Plastic Surgery Research Council
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Presenter: Alexis Donneys, MD, MS
Co-Authors: Deshpande SS; Levi B; Buchman SR
University of Michigan

Purpose: Radiotherapy is known to impede the processes of angiogenesis leading to devastating consequences in affected tissues over time. The potential to reverse this side effect may have important clinical implications. Deferoxamine (DFO) has been shown to upregulate VEGF production via the HIF 1-alpha pathway. Here we investigate the effect of DFO on endothelial cells exposed to radiation. We posit that radiation will significantly diminish the ability of endothelial cells to form tubules; and subsequently, that the addition of DFO will effect a restoration of tubule formation.

Methods: Four groups of HUVEC cells (control, radiated, radiated + low dose DFO, or radiated + high dose DFO) were incubated in Matrigel and video recorded in real-time over 12 hours. DFO groups received either 25 or 50M doses at the time of incubation. Tubule formation was photographed at 100x magnification every four hours. Tubule numbers between groups were compared using ANOVA with p< 0.05 considered statistically significant.

Results: We observed a severe diminution in endothelial tubule formation after radiotherapy. Specifically, tubule formation was diminished 30%, 34%, and 27% respectively, compared to control values (p= 0.01, at 4, 8, and 12 hours). The effects of radiation were strikingly remediated by treatment with high-dose DFO. High dose DFO cells demonstrated organized tubule formation that was significantly increased in comparison to radiated cells (p= 0.02 at 4, 8, and 12 hours), and reached or exceeded normal levels at each respective time point. These findings were clearly observed with real-time recording. High-dose DFO cultures appeared to organize within 2 hours of incubation and achieved a robust vascular network that was visibly superior to all other experimental groups in an accelerated fashion (Figure 1).

Conclusion: Our evidence supports the contention that DFO strongly remediates the effects of radiation on endothelial tubule formation. Further examination of the utility of DFO in the prevention and treatment of radionecrosis is therefore warranted.

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