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Endothelial Cell Proliferation is Enhanced by Low Dose Non-Thermal Plasma Through Fibroblast Growth Factor-2 Release

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Abstract

Non-thermal dielectric barrier discharge plasma is being developed for a wide range of medical applications, including wound healing, blood coagulation, and malignant cell apoptosis. However, the effect of non-thermal plasma on the vasculature is unclear. Blood vessels are affected during plasma treatment of many tissues and may be an important potential target for clinical plasma therapy. Porcine aortic endothelial cells were treated in vitro with a custom non-thermal plasma device. Low dose plasma (up to 30 s or 4 J cm−2) was relatively non-toxic to endothelial cells while treatment at longer exposures (60 s and higher or 8 J cm−2) led to cell death. Endothelial cells treated with plasma for 30 s demonstrated twice as much proliferation as untreated cells five days after plasma treatment. Endothelial cell release of fibroblast growth factor-2 (FGF2) peaked 3 h after plasma treatment. The plasma proliferative effect was abrogated by an FGF2 neutralizing antibody, and FGF2 release was blocked by reactive oxygen species scavengers. These data suggest that low dose non-thermal plasma enhances endothelial cell proliferation due to reactive oxygen species mediated FGF2 release. Plasma may be a novel therapy for dose-dependent promotion or inhibition of endothelial cell mediated angiogenesis.

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References

  1. Ayan, H., G. Fridman, D. Staack, A. F. Gutsol, V. N. Vasilets, A. A. Fridman, and G. Friedman. Heating effect of dielectric barrier discharges for direct medical treatment. IEEE Trans. Plasma Sci. 37(1):113–120, 2009.

    Article  Google Scholar 

  2. Balasubramanian, M., A. Sebastian, M. Peddinghaus, G. Fridman, A. Fridman, A. Gutsol, G. Friedman, and B. Ari. Dielectric barrier discharge plasma in coagulation and sterilization. Blood 108(11):89b-89b, 2006.

    Google Scholar 

  3. Callaghan, M. J., E. I. Chang, N. Seiser, S. Aarabi, S. Ghali, E. R. Kinnucan, B. J. Simon, and G. C. Gurtner. Pulsed electromagnetic fields accelerate normal and diabetic wound healing by increasing endogenous FGF-2 release. Plast. Reconstr. Surg. 121(1):130–141, 2008.

    Article  CAS  PubMed  Google Scholar 

  4. Caplice, N. M., C. N. Aroney, J. H. N. Bett, J. Cameron, J. H. Campbell, N. Hoffmann, P. T. McEniery, and M. J. West. Growth factors released into the coronary circulation after vascular injury promote proliferation of human vascular smooth muscle cells in culture. J. Am. Coll. Cardiol. 29(7):1536–1541, 1997.

    Article  CAS  PubMed  Google Scholar 

  5. Chang, P. Y., K. A. Bjornstad, E. Chang, M. McNamara, M. H. Barcellos-Hoff, S. P. Lin, G. Aragon, J. R. Polansky, G. M. Lui, and E. A. Blakely. Particle irradiation induces FGF2 expression in normal human lens cells. Radiat. Res. 154(5):477–484, 2000.

    Article  CAS  PubMed  Google Scholar 

  6. Clyne, A. M., H. Zhu, and E. R. Edelman. Elevated fibroblast growth factor-2 increases tumor necrosis factor-alpha, induced endothelial cell death in high glucose. J. Cell. Physiol. 217(1):86–92, 2008.

    Article  CAS  PubMed  Google Scholar 

  7. Coulombe, S. Live cell permeabilization using the APGD-t. 1st International Conference on Plasma Medicine (ICPM), Corpus Christi, TX, 2007.

  8. Coulombe, S., V. Leveille, S. Yonson, and R. L. Leask. Miniature atmospheric pressure glow discharge torch (APGD-t) for local biomedical applications. Pure Appl. Chem. 78(6):1147–1156, 2006.

    Article  CAS  Google Scholar 

  9. Danpure, C. J. Lactate-dehydrogenase and cell injury. Cell Biochem. Funct. 2(3):144–148, 1994.

    Article  Google Scholar 

  10. Eliasson, B., W. Egli, and U. Kogelschatz. Modeling of dielectric barrier discharge chemistry. Pure Appl. Chem. 66(8):U1766–U1778, 1994.

    Google Scholar 

  11. Fiers, W., R. Beyaert, W. Declercq, and P. Vandenabeele. More than one way to die: apoptosis, necrosis and reactive oxygen damage. Oncogene 18(54):7719–7730, 1999.

    Article  CAS  PubMed  Google Scholar 

  12. Folkman, J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat. Med. 1(1):27–31, 1995.

    Article  CAS  PubMed  Google Scholar 

  13. Folkman, J. Angiogenesis. Annu. Rev. Med. 57:1–18, 2006.

    Article  CAS  PubMed  Google Scholar 

  14. Fridman, A. Plasma Biology and Plasma Medicine. New York: Cambridge University Press, 2008.

    Google Scholar 

  15. Fridman, G., A. D. Brooks, M. Balasubramanian, A. Fridman, A. Gutsol, V. N. Vasilets, H. Ayan, and G. Friedman. Comparison of direct and indirect effects of non-thermal atmospheric-pressure plasma on bacteria. Plasma Processes Polym. 4(4):370–375, 2007.

    Article  CAS  Google Scholar 

  16. Fridman, G., M. Peddinghaus, H. Ayan, A. Fridman, M. Balasubramanian, A. Gutsol, A. Brooks, and G. Friedman. Blood coagulation and living tissue sterilization by floating-electrode dielectric barrier discharge in air. Plasma. Chem. Plasma Process. 26(4):425–442, 2006.

    Article  CAS  Google Scholar 

  17. Fridman, G., A. Shereshevsky, M. M. Jost, A. D. Brooks, A. Fridman, A. Gutsol, V. Vasilets, and G. Friedman. Floating electrode dielectric barrier discharge plasma in air promoting apoptotic behavior in melanoma skin cancer cell lines. Plasma. Chem. Plasma Process. 27(2):163–176, 2007.

    Article  CAS  Google Scholar 

  18. Fuks, Z., R. S. Persaud, A. Alfieri, M. Mcloughlin, D. Ehleiter, J. L. Schwartz, A. P. Seddon, C. Cordoncardo, and A. Haimovitzfriedman. Basic fibroblast growth-factor protects endothelial-cells against radiation-induced programmed cell-death in-vitro, and in-vivo. Cancer Res. 54(10):2582–2590, 1994.

    CAS  PubMed  Google Scholar 

  19. Gallicchio, V. S., N. K. Hughes, B. C. Hulette, R. Dellapuca, and L. Noblitt. Basic fibroblast growth-factor (B-Fgf) induces early-stage (Cfu-S) and late-stage hematopoietic progenitor-cell colony formation (Cfu-Gm, Cfu-Meg, and Bfu-E) by synergizing with Gm-Csf, Meg-Csf, and erythropoietin, and is a radioprotective agent in vitro. Int. J. Cell Cloning 9(3):220–232, 1991.

    Article  CAS  PubMed  Google Scholar 

  20. Gebicki, S., and J. M. Gebicki. Formation of peroxides in amino-acids and proteins exposed to oxygen free-radicals. Biochem. J. 289:743–749, 1993.

    CAS  PubMed  Google Scholar 

  21. Gostev, V., and D. Dobrynin. Medical microplasmatron. 3rd International Workshop on Microplasmas (IWM-2006), Greifswald, Germany, 2006.

  22. Haimovitzfriedman, A., N. Balaban, M. Mcloughlin, D. Ehleiter, J. Michaeli, I. Vlodavsky, and Z. Fuks. Protein-kinase-C mediates basic fibroblast growth-factor protection of endothelial-cells against radiation-induced apoptosis. Cancer Res. 54(10):2591–2597, 1994.

    CAS  Google Scholar 

  23. Haimovitzfriedman, A., I. Vlodavsky, A. Chaudhuri, L. Witte, and Z. Fuks. Autocrine effects of fibroblast growth-factor in repair of radiation-damage in endothelial-cells. Cancer Res. 51(10):2552–2558, 1991.

    CAS  Google Scholar 

  24. Houchen, C. W., R. J. George, M. A. Sturmoski, and S. M. Cohn. FGF-2 enhances intestinal stem cell survival and its expression is induced after radiation injury. Am. J. Physiol. Gastrointest. Liver Physiol. 276(1):G249–G258, 1999.

    CAS  Google Scholar 

  25. Kalghatgi, S. U., G. Fridman, M. Cooper, G. Nagaraj, M. Peddinghaus, M. Balasubramanian, V. N. Vasilets, A. F. Gutsol, A. Fridman, and G. Friedman. Mechanism of blood coagulation by nonthermal atmospheric pressure dielectric barrier discharge plasma. IEEE Trans. Plasma Sci. 35(5):1559–1566, 2007.

    Article  CAS  Google Scholar 

  26. Kieft, I. E., D. Darios, A. J. M. Roks, and E. Stoffels. Plasma treatment of mammalian vascular cells: a quantitative description. IEEE Trans. Plasma Sci. 33(2):771–775, 2005.

    Article  Google Scholar 

  27. Kieft, I. E., M. Kurdi, and E. Stoffels. Reattachment and apoptosis after plasma-needle treatment of cultured cells. IEEE Trans. Plasma Sci. 34(4):1331–1336, 2006.

    Article  CAS  Google Scholar 

  28. Ku, P. T., and P. A. Damore. Regulation of basic fibroblast growth-factor (Bfgf) gene and protein expression following its release from sublethally injured endothelial-cells. J. Cell. Biochem. 58(3):328–343, 1995.

    Article  CAS  PubMed  Google Scholar 

  29. Majno, G., and I. Joris. Apoptosis, oncosis, and necrosis—an overview of cell-death. Am. J. Pathol. 146(1):3–15, 1995.

    CAS  PubMed  Google Scholar 

  30. Morss, A. S., and E. R. Edelman. Glucose modulates basement membrane fibroblast growth factor-2 via alterations in endothelial cell permeability. J. Biol. Chem. 282(19):14635–14644, 2007.

    Article  CAS  PubMed  Google Scholar 

  31. Muthukrishnan, L., E. Warder, and P. L. Mcneil. Basic fibroblast growth-factor is efficiently released from a cytolsolic storage site through plasma-membrane disruptions of endothelial-cells. J. Cell. Physiol. 148(1):1–16, 1991.

    Article  CAS  PubMed  Google Scholar 

  32. Nugent, M. A., and R. V. Iozzo. Fibroblast growth factor-2. Int. J. Biochem. Cell Biol. 32(2):115–120, 2000.

    Article  CAS  PubMed  Google Scholar 

  33. Rath, P. C., and B. B. Aggarwal. TNF-induced signaling in apoptosis. J. Clin. Immunol. 19(6):350–364, 1999.

    Article  CAS  PubMed  Google Scholar 

  34. Shekhter, A. B., V. A. Serezhenkov, T. G. Rudenko, A. V. Pekshev, and A. F. Vanin. Beneficial effect of gaseous nitric oxide on the healing of skin wounds. Nitric Oxide Biol. Chem. 12(4):210–219, 2005.

    Article  CAS  Google Scholar 

  35. Siemens, C. W. On the electrical tests employed during the construction of the Malta and Alexandria Telegraph, and on insulating and protecting submarine cables. J. Franklin Inst. 74(3):166–170, 1862.

    Article  Google Scholar 

  36. Sudhir, K., K. Hashimura, A. Bobik, R. J. Dilley, G. L. Jennings, and P. J. Little. Mechanical strain stimulates a mitogenic response in coronary vascular smooth muscle cells via release of basic fibroblast growth factor. Am. J. Hypertens. 14(11):1128–1134, 2001.

    Article  CAS  PubMed  Google Scholar 

  37. Tepper, O. M., M. J. Callaghan, E. I. Chang, R. D. Galiano, K. A. Bhatt, S. Baharestani, J. Gan, B. Simon, R. A. Hopper, J. P. Levine, et al. Electromagnetic fields increase in vitro and in vivo angiogenesis through endothelial release of FGF-2. FASEB J. 18(9):1231, 2004.

    CAS  PubMed  Google Scholar 

  38. Vargo, J. J. Clinical applications of the argon plasma coagulator. Gastrointest. Endosc. 59(1):81–88, 2004.

    Article  PubMed  Google Scholar 

  39. Wajant, H., K. Pfizenmaier, and P. Scheurich. Tumor necrosis factor signaling. Cell Death Differ. 10(1):45–65, 2003.

    Article  CAS  PubMed  Google Scholar 

  40. Wong, M. K. K., and A. I. Gotlieb. In vitro reendothelialization of a single-cell wound—role of microfilament bundles in rapid lamellipodia-mediated wound closure. Lab. Invest. 51(1):75–81, 1984.

    CAS  PubMed  Google Scholar 

  41. Yamada, H., E. Yamada, N. Kwak, A. Ando, A. Suzuki, N. Esumi, D. J. Zack, and P. A. Campochiaro. Cell injury unmasks a latent proangiogenic phenotype in mice with increased expression of FGF2 in the retina. J. Cell. Physiol. 185(1):135–142, 2000.

    Article  CAS  PubMed  Google Scholar 

  42. Yenpatton, G. P. A., W. F. Patton, D. M. Beer, and B. S. Jacobson. Endothelial-cell response to pulsed electromagnetic-fields—stimulation of growth-rate and angiogenesis in vitro. J. Cell. Physiol. 134(1):37–46, 1988.

    Article  CAS  Google Scholar 

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Acknowledgment

We would like to thank Gregory Fridman for building the plasma device.

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Authors and Affiliations

  1. Electrical and Computer Engineering, Drexel University, Philadelphia, PA, 19104, USA

    Sameer Kalghatgi & Gary Friedman

  2. Mechanical Engineering and Mechanics, Drexel University, 3141 Chestnut Street, Philadelphia, PA, 19104, USA

    Alexander Fridman & Alisa Morss Clyne

  3. School of Biomedical Engineering, Science, and Health Systems, Drexel University, Philadelphia, PA, 19104, USA

    Alisa Morss Clyne

Authors
  1. Sameer Kalghatgi
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  2. Gary Friedman
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  4. Alisa Morss Clyne
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Correspondence to Alisa Morss Clyne.

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Associate Editor Julia E. Babensee oversaw the review of this article.

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Kalghatgi, S., Friedman, G., Fridman, A. et al. Endothelial Cell Proliferation is Enhanced by Low Dose Non-Thermal Plasma Through Fibroblast Growth Factor-2 Release. Ann Biomed Eng 38, 748–757 (2010). https://doi.org/10.1007/s10439-009-9868-x

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  • DOI: https://doi.org/10.1007/s10439-009-9868-x

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