Skip to main content
SpringerLink
Log in

Oscillating shear stress mediates mesenchymal transdifferentiation of EPCs by the Kir2.1 channel

  • Original Article
  • Published:
Heart and Vessels Aims and scope Submit manuscript

Abstract

Although endothelial progenitor cells (EPCs) are considered to be an essential source of vascular endothelial repair, their bidirectional differentiation determines that they play a double-edged role in the restoration of endothelial injury. In this research, we investigated the effect of Kir2.1 ion channel on the transdifferentiation of endothelial progenitor cells (EPCs) under the oscillating shear stress (OSS) and the molecular mechanisms underlying the pathological vascular remodeling. EPCs were treated with OSS (± 3.5 dynes/cm2, 1 Hz) simulated with the parallel flow chamber system. The results have shown that OSS promoted the expression of α-SMA and SM22, markers of mesenchymal cells on EPCs. Moreover, OSS also increased expression of Kir2.1 in EPCs. The down-regulation of Kir2.1 reduced OSS-induced EPC mesenchymal transdifferentiation. The overexpression of Kir2.1 suppressed the angiogenic abilities of EPCs in vitro. In parallel, the overexpression of Kir2.1 on EPCs thickened the carotid tunica intima in rat carotid artery balloon injured model in vivo. Taken together, those data indicated that the OSS could facilitate the transdifferentiation of EPCs by increasing Kir2.1 expression. This study provides a novel insight into the pathogenesis of cardiovascular diseases and gives evidence for Kir2.1 as a potential therapeutic target.

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
Fig. 4

Similar content being viewed by others

References

  1. Shi N, Mei X, Chen SY (2019) Smooth muscle cells in vascular remodeling. Arterioscler Thromb Vasc Biol 39(12):e247–e252

    Article  CAS  PubMed  Google Scholar 

  2. Zhao H, Mao J, Yuan Y, Feng J, Cheng H, Fan G, Zhang Y, Li T (2019) Sodium dichloroacetate stimulates angiogenesis by improving endothelial precursor cell function in an AKT/GSK-3beta/Nrf2 dependent pathway in vascular dementia rats. Front Pharmacol 10:523

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Hong SH, Jang HH, Lee SR, Lee KH, Woo JS, Kim JB, Kim WS, Min BI, Cho KH, Kim KS, Cheng X, Kim W (2015) Impact of lysophosphatidylcholine on survival and function of UEA-1(+)acLDL (+) endothelial progenitor cells in patients with coronary artery disease. Heart Vessels 30(1):115–125

    Article  PubMed  Google Scholar 

  4. Valencia-Nunez DM, Kreutler W, Moya-Gonzalez J, Alados-Arboledas P, Munoz-Carvajal I, Carmona A, Ramirez-Chamond R, Carracedo-Anon J (2017) Endothelial vascular markers in coronary surgery. Heart Vessels 32(11):1390–1399

    Article  PubMed  Google Scholar 

  5. Cheng M, Li X, Guo Z, Cui X, Li H, Jin C, Zhang X, Guan X (2013) Puerarin accelerates re-endothelialization in a carotid arterial injury model: impact on vasodilator concentration and vascular cell functions. J Cardiovasc Pharmacol 62(4):361–368

    Article  CAS  PubMed  Google Scholar 

  6. Li H, Zhang X, Guan X, Cui X, Wang Y, Chu H, Cheng M (2012) Advanced glycation end products impair the migration, adhesion and secretion potentials of late endothelial progenitor cells. Cardiovasc Diabetol 11:46

    Article  PubMed  PubMed Central  Google Scholar 

  7. Zhang C, Zeng L, Emanueli C, Xu Q (2013) Blood flow and stem cells in vascular disease. Cardiovasc Res 99(2):251–259

    Article  CAS  PubMed  Google Scholar 

  8. Ji H, Atchison L, Chen Z, Chakraborty S, Jung Y, Truskey GA, Christoforou N, Leong KW (2016) Transdifferentiation of human endothelial progenitors into smooth muscle cells. Biomaterials 85:180–194

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Cheng M, Guan X, Li H, Cui X, Zhang X, Li X, Jing X, Wu H, Avsar E (2013) Shear stress regulates late EPC differentiation via mechanosensitive molecule-mediated cytoskeletal rearrangement. PLoS One 8(7):e67675

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Cui X, Zhang X, Guan X, Li H, Li X, Lu H, Cheng M (2012) Shear stress augments the endothelial cell differentiation marker expression in late EPCs by upregulating integrins. Biochem Biophys Res Commun 425(2):419–425

    Article  CAS  PubMed  Google Scholar 

  11. Baeyens N, Bandyopadhyay C, Coon BG, Yun S, Schwartz MA (2016) Endothelial fluid shear stress sensing in vascular health and disease. J Clin Investig 126(3):821–828

    Article  PubMed  Google Scholar 

  12. Chiu JJ, Chien S (2011) Effects of disturbed flow on vascular endothelium: pathophysiological basis and clinical perspectives. Physiol Rev 91(1):327–387

    Article  PubMed  Google Scholar 

  13. Mulla Y, MacKintosh FC, Koenderink GH (2019) Origin of slow stress relaxation in the cytoskeleton. Phys Rev Lett 122(21):218102

    Article  CAS  PubMed  Google Scholar 

  14. Ahn SJ, Fancher IS, Bian JT, Zhang CX, Schwab S, Gaffin R, Phillips SA, Levitan I (2017) Inwardly rectifying K(+) channels are major contributors to flow-induced vasodilatation in resistance arteries. J Physiol 595(7):2339–2364

    Article  CAS  PubMed  Google Scholar 

  15. Hibino H, Inanobe A, Furutani K, Murakami S, Findlay I, Kurachi Y (2010) Inwardly rectifying potassium channels: their structure, function, and physiological roles. Physiol Rev 90(1):291–366

    Article  CAS  PubMed  Google Scholar 

  16. Gonzalez C, Baez-Nieto D, Valencia I, Oyarzun I, Rojas P, Naranjo D, Latorre R (2012) K(+) channels: function-structural overview. Compr Physiol 2(3):2087–2149

    PubMed  Google Scholar 

  17. Fang Y, Schram G, Romanenko VG, Shi C, Conti L, Vandenberg CA, Davies PF, Nattel S, Levitan I (2005) Functional expression of Kir2.x in human aortic endothelial cells: the dominant role of Kir2.2. Am J Physiol Cell Physiol 289(5):C1134–1144

    Article  CAS  PubMed  Google Scholar 

  18. Hoger JH, Ilyin VI, Forsyth S, Hoger A (2002) Shear stress regulates the endothelial Kir2.1 ion channel. Proc Natl Acad Sci USA 99(11):7780–7785

    Article  CAS  PubMed  Google Scholar 

  19. Zhang X, Cui X, Li X, Yan H, Li H, Guan X, Wang Y, Liu S, Qin X, Cheng M (2019) Inhibition of Kir2.1 channel-induced depolarization promotes cell biological activity and differentiation by modulating autophagy in late endothelial progenitor cells. J Mol Cell Cardiol 127:57–66

    Article  CAS  PubMed  Google Scholar 

  20. Kutikhin AG, Sinitsky MY, Yuzhalin AE, Velikanova EA (2018) Shear stress: An essential driver of endothelial progenitor cells. J Mol Cell Cardiol 118:46–69

    Article  CAS  PubMed  Google Scholar 

  21. Hu Q, Zhang T, Li Y, Feng J, Nie R, Wang X, Peng C, Ke X (2020) beta2AR-dependent signaling contributes to in-vivo reendothelialization capacity of endothelial progenitor cells by shear stress. J Hypertens 38(1):82–94

    Article  CAS  PubMed  Google Scholar 

  22. He J, Han X, Wang S, Zhang Y, Dai X, Liu B, Liu L, Zhao X (2019) Cell sheets of co-cultured BMP-2-modified bone marrow stromal cells and endothelial progenitor cells accelerate bone regeneration in vitro. Exp Ther Med 18(5):3333–3340

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Jin P, Jan LY, Jan YN (2020) Mechanosensitive ion channels: structural features relevant to mechanotransduction mechanisms. Annu Rev Neurosci. https://doi.org/10.1146/annurev-neuro-070918-050509

    Article  PubMed  Google Scholar 

  24. Qiao Y, Tang C, Wang Q, Wang D, Yan G, Zhu B (2016) Kir2.1 regulates rat smooth muscle cell proliferation, migration, and post-injury carotid neointimal formation. Biochem Biophys Res Commun 477(4):774–780

    Article  CAS  PubMed  Google Scholar 

  25. Leem YE, Jeong HJ, Kim HJ, Koh J, Kang K, Bae GU, Cho H, Kang JS (2016) Cdo regulates surface expression of Kir21 K+ channel in myoblast differentiation. PLoS One 11(7):e0158707

    Article  PubMed  PubMed Central  Google Scholar 

  26. van Vliet P, de Boer TP, van der Heyden MA, El Tamer MK, Sluijter JP, Doevendans PA, Goumans MJ (2010) Hyperpolarization induces differentiation in human cardiomyocyte progenitor cells. Stem Cell Rev Rep 6(2):178–185

    Article  PubMed  Google Scholar 

  27. Ji CD, Wang YX, Xiang DF, Liu Q, Zhou ZH, Qian F, Yang L, Ren Y, Cui W, Xu SL, Zhao XL, Zhang X, Wang Y, Zhang P, Wang JM, Cui YH, Bian XW (2018) Kir21 interaction with Stk38 promotes invasion and metastasis of human gastric cancer by enhancing MEKK2-MEK1/2-ERK1/2 signaling. Cancer Res 78(11):3041–3053

    Article  CAS  PubMed  Google Scholar 

  28. Criem N, Zwijsen A (2018) The epicardium obscures interpretations on endothelial-to-mesenchymal transition in the mouse atrioventricular canal explant assay. Sci Rep 8(1):4722

    Article  PubMed  PubMed Central  Google Scholar 

  29. Luan Z, Hu B, Wu L, Jin S, Ma X, Zhang J, Wang A (2018) Unfractionated heparin alleviates human lung endothelial barrier dysfunction induced by high mobility group box 1 through regulation of P38-GSK3beta-snail signaling pathway. Cell Physiol Biochem 46(5):1907–1918

    Article  CAS  PubMed  Google Scholar 

  30. Ji Y, Dou YN, Zhao QW, Zhang JZ, Yang Y, Wang T, Xia YF, Dai Y, Wei ZF (2016) Paeoniflorin suppresses TGF-beta mediated epithelial–mesenchymal transition in pulmonary fibrosis through a Smad-dependent pathway. Acta Pharmacol Sin 37(6):794–804

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Cantoni S, Bianchi F, Galletti M, Olivi E, Alviano F, Galie N, Ventura C (2015) Occurring of in vitro functional vasculogenic pericytes from human circulating early endothelial precursor cell culture. Stem Cells Int 2015:943671

    Article  PubMed  PubMed Central  Google Scholar 

  32. Sa da Bandeira D, Casamitjana J, Crisan M (2017) Pericytes, integral components of adult hematopoietic stem cell niches. Pharmacol Ther 171:104–113

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This work was supported by the National Natural Science Foundation of China (Grants 81700406, 81870237, and 31570941), the Natural Science Foundation of Shandong Province (ZR2016CM20 and ZR2014JL018), and the Project of Shandong Province Higher Educational Science and Technology Program (J15LK08).

Author information

Author notes

  1. Jifeng Li, Yanting He, Hongnan Bu authors have contributed equally to this study.

Authors and Affiliations

  1. School of Basic Medical Sciences, Weifang Medical University, Weifang, 261053, Shandong, People’s Republic of China

    Jifeng Li, Yanting He, Meiyue Wang, Jie Yu, Lanlan Li, Hong Li, Xiaoyun Zhang, Xiaodong Cui & Min Cheng

  2. Department of Gynaecology and Obstetrics, The 89 Hospital of Chinese PLA, Weifang, 261021, Shandong, People’s Republic of China

    Hongnan Bu

Authors
  1. Jifeng Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yanting He
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hongnan Bu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Meiyue Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jie Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lanlan Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hong Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Xiaoyun Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Xiaodong Cui
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Min Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Xiaodong Cui or Min Cheng.

Ethics declarations

Conflict of interest

All authors in this paper declare that they have no conflicts 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

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, J., He, Y., Bu, H. et al. Oscillating shear stress mediates mesenchymal transdifferentiation of EPCs by the Kir2.1 channel. Heart Vessels 35, 1473–1482 (2020). https://doi.org/10.1007/s00380-020-01625-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00380-020-01625-w

Keywords

Search

Navigation