A Radioprotective Role For Ferritin In Brain Microvascular Endothelial Cells

McInerney James1, Padmavathi Ponnuru1, Elizabeth B. Neely1, Xiaoli Liu1

1Department of Neurosurgery, Penn State University College of Medicine, Hershey, PA 17033, USA

Keywords: animal model, technique, radiobiology, vascular, radiation injury

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Abstract

     Ferritin is traditionally considered an intracellular iron storage protein that provides protection to cells via its capacity to sequester iron. The role of ferritin is expanding to include iron delivery to cells and angiogenesis. We are investigating the role of ferritin in cancer cells and have found that the presence of ferritin is protective against radiation and chemotoxins. This observation in addition to the angiogenic function of ferritin makes this protein a potential target for therapeutic interventions. Alternatively, promoting the angiogenic properties of ferritin may be of clinical benefit in treating vascular malformations.
     The purpose of the present study is to investigate the effect of ferritin on brain microvascular endothelial cell proliferation and sensitivity to radiation.
     Endothelial cells from rabbit brain microvasculature were cultured.
     They were exposed to gamma radiation (0-20Gy) with or without pre-treatment with recombinant H-ferritin (rHFrt, 0-11ug/mL). Proliferation assays were performed at 24, 48 and 72hr after exposure to radiation. The effect of r-HFrt on the expression of vascular endothelial growth factor (VEGF) and its receptors (VEGFR1 and VEGFR2) was also determined.
     Exposure to gamma radiation is associated with a decrease in endothelial cell proliferation and expression of VEGF and VEGFR.  Pre-treating endothelial cells with rHFrt (for 24hrs), not only protected the endothelial cells from radiation but was associated with a significant increase in cell proliferation following radiation exposure. Moreover, ferritin increased the expression of VEGF and VEGFR1 and the phosphorylated (active) form of VEGFR2. 
     This is a retrospective study.
     Ferritin not only limits the negative effect of gamma radiation on endothelial cell proliferation, but actually enhanced proliferation of microvascular endothelial cells after exposure to gamma radiation. The upregulation of VEGF and its receptors after ferritin exposure is consistent with the increase in proliferation. 
     These data suggest that delivery of ferritin to endothelial cells may provide opportunities to use gamma radiation in conditions where endothelial cell proliferation should be encouraged and limiting ferritin in endothelial cells may enhance radiosensitivity when angiogenesis is problematic such as in tumor proliferation.


Acknowledgements

Project Roles:

M. James (), P. Ponnuru (), E. Neely (), X. Liu ()