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Clarifying the relative impacts of vascular and nerve injury that culminate in erectile dysfunction in a pilot study using a rat model of prostate irradiation and a thrombopoietin mimetic

Kathleen A. Ashcraft, Johanna L. Hannan, Gary Eichenbaum, Xiaojie Zhang, Elena S. Pak, Austin M. Faught, Pranalee Patel, Mark W. Dewhirst, Bridget F. Koontz
International Journal of Radiation Oncology*Biology*Physics2018
PURPOSE: Radiation therapy (RT) offers an important and curative approach to treating prostate cancer but is associated with a high incidence of erectile dysfunction (ED). It is not clear if the etiology of radiation-induced ED (RI-ED) is driven by RT-mediated injury to the vasculature, the nerves, or both. This pilot study sought to distinguish the impacts of vascular and nerve injury in RI-ED by applying a vascular radioprotectant in a rat model of prostate RT. METHODS: A single dose of the thrombopoietin mimetic, TPOm (RWJ-800088), previously shown to mitigate radiation-induced vascular injury, was administered ten minutes after a single fraction conformal prostate RT. Nine weeks post-RT, rats were assessed for erectile and arterial function. Nerve markers were quantified via RT-PCR. Immunofluorescent microscopy further characterized vascular effects of RT and TPOm. RESULTS: Sham animals and animals that received RT and TPOm showed significant arterial vasodilation in response to systemic hydralazine (24.1±7.3% increase, p=0.03 in paired t-test). However, animals that received RT and vehicle were unable to mount a vasodilatory response (-7.4±9.9% increase, p=0.44 in paired t-test). TPOm prevented RT-induced change in penile artery cross-sectional area (p=0.036), but did not ameliorate cavernous nerve injury as evaluated by gene expression of neuronal injury markers. Despite significant structural and functional vascular protective effects, TPOm did not prevent RI-ED at 9 weeks as assessed by intracavernous pressure monitoring following cavernous nerve stimulation. CONCLUSIONS: These data suggest that vascular protection alone is not sufficient to prevent RI-ED and that cavernous nerve injury plays a key role in RI-ED. Further research is required to delineate the multifactorial nature of RI-ED.
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