Effects of Hindlimb Unloading and Ionizing Radiation on Skeletal 1 Muscle Resistance Artery Vasodilation and Its Relation to Cancellous 2 Bone in Mice

33 Spaceflight has profound effects on vascular function as a result of weightlessness that 34 may be further compounded by radiation exposure. The purpose of the present study was 35 to assess the individual and combined effects of hindlimb unloading (HU) and radiation 36 (Rad) on vasodilator responses in the skeletal muscle vasculature. Adult male C57BL/6J 37 mice were randomized to one of four groups: control (Con), HU (tail suspension for 15 38 days), Rad (200cGy of Cs), and HU-Rad (15 day tail suspension and 200cGy of Cs). 39 Endothelium-dependent vasodilation of gastrocnemius feed arteries was assessed in vitro 40 using acetylcholine (ACh, 10-10 M) and inhibitors of nitric oxide synthase (NOS) and 41 cyclooxygenase (COX). Endothelium-independent vasodilation was assessed using Dea42 NONOate (10-10 M). Endothelium-dependent and -independent vasodilator responses 43 were impaired relative to Con responses in all treatment groups, however, there was no 44 further impairment from the combination of treatments (HU-Rad) relative to that in the 45 HU and Rad groups. The NOS-mediated contribution to endothelium-dependent 46 vasodilation was depressed with HU and Rad. This impairment in NOS signaling may 47 have been partially compensated for by an enhancement of PGI2-mediated dilation. 48 Changes in endothelium-dependent vasodilation were also associated with decrements in 49 trabecular bone volume in the proximal tibia metaphysis. These data demonstrate that the 50 simulated space environment (i.e., radiation exposure and unloading of muscle and bone) 51 significantly impairs skeletal muscle artery vasodilation, mediated through endothelium52 dependent reductions in NOS signaling and decrements in vascular smooth muscle cell 53 responsiveness to NO. 54 by 10.0.33.5 on O cber 5, 2017 http://jaysiology.org/ D ow nladed fom