Skip to main content
Log in

Electroacupuncture Attenuated Phenotype Transformation of Vascular Smooth Muscle Cells via PI3K/Akt and MAPK Signaling Pathways in Spontaneous Hypertensive Rats

  • Acupuncture Research
  • Published:
Chinese Journal of Integrative Medicine Aims and scope Submit manuscript

Abstract

Objective

To investigate whether the antihypertensive mechanism of electroacupuncture (EA) is associated with attenuating phenotype transformation of vascular smooth muscle cells (VSMCs) via phosphoinositide3-kinase (PI3K)/protein kinase B (Akt) and mitogen-activated protein kinase (MAPK) signaling pathways.

Methods

Eight Wistar-ktoyo (WKY) rats were set as normal blood pressure group (normal group). A total of 32 spontaneous hypertensive rats (SHRs) were randomly divided into 4 groups using random number tables: a model group, an EA group, an EA+PI3K antagonist group (EA+P group), and an EA+p38 MAPK agonist+extracellular signal-regulated kinase (ERK) agonist group (EA+M group) (n=8/group). SHRs in EA group, EA+P group and EA+M group received EA treatment 5 sessions per week for continuous 4 weeks, while rats in the normal and model groups were bundled in same condition. The systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) of each rat was measured at 0 week and the 4th week. After 4-week intervention, thoracic aorta was collected for hematoxylin-eosin (HE) staining, immunohistochemistry [the contractile markers α-smooth muscle actin (α-SMA) and calponin and the synthetic marker osteopontin (OPN)] and Western blot [α-SMA, calponin, OPN, PI3K, phosphorylated-Akt (p-Akt), Akt, p-p42/44 ERK, total p42/44 ERK, p-p38 MAPK and total p38 MAPK].

Results

EA significantly reduced SBP, DBP and MAP (P<0.01). HE staining showed that the wall thickness of thoracic aorta in EA group was significantly decreased (P<0.01). From results of immunohistochemistry and Western blot, EA increased the expression of α-SMA and calponin, and decreased the expression of OPN (P<0.01). In addition, the expression of PI3K and p-Akt increased (P<0.01), while the expression of p-p42/44 ERK and p-p38 MAPK decreased in EA group (P<0.01). However, these effects were reversed by PI3K antagonist, p38 MAPK agonist and ERK agonist.

Conclusions

EA was an effective treatment for BP management. The antihypertensive effect of EA may be related with inhibition of phenotypic transformation of VSMCs, in which the activation of PI3K/Akt and the repression of MAPK pathway were involved.

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

Access this article

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

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Availability of Data and Materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. Mills KT, Stefanescu A. The global epidemiology of hypertension. Nat Rev Nephrol 2020;16:223–237.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Wang Z, Chen Z, Zhang L, Wang X, Hao G, Zhang Z, et al. Status of hypertension in China: results from the China hypertension survey, 2012–2015. Circulation 2018;137:2344–2356.

    Article  PubMed  Google Scholar 

  3. Himani N, Vijay KS. Gender prevalence of cardiovascular diseases in the geriatric population of India: a meta-analysis using R. World J Metaanal 2020;8:18–29.

    Google Scholar 

  4. 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;310:959–968.

    Article  CAS  PubMed  Google Scholar 

  5. Zhang LL, Wei PF, Chen SZ. Current situation and existing problems of acupuncture for primary hypertension. Chin Acupunct Moxibust (Chin) 2018;3:338–342.

    Google Scholar 

  6. Li M, Tjen ALSC, Guo ZL, Longhurst JC. Repetitive electroacupuncture attenuates cold-Induced hypertension through enkephalin in the rostral ventral lateral medulla. Sci Rep 2016;6:35791.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Zheng H, Li J, Li Y, Zhao L, Wu X, Chen J, et al. Acupuncture for patients with mild hypertension: a randomized controlled trial. J Clin Hypertens 2019;21:412–420.

    Article  Google Scholar 

  8. Baumbach GL, Heistad DD. Remodeling of cerebral arterioles in chronic hypertension. Hypertension 1989;13:968–972.

    Article  CAS  PubMed  Google Scholar 

  9. Renna NF, de las Heras N, Miatello RM. Pathophysiology of vascular remodeling in hypertension. Int J Hypertens 2013;2013:1–7.

    Article  Google Scholar 

  10. Wen J, Wang J, Guo L, Cai W, Wu Y, Chen W, et al. Chemerin stimulates aortic smooth muscle cell proliferation and migration via activation of autophagy in VSMCs of metabolic hypertension rats. Am J Transl Res 2019;11:1327–1342.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Yoshida T, Owens GK. Molecular determinants of vascular smooth muscle cell diversity. Circ Res 2005;96:280–291.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  13. 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;71:262–272.

    Article  CAS  PubMed  Google Scholar 

  14. 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;1864:2154–2168.

    Article  CAS  PubMed  Google Scholar 

  15. Choi KH, Kim JE, Song NR, Son JE, Hwang MK, Byun S, et al. Phosphoinositide 3-kinase is a novel target of piceatannol for inhibiting PDGF-BB-induced proliferation and migration in human aortic smooth muscle cells. Cardiovasc Res 2010;85:836–844.

    Article  CAS  PubMed  Google Scholar 

  16. Li F, Zhang L, Qiao T, Liang K, Zheng B. Effect of electroacupuncture stimulation of “Zusanli” “Quchi” on cell adhesion molecules P-selectin, E-selectin of prehypertension rats. J Liaoning Univ Tradit Chin Med (Chin) 2017;19:107–109.

    Google Scholar 

  17. Goncharova EA, Ammit AJ, Irani C, Carroll RG, Eszterhas AJ, Panettieri RA, et al. PI3K is required for proliferation and migration of human pulmonary vascular smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 2002;283:L354–L363.

    Article  CAS  PubMed  Google Scholar 

  18. Li C, Hu Y, Sturm G, Wick G, Xu Q. Ras/Rac-dependent activation of p38 mitogen-activated protein kinases in smooth muscle cells stimulated by cyclic strain stress. Arterioscler Thromb Vasc Biol 2000;20:E1–E9.

    Article  CAS  PubMed  Google Scholar 

  19. Li MX. Molecular mechanism of electroacupuncture therapy for hypertension based on Ghrelin-mediated PI3K/AKT/eNOS signaling pathway [Dissertation]. Chengdu: Chengdu Unversity of Traditional Chinese Medicine, 2019.

    Google Scholar 

  20. Liu X. The mechanism of acupuncture on YangMing meridian for hypertension based on the Ghrelin by gut microbiota regulation modulated p38MAPK/eNOS signal pathway [Dissertaion]. Chengdu: Chengdu Unversity of Traditional Chinese Medicine, 2020.

    Google Scholar 

  21. Hayashi K, Takahashi M, Kimura K, Nishida W, Saga H, Sobue K. Changes in the balance of phosphoinositide 3-kinase/protein kinase B (Akt) and the mitogen-activated protein kinases (ERK/p38MAPK) determine a phenotype of visceral and vascular smooth muscle cells. J Cell Biol 1999;145:727–740.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Thored P, Wood J, Arvidsson A, Cammenga J, Kokaia Z, Lindvall O. Long-term neuroblast migration along blood vessels in an area with transient angiogenesis and increased vascularization after stroke. Stroke 2007;38:3032–3039.

    Article  PubMed  Google Scholar 

  23. Yu H, Li W, Cao X, Wang X, Zhao Y, Song L, et al. Echinocystic acid, a natural plant extract, alleviates cerebral ischemia/reperfusion injury via inhibiting the JNK signaling pathway. Eur J Pharmacol 2019;861:172610.

    Article  CAS  PubMed  Google Scholar 

  24. Zhao TC, Zhang L, Liu JT, Guo TL. Disruption of Nox2 and TNFRp55/p75 eliminates cardioprotection induced by anisomycin. Am J Physiol Heart Circ Physiol 2012;303:H1263–H1272.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Zheng J, Sun H, Shen P. Effect of electro-acupuncture in Renying (ST9) on systolic blood pressure and contents of MDA, SOD, CAT, T-AOC in Serum of spontaneous hypertension rats. J Shandong Univ Tradit Chin Med (Chin) 2018;37:847–850.

    Google Scholar 

  26. Yang Q, Xu Y, Feng G, Hu C, Zhang Y, Cheng S, et al. p38 MAPK signal pathway involved in anti-inflammatory effect of Chaihu-Shugan-San and Shen-ling-bai-zhu-San on hepatocyte in non-alcoholic steatohepatitis rats. Afr J Tradit Complement Altern Med 2014;11:213–221.

    PubMed  Google Scholar 

  27. Collaborators GRF. Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet 2017;390:1345–1422.

    Article  Google Scholar 

  28. Sha R, Zhang B, Han X, Peng J, Zheng C, Zhang F, et al. Electroacupuncture alleviates ischemic brain injury by inhibiting the miR-223/NLRP3 pathway. Med Sci Monit 2019;25:4723–4733.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Zhang X, Lan D, Ning S, Jia H, Yu S. Botulinum toxin type A prevents the phenotypic transformation of fibroblasts induced by TGF-β 1 via the PTEN/PI3K/Akt signaling pathway. Int J Mol Med 2019;44:661–671.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Liu ML, Liang YJ, Li K, Yang K, Ma ZJ, Wu R, et al. Effect of silencing TRAF6 expression on phenotype transformation and expression of inflammatory cytokines in renal tubular epithelial cells induced by lipopolysaccharide. J Lanzhou Univ (Med Sci, Chin) 2017;43:32–38.

    Google Scholar 

  31. Li J, Sun M. The mechanism of acupuncture in treating essential hypertension: a narrative review. Int J Hypertens 2019;2019:8676490.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Li J. The clinical effectiveness of acupuncture at acupoints on the involved meridian according to syndrome differention for essential hypertension [Dissertation]. Chengdu: Chengdu University of Traditional Chinese Mdeicine, 2015.

    Google Scholar 

  33. Li P, Tjen ALSC, Cheng L, Liu D, Painovich J, Vinjamury S, et al. Long-lasting reduction of blood pressure by electroacupuncture in patients with hypertension: randomized controlled trial. Med Acupunct 2015;27:253–266.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Hwang HS, Kim YS, Ryu YH, Lee JE, Lee MS. Electroacupuncture delays hypertension development through enhancing NO/NOS activity in spontaneously hypertensive rats. Evid Based Complement Alternat Med 2010;2011:1–6.

    Article  Google Scholar 

  35. Tan X, Pan Y, Su W, Gong S, Zhu H, Chen H, et al. Acupuncture therapy for essential hypertension: a network meta-analysis. Ann Transl Med 2019;7:266.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Kapustin AN, Shanahan CM. Emerging roles for vascular smooth muscle cell exosomes in calcification and coagulation. J Physiol 2016;594:2905–2914.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Lavigne MC, Ramwell PW, Clarke R. Growth and phenotypic characterization of porcine coronary artery smooth muscle cells. In Vitro Cell Dev Biol Anim 1999;35:136–143.

    Article  CAS  PubMed  Google Scholar 

  38. Owens GK. Molecular control of vascular smooth muscle cell differentiation and phenotypic plasticity. Novartis Found Symp 2007;283:174–191.

    Article  CAS  PubMed  Google Scholar 

  39. Winder SJ, Sutherland C, Walsh MP. Biochemical and functional characterization of smooth muscle calponin. Adv Exp Med Biol 1991;304:37–51.

    Article  CAS  PubMed  Google Scholar 

  40. Pfisterer L, Feldner A, Hecker M, Korff T. Hypertension impairs myocardin function: a novel mechanism facilitating arterial remodelling. Cardiovasc Res 2012;96:120–129.

    Article  CAS  PubMed  Google Scholar 

  41. He F, Chu JF, Chen HW, Lin W, Lin S, Chen YQ, et al. Qingxuan Jiangya Decoction prevents blood pressure elevation and ameliorates vascular structural remodeling via modulating TGF-β 1/Smad pathway in spontaneously hypertensive rats. Chin J Integr Med 2020;26:180–187.

    Article  CAS  PubMed  Google Scholar 

  42. Guo Y, Lu J, Liang J, Zhao R, Xu J, Zhang W, et al. Effect of acupuncture at Renying (ST 9) on gene expression profile of hypothalamus in spontaneously hypertensive rats. J Tradit Chin Med 2018;38:227–241.

    Article  PubMed  Google Scholar 

  43. Touyz RM. Vascular remodeling, retinal arteries, and hypertension. Hypertension 2007;50:603–604.

    Article  CAS  PubMed  Google Scholar 

  44. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Zhang MJ, Liu Y, Hu ZC, Zhou Y, Pi Y, Guo L, et al. TRPV1 attenuates intracranial arteriole remodeling through inhibiting VSMC phenotypic modulation in hypertension. Histochem Cell Biol 2017;147:511–521.

    Article  CAS  PubMed  Google Scholar 

  46. Hao RW, Guan W, Guo JL, Wang HJ, Ji LX. Effects of electroacupuncture on blood pressure and vascular remodeling in rats with two-kidney and one-clip hypertension J Shanxi Univ Tradit Chin Med (Chin) 2017;18:16–19.

    Google Scholar 

  47. Dong J. Experimental study on the effect of electroacupuncture at “Zusanli” and “Quchi” points on p38MAPK signaling pathway in rats with prehypertension [Dissertation]. Shenyang: Liaoning University of Traditional Chinese Mdeicine, 2015.

    Google Scholar 

  48. Fu N. Effect of electroacupuncture at “Zusanli” and “Quchi” points on p38MAPK pathway in renal tissue of prehypertension rats [Dissertation]. Shenyang: Liaoning University of Traditional Chinese Mdeicine, 2017.

    Google Scholar 

  49. Ji Z, Liang J, Wu J, Zhang Y, Jia W. Effects of electroacupuncture at Taichong (LR 3) and Baihui (DU 20) on cardiac hypertrophy in rats with spontaneous hypertension. J Tradit Chin Med 2019;39:502–508.

    PubMed  Google Scholar 

  50. Hayashi K, Saga H, Chimori Y, Kimura K, Yamanaka Y, Sobue K. Differentiated phenotype of smooth muscle cells depends on signaling pathways through insulin-like growth factors and phosphatidylinositol 3-kinase. J Biol Chem 1998;273:28860–28867.

    Article  CAS  PubMed  Google Scholar 

  51. Zhang L, Zhang Y, Wu Y, Yu J, Zhang Y, Zeng F, et al. Role of the balance of Akt and MAPK pathways in the exercise-regulated phenotype switching in spontaneously hypertensive rats. Int J Mol Sci 2019;20.

  52. Zhang L, Xu Z, Wu Y, Liao J, Zeng F, Shi L. Akt/eNOS and MAPK signaling pathways mediated the phenotypic switching of thoracic aorta vascular smooth muscle cells in aging/hypertensive rats. Physiol Res 2018;67:543–553.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to thank Professor ZHENG Hui to help us copyedit the manuscript.

Author information

Authors and Affiliations

Authors

Contributions

The experiment was carried out by all the authors. Chen XY, Yang LP and Zheng YL drafted the manuscript. Li YX and Zhong DL analyzed the data. Jin RJ and Li J revised the manuscript.

Corresponding author

Correspondence to Juan Li.

Ethics declarations

The authors declare that they have no competing interests.

Additional information

Supported by the National Natural Science Foundation of China (Nos. 81704137, 82074516) and Sichuan Science and Technology Department (No. 2019YJ0331)

Electronic Supplementary Material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chen, Xy., Yang, Lp., Zheng, Yl. et al. Electroacupuncture Attenuated Phenotype Transformation of Vascular Smooth Muscle Cells via PI3K/Akt and MAPK Signaling Pathways in Spontaneous Hypertensive Rats. Chin. J. Integr. Med. 28, 357–365 (2022). https://doi.org/10.1007/s11655-021-2883-y

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11655-021-2883-y

Keywords

Navigation