Vascular Damage in the Aorta of Wild-Type Mice Exposed to Ionizing Radiation: Sparing and Enhancing Effects of Dose Protraction

SIMPLE SUMMARY: The circulatory system receives ionizing radiation at various dose rates. Here, we analyzed changes in the circulatory system of wild-type mice at six months after starting acute, intermittent or continuous irradiation with 5 Gy of photons. Irradiation had little effect on left ventricular function, heart weight, and kidney weight. In the aorta, acute exposure caused structural disorganizations and detachment of the aortic endothelium and intima-media thickening. These morphological changes were concomitant with increases in markers for profibrosis, fibrosis, proinflammation, and macrophages, along with decreases in markers for cell adhesion and vascular functionality in the aortic endothelium. Compared with acute exposure, the magnitude of such aortic changes was overall greater in 25 fractions, smaller in 100 fractions, and much smaller in chronic exposure. These findings suggest that dose protraction alters aortic vascular damage, in a way that is not a simple function of dose rate. ABSTRACT: During medical (therapeutic or diagnostic) procedures or in other settings, the circulatory system receives ionizing radiation at various dose rates. Here, we analyzed prelesional changes in the circulatory system of wild-type mice at six months after starting acute, intermittent, or continuous irradiation with 5 Gy of photons. Independent of irradiation regimens, irradiation had little impact on left ventricular function, heart weight, and kidney weight. In the aorta, a single acute exposure delivered in 10 minutes led to structural disorganizations and detachment of the aortic endothelium, and intima-media thickening. These morphological changes were accompanied by increases in markers for profibrosis (TGF-β1), fibrosis (collagen fibers), proinflammation (TNF-α), and macrophages (F4/80 and CD68), with concurrent decreases in markers for cell adhesion (CD31 and VE-cadherin) and vascular functionality (eNOS) in the aortic endothelium. Compared with acute exposure, the magnitude of such aortic changes was overall greater when the same dose was delivered in 25 fractions spread over 6 weeks, smaller in 100 fractions over 5 months, and much smaller in chronic exposure over 5 months. These findings suggest that dose protraction alters vascular damage in the aorta, but in a way that is not a simple function of dose rate.