Ionizing radiation induces vascular dysfunction through xanthine oxidase activation

This dissertation investigated the effect of ionizing radiation on vascular and endothelial function. Two types of ionizing radiation were investigated: gamma (gamma) radiation as a model of medical radiation, and high atomic number, high energy iron (Fe) radiation as a model of space radiation.;Rats and mice were exposed to a single, whole-body exposure of radiation at various doses. In vivo aortic stiffness and ex vivo aortic tension responses were measured as indictors of vascular injury. Significantly increased aortic stiffness was exhibited by rats exposed to gamma and Fe radiation. Endothelial function of aorta from irradiated rats was significantly attenuated from the unirradiated group, as characterized by endothelial-dependent relaxation. Remarkably, acute xanthine oxidase (XO) inhibition or reactive oxygen species (ROS) scavenging restored the relaxation response. It was determined that XO activity is significantly elevated in rat aorta after whole-body gamma and Fe irradiation. Dietary XO inhibition completely blocked radiation-dependent XO activation. Furthermore, ROS and nitric oxide (NO) were measured through fluorescent microscopy. Whereas aortic ROS production rate was elevated by gamma irradiation, NO response was significantly impaired. Fe irradiation yielded a similar NO response. Restoration of NO and ROS production rates were attained by dietary XO inhibition. Accordingly, the benefits of chronic XO inhibition were extended to endothelial function and aortic stiffness. As an additional mechanism of radiation injury, endothelial regenerative capacity was measured using a three-dimensional aortic angiogenesis assay. Whole-body exposure of mice to gamma radiation produced a dose-dependent decrease in cell outgrowth. A similar dose-response was generated if aorta was irradiated ex vivo. Impaired angiogenic ability remained depressed through 2 weeks after whole-body irradiation. This effect was confirmed with whole-body Fe radiation 1-month post-radiation. Furthermore, acute XO inhibition or antioxidant treatment improved cell outgrowth after ex vivo irradiation.;This dissertation demonstrates that ionizing radiation induces chronic vascular dysfunction. The data suggests that XO activation is a primary contributor and potential target for radiation injury. In addition, radiation exposure may inhibit endothelial regeneration after vascular injury. Enhancing the understanding of vascular radiation response will hopefully lead to the development of effective methods to ameliorate radiation damage to the vasculature.