao Z, Tong XZ, Xie HQ, Luo T, et al. miR-155 functions downstream of angiotensin II receptor subtype 1 and calcineurin to regulate cardiac hypertrophy. Exp Ther Med. 2016;12(3):1556–62. doi:10.3892/etm.2016.3506.

    PubMed  PubMed Central  Google Scholar 

  54. •• Karolina DS, Tavintharan S, Armugam A, Sepramaniam S, Pek SL, Wong MT, et al. Circulating miRNA profiles in patients with metabolic syndrome. J Clin Endocrinol Metab. 2012;97(12):E2271–6. doi:10.1210/jc.2012-1996. Implication of circulating microRNAs in metabolic syndrome.

    Article  CAS  PubMed  Google Scholar 

  55. Wei C, Henderson H, Spradley C, Li L, Kim IK, Kumar S, et al. Circulating miRNAs as potential marker for pulmonary hypertension. PLoS One. 2013;8(5):e64396. doi:10.1371/journal.pone.0064396.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Cengiz M, Karatas OF, Koparir E, Yavuzer S, Ali C, Yavuzer H, et al. Differential expression of hypertension-associated microRNAs in the plasma of patients with white coat hypertension. Medicine (Baltimore). 2015;94(13):e693. doi:10.1097/MD.0000000000000693.

    Article  CAS  Google Scholar 

  57. Park MY, Herrmann SM, Saad A, Widmer RJ, Tang H, Zhu XY, et al. Circulating and renal vein levels of microRNAs in patients with renal artery stenosis. Nephrol Dial Transplant. 2015;30(3):480–90. doi:10.1093/ndt/gfu341.

    Article  PubMed  Google Scholar 

  58. Marques FZ, Romaine SP, Denniff M, Eales J, Dormer J, Garrelds IM, et al. Signatures of miR-181a on renal transcriptome and blood pressure. Mol Med. 2015; doi:10.2119/molmed.2015.00096.

    PubMed  PubMed Central  Google Scholar 

  59. Mandraffino G, Imbalzano E, Sardo MA, D'Ascola A, Mamone F, Lo Gullo A, et al. Circulating progenitor cells in hypertensive patients with different degrees of cardiovascular involvement. J Hum Hypertens. 2014;28(9):543–50. doi:10.1038/jhh.2014.7.

    Article  CAS  PubMed  Google Scholar 

  60. • Yang Q, Jia C, Wang P, Xiong M, Cui J, Li L, et al. MicroRNA-505 identified from patients with essential hypertension impairs endothelial cell migration and tube formation. Int J Cardiol. 2014;177(3):925–34. doi:10.1016/j.ijcard.2014.09.204. Role of circulating miRNA on angiogenesis.

    Article  PubMed  Google Scholar 

  61. Thulasingam S, Massilamany C, Gangaplara A, Dai H, Yarbaeva S, Subramaniam S, et al. miR-27b*, an oxidative stress-responsive microRNA modulates nuclear factor-kB pathway in RAW 264.7 cells. Mol Cell Biochem. 2011;352(1–2):181–8. doi:10.1007/s11010-011-0752-2.

    Article  CAS  PubMed  Google Scholar 

  62. Zhang W, Yan L, Li Y, Chen W, Hu N, Wang H, et al. Roles of miRNA-24 in regulating endothelial nitric oxide synthase expression and vascular endothelial cell proliferation. Mol Cell Biochem. 2015;405(1–2):281–9. doi:10.1007/s11010-015-2418-y.

    Article  CAS  PubMed  Google Scholar 

  63. Sun HX, Zeng DY, Li RT, Pang RP, Yang H, Hu YL, et al. Essential role of microRNA-155 in regulating endothelium-dependent vasorelaxation by targeting endothelial nitric oxide synthase. Hypertension. 2012;60(6):1407–14. doi:10.1161/HYPERTENSIONAHA.112.197301.

    Article  CAS  PubMed  Google Scholar 

  64. Magenta A, Greco S, Gaetano C, Martelli F. Oxidative stress and microRNAs in vascular diseases. Int J Mol Sci. 2013;14(9):17319–46. doi:10.3390/ijms140917319.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Wang L, Yuan Y, Li J, Ren H, Cai Q, Chen X, et al. MicroRNA-1 aggravates cardiac oxidative stress by post-transcriptional modification of the antioxidant network. Cell Stress Chaperones. 2015;20(3):411–20. doi:10.1007/s12192-014-0565-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Hulsmans M, Holvoet P. The vicious circle between oxidative stress and inflammation in atherosclerosis. J Cell Mol Med. 2010;14(1–2):70–8. doi:10.1111/j.1582-4934.2009.00978.x.

    Article  CAS  PubMed  Google Scholar 

  67. Celic T, Metzinger-Le Meuth V, Six I, Massy ZA, Metzinger L. The mir-221/222 cluster is a key player in vascular biology via the fine-tuning of endothelial cell physiology. Curr Vasc Pharmacol. 2017;15(1):40–6.

    Article  CAS  PubMed  Google Scholar 

  68. Santovito D, Mandolini C, Marcantonio P, De Nardis V, Bucci M, Paganelli C, et al. Overexpression of microRNA-145 in atherosclerotic plaques from hypertensive patients. Expert Opin Ther Targets. 2013;17(3):217–23. doi:10.1517/14728222.2013.745512.

    Article  CAS  PubMed  Google Scholar 

  69. Li N, Hwangbo C, Jaba IM, Zhang J, Papangeli I, Han J, et al. miR-182 modulates myocardial hypertrophic response induced by angiogenesis in heart. Sci Rep. 2016;6:21228. doi:10.1038/srep21228.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Nicoli S, Standley C, Walker P, Hurlstone A, Fogarty KE, Lawson ND. MicroRNA-mediated integration of haemodynamics and Vegf signalling during angiogenesis. Nature. 2010;464(7292):1196–200. doi:10.1038/nature08889.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Otsuka M, Zheng M, Hayashi M, Lee JD, Yoshino O, Lin S, et al. Impaired microRNA processing causes corpus luteum insufficiency and infertility in mice. J Clin Invest. 2008;118(5):1944–54. doi:10.1172/JCI33680.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Bonauer A, Carmona G, Iwasaki M, Mione M, Koyanagi M, Fischer A, et al. MicroRNA-92a controls angiogenesis and functional recovery of ischemic tissues in mice. Science. 2009;324(5935):1710–3. doi:10.1126/science.1174381.

    Article  CAS  PubMed  Google Scholar 

  73. •• Kato N, Loh M, Takeuchi F, Verweij N, Wang X, Zhang W, et al. Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation. Nat Genet. 2015;47(11):1282–93. Role of DNA methylation in blood pressure regulation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Raftopoulos L, Katsi V, Makris T, Tousoulis D, Stefanadis C, Kallikazaros I. Epigenetics, the missing link in hypertension. Life Sci. 2015;129:22–6.

    Article  CAS  PubMed  Google Scholar 

  75. Udali S, Guarini P, Moruzzi S, Choi SW, Friso S. Cardiovascular epigenetics: from DNA methylation to microRNAs. Mol Asp Med. 2013;34(4):883–901. doi:10.1016/j.mam.2012.08.001.

    Article  CAS  Google Scholar 

  76. Friso S, Carvajal CA, Fardella CE, Olivieri O. Epigenetics and arterial hypertension: the challenge of emerging evidence. Transl Res. 2015;165(1):154–165. doi:10.1016/j.trsl.2014.06.007.

  77. Bavishi C, Bangalore S, Messerli FH. Renin angiotensin aldosterone system inhibitors in hypertension: is there evidence for benefit independent of blood pressure reduction? Prog Cardiovasc Dis. 2016;59(3):253–61. doi:10.1016/j.pcad.2016.10.002.

    Article  PubMed  Google Scholar 

  78. Pei F, Wang X, Yue R, Chen C, Huang J, Huang J, et al. Differential expression and DNA methylation of angiotensin type 1A receptors in vascular tissues during genetic hypertension development. Mol Cell Biochem. 2015;402(1–2):1–8. doi:10.1007/s11010-014-2295-9.

    Article  CAS  PubMed  Google Scholar 

  79. De Vries N, Prestes P, Rana I, Harrap SB, Charchar FJ. YIA 03-04 epigenetic changes after acute treatment with acute angiotensin converting enzyme inhibitors (ACEi). J Hypertens. 2016;34(Suppl 1 - ISH 2016 Abstract Book):e204–e5. doi:10.1097/01.hjh.0000500443.76719.d5.

    Article  PubMed  Google Scholar 

  80. Chu A, Gozal D, Cortese R, Wang Y. Cardiovascular dysfunction in adult mice following postnatal intermittent hypoxia. Pediatr Res. 2015;77(3):425–33. doi:10.1038/pr.2014.197.

    Article  CAS  PubMed  Google Scholar 

  81. Ast J, Jablecka A, Bogdanski P, Smolarek I, Krauss H, Chmara E. Evaluation of the antihypertensive effect of L-arginine supplementation in patients with mild hypertension assessed with ambulatory blood pressure monitoring. Med Sci Monit. 2010;16(5):CR266–71.

    PubMed  Google Scholar 

  82. Seckl JR, Meaney MJ. Glucocorticoid programming. Ann N Y Acad Sci. 2004;1032:63–84. doi:10.1196/annals.1314.006.

    Article  CAS  PubMed  Google Scholar 

  83. Pojoga LH, Williams JS, Yao TM, Kumar A, Raffetto JD, do Nascimento GR, et al. Histone demethylase LSD1 deficiency during high-salt diet is associated with enhanced vascular contraction, altered NO-cGMP relaxation pathway, and hypertension. Am J Physiol Heart Circ Physiol. 2011;301(5):H1862–71. doi:10.1152/ajpheart.00513.2011.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Wang S, Aurora AB, Johnson BA, Qi X, McAnally J, Hill JA, et al. The endothelial-specific microRNA miR-126 governs vascular integrity and angiogenesis. Dev Cell. 2008;15(2):261–71. doi:10.1016/j.devcel.2008.07.002.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. Menghini R, Casagrande V, Cardellini M, Martelli E, Terrinoni A, Amati F, et al. MicroRNA 217 modulates endothelial cell senescence via silent information regulator 1. Circulation. 2009;120(15):1524–32. doi:10.1161/CIRCULATIONAHA.109.864629.

    Article  CAS  PubMed  Google Scholar 

  86. Sabatel C, Malvaux L, Bovy N, Deroanne C, Lambert V, Gonzalez ML, et al. MicroRNA-21 exhibits antiangiogenic function by targeting RhoB expression in endothelial cells. PLoS One. 2011;6(2):e16979. doi:10.1371/journal.pone.0016979.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Sequeira-Lopez ML, Weatherford ET, Borges GR, Monteagudo MC, Pentz ES, Harfe BD, et al. The microRNA-processing enzyme dicer maintains juxtaglomerular cells. J Am Soc Nephrol. 2010;21(3):460–7. doi:10.1681/ASN.2009090964.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Li D, Yang P, Xiong Q, Song X, Yang X, Liu L, et al. MicroRNA-125a/b-5p inhibits endothelin-1 expression in vascular endothelial cells. J Hypertens. 2010;28(8):1646–54. doi:10.1097/HJH.0b013e32833a4922.

    Article  CAS  PubMed  Google Scholar 

  89. Pankratz F, Bemtgen X, Zeiser R, Leonhardt F, Kreuzaler S, Hilgendorf I, et al. MicroRNA-155 exerts cell-specific antiangiogenic but proarteriogenic effects during adaptive neovascularization. Circulation. 2015;131(18):1575–89. doi:10.1161/CIRCULATIONAHA.114.014579.

    Article  CAS  PubMed  Google Scholar 

  90. Liao YC, Wang YS, Guo YC, Lin WL, Chang MH, Juo SH. Let-7g improves multiple endothelial functions through targeting transforming growth factor-beta and SIRT-1 signaling. J Am Coll Cardiol. 2014;63(16):1685–94. doi:10.1016/j.jacc.2013.09.069.

    Article  CAS  PubMed  Google Scholar 

  91. Xin M, Small EM, Sutherland LB, Qi X, McAnally J, Plato CF, et al. MicroRNAs miR-143 and miR-145 modulate cytoskeletal dynamics and responsiveness of smooth muscle cells to injury. Genes Dev. 2009;23(18):2166–78. doi:10.1101/gad.1842409.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Head GA, Gueguen C, Marques FZ, Jackson KL, Eikelis N, Stevenson ER, et al. 6b.01: effect of renal denervation on blood pressure and microRNA 181a in hypertensive Schlager mice. J Hypertens. 2015;33(Suppl 1):e76. doi:10.1097/01.hjh.0000467556.72842.0d.

    Article  PubMed  Google Scholar 

  93. Marques FZ, Booth SA, Charchar FJ. The emerging role of non-coding RNA in essential hypertension and blood pressure regulation. J Hum Hypertens. 2015;29(8):459–67. doi:10.1038/jhh.2014.99.

    Article  CAS  PubMed  Google Scholar 

  94. Liu Y, Taylor NE, Lu L, Usa K, Cowley Jr AW, Ferreri NR, et al. Renal medullary microRNAs in Dahl salt-sensitive rats: miR-29b regulates several collagens and related genes. Hypertension. 2010;55(4):974–82. doi:10.1161/HYPERTENSIONAHA.109.144428.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Gu Q, Wang B, Zhang XF, Ma YP, Liu JD, Wang XZ. Contribution of renin-angiotensin system to exercise-induced attenuation of aortic remodeling and improvement of endothelial function in spontaneously hypertensive rats. Cardiovasc Pathol. 2014;23(5):298–305. doi:10.1016/j.carpath.2014.05.006.

    Article  CAS  PubMed  Google Scholar 

  96. Haugen AC, Schug TT, Collman G, Heindel JJ. Evolution of DOHaD: the impact of environmental health sciences. J Dev Orig Health Dis. 2015;6(2):55–64. doi:10.1017/S2040174414000580.

    Article  CAS  PubMed  Google Scholar 

  97. •• Barker DJ, Osmond C. Infant mortality, childhood nutrition, and ischaemic heart disease in England and Wales. Lancet. 1986;1(8489):1077–81. Undernutrition in early life increases metabolic disorder as well as hypertension.

    Article  CAS  PubMed  Google Scholar 

  98. Hoy WE, Hughson MD, Bertram JF, Douglas-Denton R, Amann K. Nephron number, hypertension, renal disease, and renal failure. J Am Soc Nephrol. 2005;16(9):2557–64. doi:10.1681/ASN.2005020172.

    Article  PubMed  Google Scholar 

  99. Paixao AD, Alexander BT. How the kidney is impacted by the perinatal maternal environment to develop hypertension. Biol Reprod. 2013;89(6):144. doi:10.1095/biolreprod.113.111823.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  100. Hogg K, Blair JD, McFadden DE, von Dadelszen P, Robinson WP. Early onset pre-eclampsia is associated with altered DNA methylation of cortisol-signalling and steroidogenic genes in the placenta. PLoS One. 2013;8(5):e62969. doi:10.1371/journal.pone.0062969.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Drake AJ, McPherson RC, Godfrey KM, Cooper C, Lillycrop KA, Hanson MA, et al. An unbalanced maternal diet in pregnancy associates with offspring epigenetic changes in genes controlling glucocorticoid action and foetal growth. Clin Endocrinol. 2012;77(6):808–15. doi:10.1111/j.1365-2265.2012.04453.x.

    Article  CAS  Google Scholar 

  102. Pham TD, MacLennan NK, Chiu CT, Laksana GS, Hsu JL, Lane RH. Uteroplacental insufficiency increases apoptosis and alters p53 gene methylation in the full-term IUGR rat kidney. Am J Physiol Regul Integr Comp Physiol. 2003;285(5):R962–70. doi:10.1152/ajpregu.00201.2003.

    Article  CAS  PubMed  Google Scholar 

  103. DuPont JJ, McCurley A, Davel AP, McCarthy J, Bender SB, Hong K, et al. Vascular mineralocorticoid receptor regulates microRNA-155 to promote vasoconstriction and rising blood pressure with aging. JCI Insight. 2016;1(14):e88942. doi:10.1172/jci.insight.88942.

    Article  PubMed  PubMed Central  Google Scholar 

  104. Parthenakis F, Marketou M, Kontaraki J, Patrianakos A, Nakou H, Touloupaki M, et al. Low levels of microRNA-21 are a marker of reduced arterial stiffness in well-controlled hypertension. J Clin Hypertens (Greenwich). 2016; doi:10.1111/jch.12900.

    Google Scholar 

  105. Li H, Zhang X, Wang F, Zhou L, Yin Z, Fan J, et al. MicroRNA-21 lowers blood pressure in spontaneous hypertensive rats by upregulating mitochondrial translation. Circulation. 2016;134(10):734–51. doi:10.1161/CIRCULATIONAHA.116.023926.

    Article  CAS  PubMed  Google Scholar 

  106. 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 Invest. 2016;126(7):2495–508. doi:10.1172/JCI83361.

    Article  PubMed  PubMed Central  Google Scholar 

  107. Gubrij IB, Pangle AK, Pang L, Johnson LG. Reversal of microRNA dysregulation in an animal model of pulmonary hypertension. PLoS One. 2016;11(1):e0147827. doi:10.1371/journal.pone.0147827.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Acknowledgments

The current work was supported by the J.A. deSève Research Chair in Nutrition.

Author information

Authors and Affiliations

  1. Research Centre, Sainte-Justine University Hospital Health Centre, Montreal, Quebec, H3T 1C5, Canada

    Emile Levy, Schohraya Spahis, Jean-Luc Bigras & Edgard Delvin

  2. Department of Nutrition, Université de Montréal, Montreal, Quebec, H3C 3J7, Canada

    Emile Levy & Schohraya Spahis

  3. Institute of Nutrition and Functional Foods, Laval University, Quebec, Quebec, G1V 0A6, Canada

    Emile Levy & Schohraya Spahis

  4. EPODE International Network, Paris, France

    Emile Levy & Jean-Michel Borys

  5. GI-Nutrition Unit, Sainte-Justine University Hospital Health Centre, 3175 Ste-Catherine Road, Montreal, Quebec, H3T 1C5, Canada

    Emile Levy

Authors
  1. Emile Levy
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Schohraya Spahis
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jean-Luc Bigras
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Edgard Delvin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jean-Michel Borys
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Emile Levy.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflicts of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on Hypertension and Metabolic Syndrome

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Levy, E., Spahis, S., Bigras, JL. et al. The Epigenetic Machinery in Vascular Dysfunction and Hypertension. Curr Hypertens Rep 19, 52 (2017). https://doi.org/10.1007/s11906-017-0745-y

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11906-017-0745-y

Keywords

Search

Navigation