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Annals of Biomedical Engineering

, Volume 38, Issue 3, pp 748–757 | Cite as

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

  • Sameer Kalghatgi
  • Gary Friedman
  • Alexander Fridman
  • Alisa Morss ClyneEmail author
Article
First Online:

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.

Keywords

Angiogenesis Plasma medicine Reactive oxygen species Apoptosis Wound healing 
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Notes

Acknowledgment

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

References

  1. 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.CrossRefGoogle Scholar
  2. 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. 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.CrossRefPubMedGoogle Scholar
  4. 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.CrossRefPubMedGoogle Scholar
  5. 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.CrossRefPubMedGoogle Scholar
  6. 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.CrossRefPubMedGoogle Scholar
  7. 7.
    Coulombe, S. Live cell permeabilization using the APGD-t. 1st International Conference on Plasma Medicine (ICPM), Corpus Christi, TX, 2007.Google Scholar
  8. 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.CrossRefGoogle Scholar
  9. 9.
    Danpure, C. J. Lactate-dehydrogenase and cell injury. Cell Biochem. Funct. 2(3):144–148, 1994.CrossRefGoogle Scholar
  10. 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. 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.CrossRefPubMedGoogle Scholar
  12. 12.
    Folkman, J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat. Med. 1(1):27–31, 1995.CrossRefPubMedGoogle Scholar
  13. 13.
    Folkman, J. Angiogenesis. Annu. Rev. Med. 57:1–18, 2006.CrossRefPubMedGoogle Scholar
  14. 14.
    Fridman, A. Plasma Biology and Plasma Medicine. New York: Cambridge University Press, 2008.Google Scholar
  15. 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.CrossRefGoogle Scholar
  16. 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.CrossRefGoogle Scholar
  17. 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.CrossRefGoogle Scholar
  18. 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.PubMedGoogle Scholar
  19. 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.CrossRefPubMedGoogle Scholar
  20. 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.PubMedGoogle Scholar
  21. 21.
    Gostev, V., and D. Dobrynin. Medical microplasmatron. 3rd International Workshop on Microplasmas (IWM-2006), Greifswald, Germany, 2006.Google Scholar
  22. 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.Google Scholar
  23. 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.Google Scholar
  24. 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.Google Scholar
  25. 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.CrossRefGoogle Scholar
  26. 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.CrossRefGoogle Scholar
  27. 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.CrossRefGoogle Scholar
  28. 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.CrossRefPubMedGoogle Scholar
  29. 29.
    Majno, G., and I. Joris. Apoptosis, oncosis, and necrosis—an overview of cell-death. Am. J. Pathol. 146(1):3–15, 1995.PubMedGoogle Scholar
  30. 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.CrossRefPubMedGoogle Scholar
  31. 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.CrossRefPubMedGoogle Scholar
  32. 32.
    Nugent, M. A., and R. V. Iozzo. Fibroblast growth factor-2. Int. J. Biochem. Cell Biol. 32(2):115–120, 2000.CrossRefPubMedGoogle Scholar
  33. 33.
    Rath, P. C., and B. B. Aggarwal. TNF-induced signaling in apoptosis. J. Clin. Immunol. 19(6):350–364, 1999.CrossRefPubMedGoogle Scholar
  34. 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.CrossRefGoogle Scholar
  35. 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.CrossRefGoogle Scholar
  36. 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.CrossRefPubMedGoogle Scholar
  37. 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.PubMedGoogle Scholar
  38. 38.
    Vargo, J. J. Clinical applications of the argon plasma coagulator. Gastrointest. Endosc. 59(1):81–88, 2004.CrossRefPubMedGoogle Scholar
  39. 39.
    Wajant, H., K. Pfizenmaier, and P. Scheurich. Tumor necrosis factor signaling. Cell Death Differ. 10(1):45–65, 2003.CrossRefPubMedGoogle Scholar
  40. 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.PubMedGoogle Scholar
  41. 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.CrossRefPubMedGoogle Scholar
  42. 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.CrossRefGoogle Scholar

Copyright information

© Biomedical Engineering Society 2009

Authors and Affiliations

  • Sameer Kalghatgi
    • 1
  • Gary Friedman
    • 1
  • Alexander Fridman
    • 2
  • Alisa Morss Clyne
    • 2
    • 3
    Email author
  1. 1.Electrical and Computer EngineeringDrexel UniversityPhiladelphiaUSA
  2. 2.Mechanical Engineering and MechanicsDrexel UniversityPhiladelphiaUSA
  3. 3.School of Biomedical Engineering, Science, and Health SystemsDrexel UniversityPhiladelphiaUSA

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