title: Effects of High-LET Radiation Exposure and Hindlimb Unloading on Skeletal Muscle Resistance Artery Vasomotor Properties and Cancellous Bone Microarchitecture in Mice.
abstract: Weightlessness during spaceflight leads to functional changes in resistance arteries and loss of cancellous bone, which may be potentiated by radiation exposure. The purpose of this study was to assess the effects of hindlimb unloading (HU) and total-body irradiation (TBI) on the vasomotor responses of skeletal muscle arteries. Male C57BL/6 mice were assigned to control, HU (13-16 days), TBI (1 Gy (56)Fe, 600 MeV, 10 cGy/min) and HU-TBI groups. Gastrocnemius muscle feed arteries were isolated for in vitro study. Endothelium-dependent (acetylcholine) and -independent (Dea-NONOate) vasodilator and vasoconstrictor (KCl, phenylephrine and myogenic) responses were evaluated. Arterial endothelial nitric oxide synthase (eNOS), superoxide dismutase-1 (SOD-1) and xanthine oxidase (XO) protein content and tibial cancellous bone microarchitecture were quantified. Endothelium-dependent and -independent vasodilator responses were impaired in all groups relative to control, and acetylcholine-induced vasodilation was lower in the HU-TBI group relative to that in the HU and TBI groups. Reductions in endothelium-dependent vasodilation correlated with a lower cancellous bone volume fraction. Nitric oxide synthase inhibition abolished all group differences in endothelium-dependent vasodilation. HU and HU-TBI resulted in decreases in eNOS protein levels, while TBI and HU-TBI produced lower SOD-1 and higher XO protein content. Vasoconstrictor responses were not altered. Reductions in NO bioavailability (eNOS), lower anti-oxidant capacity (SOD-1) and higher pro-oxidant capacity (XO) may contribute to the deficits in NOS signaling in skeletal muscle resistance arteries. These findings suggest that the combination of insults experienced in spaceflight leads to impairment of vasodilator function in resistance arteries that is mediated through deficits in NOS signaling.
authors.affiliation: a   Department of Nutrition, Food and Exercise Sciences, Florida State University, Tallahassee, Florida 32306;
authors.forename: Payal
authors.initials: P
authors.lastname: Ghosh
authors.affiliation: b   Department of Kinesiology and the Johnson Cancer Research Center, Kansas State University, Manhattan, Kansas 66506;
authors.forename: Brad J
authors.initials: BJ
authors.lastname: Behnke
authors.affiliation: c   Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390;
authors.forename: John N
authors.initials: JN
authors.lastname: Stabley
authors.affiliation: d   Department of Physiology and Functional Genomics, University of Florida, Gainesville, Florida 32611;
authors.forename: Cody R
authors.initials: CR
authors.lastname: Kilar
authors.affiliation: e   Department of Health and Human Performance, University of Houston, Houston, Texas 77204;
authors.forename: Yoonjung
authors.initials: Y
authors.lastname: Park
authors.affiliation: f   Department of Medical Physiology, Texas A&M University Health Science Center, Bryan, Texas 77807; and.
authors.forename: Anand
authors.initials: A
authors.lastname: Narayanan
authors.affiliation: g   Space Biosciences Division, NASA Ames Research Center, Moffett Field, California 94035.
authors.forename: Joshua S
authors.initials: JS
authors.lastname: Alwood
authors.affiliation: g   Space Biosciences Division, NASA Ames Research Center, Moffett Field, California 94035.
authors.forename: Yasaman
authors.initials: Y
authors.lastname: Shirazi-Fard
authors.affiliation: g   Space Biosciences Division, NASA Ames Research Center, Moffett Field, California 94035.
authors.forename: Ann-Sofie
authors.initials: AS
authors.lastname: Schreurs
authors.affiliation: g   Space Biosciences Division, NASA Ames Research Center, Moffett Field, California 94035.
authors.forename: Ruth K
authors.initials: RK
authors.lastname: Globus
authors.affiliation: a   Department of Nutrition, Food and Exercise Sciences, Florida State University, Tallahassee, Florida 32306;
authors.forename: Michael D
authors.initials: MD
authors.lastname: Delp
mesh_terms: D000818:Animals; D001158:Arteries / Q000378:metabolism / Q000528:radiation effects; D006614:Hindlimb / Q000378:metabolism / Q000528:radiation effects; D006801:Humans; D008297:Male; D051379:Mice; D018482:Muscle, Skeletal / Q000378:metabolism / Q000528:radiation effects*; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D000069079:Radiation Exposure; D017382:Reactive Oxygen Species / Q000378:metabolism; D013026:Space Flight; D013482:Superoxide Dismutase / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D014664:Vasodilation / Q000528:radiation effects*; D014665:Vasodilator Agents / Q000008:administration & dosage; D014666:Vasomotor System / Q000378:metabolism / Q000528:radiation effects*; D014916:Whole-Body Irradiation; D014969:Xanthine Oxidase / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; C000606290:SOD1 protein, human; D014665:Vasodilator Agents; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D014969:Xanthine Oxidase