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Effect of a Small Physiological Electric Field on Angiogenic Activity in First-Trimester Extravillous Trophoblast Cells

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Abstract

Electrical stimulation induces significant angiogenesis in vivo. We have shown that electrical stimulation of trophoblast cells has important functions in aspects of angiogenesis. In this study, we investigated the effects of a direct current electrical field on trophoblast angiogenic tube formation. A 6-hour exposure to electric fields ranging from 50 to 150 mV/mm dose dependently increased tube growth and network formation. Additionally, the effect was time dependent, with increased tube formation occurring between 4 and 8 hours, indicating stimulation of trophoblast cell angiogenesis. Electrical fields of small physiological magnitude stimulated vascular endothelial growth factor expression by trophoblast cells in the culture. Electric field treatment also resulted in activation of Akt, while the activity of extracellular-regulated kinase 1/2, p38, and c-Jun NH2-terminal kinase was not significantly changed. Pretreatment with the vascular endothelial growth factor receptor (VEGFR)-2 inhibitor, SU1498, resulted in potent inhibition of tube growth, and the Akt inhibitor, MK-2206 2HCl, significantly reduced electric field-stimulated tubulogenesis. These data suggest the importance of the VEGFR-2 signaling pathway during electric field-induced trophoblastic angiogenesis. This novel evidence indicates that endogenous electrical fields may promote angiogenesis of trophoblast cells by stimulating the VEGFR signaling pathway.

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References

  1. Staun-Ram E, Shalev E. Human trophoblast function during the implantation process. Reprod Biol Endocrinol. 2005;3:56.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Caniggia I, Winter J, Lye SJ, Post M. Oxygen and placental development during the first trimester: implications for the pathophysiology of pre-eclampsia. Placenta. 2000;21(suppl A):S25–S30.

    Article  PubMed  Google Scholar 

  3. Whitley GS, Cartwright JE. Cellular and molecular regulation of spiral artery remodelling: lessons from the cardiovascular field. Placenta. 2010;31(6):465–474.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Zhao M, Bai H, Wang E, Forrester JV, McCaig CD. Electrical stimulation directly induces pre-angiogenic responses in vascular endothelial cells by signaling through VEGF receptors. J Cell Sci. 2004;117(3):397–405.

    Article  CAS  PubMed  Google Scholar 

  5. Bai H, Mccaig CD, Forrester JV, Zhao M. Direct current electric fields induce distinct preangiogenic responses in microvascular and macrovascular cells. Arterioscler Thromb Vasc Biol. 2004;24(7):1234–1239.

    Article  CAS  PubMed  Google Scholar 

  6. Li X, Kolega J. Effects of direct current electric fields on cell migration and actin filament distribution in bovine vascular endothelial cells. J Vasc Res. 2002;39(5):391–404.

    Article  CAS  PubMed  Google Scholar 

  7. Hudlicka O, Tyler KR. The effect of long-term intermittent high-frequency stimulation on capillary density and fibre profiles in rabbit fast muscles. J Physiol. 1984;353:435–445.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Hang J, Kong L, Gu JW, Adair TH. VEGF gene expression is upregulated in electrically stimulated rat skeletal muscle. Am J Physiol. 1995;269(2):H1827–H1831.

    CAS  PubMed  Google Scholar 

  9. Annex BH, Torgan CE, Lin P, et al. Induction and maintenance of increased VEGF protein by chronic motor nerve stimulation in skeletal muscle. Am J Physiol. 1998;274(3 pt 2):H860–H867.

    CAS  PubMed  Google Scholar 

  10. Michel JB, Ordway GA, Richardson JA, Williams RS. Biphasic induction of immediate early gene expression accompanies activity-dependent angiogenesis and myofiber remodeling of rabbit skeletal muscle. J Clin Invest. 1994;94(1):277–285.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Baba T, Kameda M, Yasuhara T, et al. Electrical stimulation of the cerebral cortex exerts antiapoptotic, angiogenic, and anti-inflammatory effects in ischemic stroke rats through phosphoinositide 3-kinase/Akt signaling pathway. Stroke. 2009;40(11):e598–e605.

    Article  PubMed  Google Scholar 

  12. Kanno S, Oda N, Abe M, et al. Establishment of a simple and practical procedure applicable to therapeutic angiogenesis. Circulation. 1999;99(20):2682–2687.

    Article  CAS  PubMed  Google Scholar 

  13. Zhang J, Ren R, Luo X, et al. A small physiological electric field mediated responses of extravillous trophoblasts derived from HTR8/SVneo cells: involvement of activation of focal adhesion kinase signaling. Plos One. 2014;9(3):e92252.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Chung IB, Yelian FD, Zaher FM, et al. Expression and regulation of vascular endothelial growth factor in a first trimester trophoblast cell line. Placenta. 2000;21(4), 320–324.

    Article  CAS  PubMed  Google Scholar 

  15. Shinkaruk S, Bayle M, Lain G, Deleris G. Vascular endothelial cell growth factor (VEGF), an emerging target for cancer chemotherapy. Curr Med Chem Anticancer Agents. 2003;3(2):95–117.

    Article  CAS  PubMed  Google Scholar 

  16. Sharkey AM, Cooper JC, Balmforth JR, et al. Maternal plasma levels of vascular endothelial growth factor in normotensive pregnancies and in pregnancies complicated by pre-eclampsia. Eur J Clin Invest. 1996;26(12):1182–1185.

    Article  CAS  PubMed  Google Scholar 

  17. Benaitreau D, Dos Santos E, Leneveu MC, et al. Effects of adiponectin on human trophoblast invasion. J Endocrinol. 2010;207(1):45–53.

    Article  CAS  PubMed  Google Scholar 

  18. Johnsen GM, Basak S, Weedon-Fekjaer MS, Staff AC, Duttaroy AK. Docosahexaenoic acid stimulates tube formation in first trimester trophoblast cells, HTR8/SVneo. Placenta. 2011;32(9):626–632.

    Article  CAS  PubMed  Google Scholar 

  19. Graham CH, Hawley TS, Hawley RG, et al. Establishment and characterization of first trimester human trophoblast cells with extended lifespan. Exp Cell Res. 1993;206(2):204–211.

    Article  CAS  PubMed  Google Scholar 

  20. Debnath J, Muthuswamy SK, Brugge JS. Morphogenesis and oncogenesis of MCF-10A mammary epithelial acini grown in three-dimensional basement membrane cultures. Methods. 2003;30(3):256–268.

    Article  CAS  PubMed  Google Scholar 

  21. Zhao M, Agius-Fernandez A, Forrester JV, McCraig CD. Orientation and directed migration of cultured corneal epithelial cells in small electric fields are serum dependent. J Cell Sci. 1996;109(pt 6):1405–1414.

    Article  CAS  PubMed  Google Scholar 

  22. Bai H, Forrester JV, Zhao M. DC electric stimulation upregulates angiogenic factors in endothelial cells through activation of VEGF receptors. Cytokine. 2011;55(1):110–115.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Song B, Gu Y, Pu J, Reid B, Zhao Z, Zhao M. Application of direct current electric fields to cells and tissues in vitro and modulation of wound electric field in vivo. Nat Protoc. 2007;2(6):1479–1489.

    Article  CAS  PubMed  Google Scholar 

  24. Ferrara N. The role of vascular endothelial growth factor in pathological angiogenesis. Breast Cancer Res Treat. 1995;36(10):127–137.

    Article  CAS  PubMed  Google Scholar 

  25. Risau W. Mechanisms of angiogenesis. Nature. 1997;386(6626):671–674.

    Article  CAS  PubMed  Google Scholar 

  26. Kim KJ, Li B, Winer J, Armanini M, Gillett N. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumor growth in vivo. Nature. 1993;362(6423):841–844.

    Article  CAS  PubMed  Google Scholar 

  27. Kendall RL, Thomas KA. Inhibition of vascular endothelial cell growth factor activity by an endogenously encoded soluble receptor. Proc Natl Acad Sci U S A. 1993;90(22):10705–10709.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Saleh M, Stacker SA, Wilks AF. Inhibition of growth of C6 glioma cells in vivo by expression of antisense vascular endothelial growth factor sequence. Cancer Res. 1996;56(2):393–401.

    CAS  PubMed  Google Scholar 

  29. Sauer H, Bekhite MM, Hescheler J, Wartenberg M. Redox control of angiogenic factors and CD31-positive vessel-like structures in mouse embryonic stem cells after direct current electrical field stimulation. Exp Cell Res. 2005;304(2):380–390.

    Article  CAS  PubMed  Google Scholar 

  30. Carmeliet P. Angiogenesis in life, disease and medicine. Nature. 2005;438(7070):932–936.

    Article  CAS  PubMed  Google Scholar 

  31. Folkman J. Angiogenesis: an organizing principle for drug discovery? Nat Rev Drug Discov. 2007;6(4):273–286.

    Article  CAS  PubMed  Google Scholar 

  32. Shen M, Gao J, Li J, Su J. Effect of stimulation frequency on angiogenesis and gene expression in ischemic skeletal muscle of rabbit. Can J Physiol Pharmacol. 2009;87(5):396–401.

    Article  CAS  PubMed  Google Scholar 

  33. Cross MJ, Dixelius J, Matsumoto T, Claesson-Welsh L. VEGF-receptor signal transduction. Trends Biochem Sci. 2003;28(9):488–494.

    Article  CAS  PubMed  Google Scholar 

  34. Thakker GD, Hajjar DP, Muller WA, Rosengart TK. The role of phosphatidylinositol 3-kinase in vascular endothelial growth factor signaling. J Biol Chem. 1999;274(15):10002–10007.

    Article  CAS  PubMed  Google Scholar 

  35. Sheikh AQ, Taghian T, Hemingway B, Cho H, Kogan AB, Narmoneva DA. Regulation of endothelial MAPK/ERK signalling and capillary morphogenesis by low-amplitude electric field. J R Soc Interface. 2013;10(78):20120548.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Nie K, Henderson A. MAP kinase activation in cells exposed to a 60 Hz electromagnetic field. J Cell Biochem. 2003;90(6):1197–1206.

    Article  CAS  PubMed  Google Scholar 

  37. Friedman J, Kraus S, Hauptman Y, Schiff Y, Seger R. Mechanism of short-term ERK activation by electromagnetic fields at mobile phone frequencies. Biochem J. 2007;405(3):559–568.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Zhao M, Song B, Pu J, et al. Electrical signals control wound healing through phosphatidylinositol-3-OH kinase-gamma and PTEN. Nature. 2006;442(7101):457–460.

    Article  CAS  PubMed  Google Scholar 

  39. Ferrara N. Vascular endothelial growth factor as a target for anticancer therapy. Oncologist. 2004;9(suppl 1):2–10.

    Article  CAS  PubMed  Google Scholar 

  40. Das MK, Basak S, Ahmed MS, Attramadal H, Duttaroy AK. Connective tissue growth factor induces tube formation and IL-8 production in first trimester human placental trophoblast cells. Eur J Obstet Gynecol Reprod Biol. 2014;181:183–188.

    Article  CAS  PubMed  Google Scholar 

  41. Pandya AD, Das MK, Sarkar A, Vilasagaram S, Basak S, Duttaroy AK. Tube formation in the first trimester placental trophoblast cells: differential effects of angiogenic growth factors and fatty acids. Cell Biol Int. 2016;40(6):652–661.

    Article  CAS  PubMed  Google Scholar 

  42. Hotary KB, Robinson KR. Endogenous electrical currents and the resultant voltage gradients in the chick embryo. Dev Biol. 1990(1);140:149–160.

    Google Scholar 

  43. Metcalf MEM, Shi RY, Borgens RB. Endogenous ionic currents and voltages in amphibian embryos. J Exp Zool. 1994;268(4):307–322.

    Article  Google Scholar 

  44. Levin M, Mercola M. Gap junctions are involved in the early generation of left-right asymmetry. Dev Biol. 1998;203(1):90–105.

    Article  CAS  PubMed  Google Scholar 

  45. Levin M, Mercola M. Gap junction-mediated transfer of left-right patterning signals in the early chick blastoderm is upstream of Shh asymmetry in the node. Development. 1999;126(21):4703–4714.

    Article  CAS  PubMed  Google Scholar 

  46. Levin M, Thorlin T, Robinson KR, Nogi T, Mercola M. Asymmetries in H+/K+-ATPase and cell membrane potentials comprise a very early step in left-right patterning. Cell. 2002;111(1):77–89.

    Article  CAS  PubMed  Google Scholar 

  47. Barker AT, Jaffe LF, Vanable JW. The glabrous epidermis of cavies contains a powerful battery. Am J Physiol. 1982;242(3):358–366.

    Google Scholar 

  48. Chiang M., Robinson KR, Vanable JW. Electrical fields in the vicinity of epithelial wounds in the isolated bovine eye. Exp Eye Res. 1992;54(6):999–1003.

    Article  CAS  PubMed  Google Scholar 

  49. Sta Iglesia DD, Vanable JW. Endogenous lateral electric fields around bovine corneal lesions are necessary for and can enhance normal rates of wound healing. Wound Repair Regen. 1998;6(6):531–542.

    Article  CAS  PubMed  Google Scholar 

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Author information

Author notes

  1. Liyan Ye MD

    Present address: Department of Obstetrics, **hua Municipal Central Hospital, **hua, Zhejiang, 321000, People’s Republic of China

Authors and Affiliations

  1. Laboratory of Genetic Disease and Perinatal Medicine and Key Laboratory of Birth Defects and Related Diseases of Women and Children of the Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, 610041, People’s Republic of China

    Liyan Ye MD, Linbo Guan MS, ** Fan MD, **ng Wei PhD, Yue Zhu MD & Huai Bai MD

  2. Department of Biochemistry and Molecular Biology, West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, Sichuan, People’s Republic of China

    Yinghui Liu MD & Yu Liu BS

  3. Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China

    Wei **ong MD

  4. Division of Peptides Related with Human Disease, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China

    Rui Liu PhD

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  1. Liyan Ye MD
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Correspondence to Huai Bai MD.

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Authors’ Note

L.Y. and L.G. performed experiments, analyzed data, and contributed to the writing of the manuscript. P.F., Y.L., W.X., R.L., and X.W. performed experiments and analyzed data. Y.Z. and Y.L. contributed reagents/materials/analysis tools. H.B. conceived the project, analyzed data, and contributed to the writing of the manuscript.

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Ye, L., Guan, L., Fan, P. et al. Effect of a Small Physiological Electric Field on Angiogenic Activity in First-Trimester Extravillous Trophoblast Cells. Reprod. Sci. 26, 745–756 (2019). https://doi.org/10.1177/1933719118792102

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