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. KoontzInternational 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.