title: Intravenous and gastric cerium dioxide nanoparticle exposure disrupts microvascular smooth muscle signaling.
abstract: Cerium dioxide nanoparticles (CeO2 NP) hold great therapeutic potential, but the in vivo effects of non-pulmonary exposure routes are unclear. The first aim was to determine whether microvascular function is impaired after intravenous and gastric CeO2 NP exposure. The second aim was to investigate the mechanism(s) of action underlying microvascular dysfunction following CeO2 NP exposure. Rats were exposed to CeO2 NP (primary diameter: 4 ± 1 nm, surface area: 81.36 m(2)/g) by intratracheal instillation, intravenous injection, or gastric gavage. Mesenteric arterioles were harvested 24 h post-exposure and vascular function was assessed using an isolated arteriole preparation. Endothelium-dependent and independent function and vascular smooth muscle (VSM) signaling (soluble guanylyl cyclase [sGC] and cyclic guanosine monophosphate [cGMP]) were assessed. Reactive oxygen species (ROS) generation and nitric oxide (NO) production were analyzed. Compared with controls, endothelium-dependent and independent dilation were impaired following intravenous injection (by 61% and 45%) and gastric gavage (by 63% and 49%). However, intravenous injection resulted in greater microvascular impairment (16% and 35%) compared with gastric gavage at an identical dose (100 µg). Furthermore, sGC activation and cGMP responsiveness were impaired following pulmonary, intravenous, and gastric CeO2 NP treatment. Finally, nanoparticle exposure resulted in route-dependent, increased ROS generation and decreased NO production. These results indicate that CeO2 NP exposure route differentially impairs microvascular function, which may be mechanistically linked to decreased NO production and subsequent VSM signaling. Fully understanding the mechanisms behind CeO2 NP in vivo effects is a critical step in the continued therapeutic development of this nanoparticle.
authors.affiliation: *Center for Cardiovascular and Respiratory Sciences and Department of Physiology and Pharmacology, West Virginia University School of Medicine, Pathology and Physiology Research Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health and Department of Mechanical and Aerospace Engineering, West Virginia University, Morgantown, West Virginia 26506 *Center for Cardiovascular and Respiratory Sciences and Department of Physiology and Pharmacology, West Virginia University School of Medicine, Pathology and Physiology Research Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health and Department of Mechanical and Aerospace Engineering, West Virginia University, Morgantown, West Virginia 26506.
authors.forename: Valerie C
authors.initials: VC
authors.lastname: Minarchick
authors.affiliation: *Center for Cardiovascular and Respiratory Sciences and Department of Physiology and Pharmacology, West Virginia University School of Medicine, Pathology and Physiology Research Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health and Department of Mechanical and Aerospace Engineering, West Virginia University, Morgantown, West Virginia 26506 *Center for Cardiovascular and Respiratory Sciences and Department of Physiology and Pharmacology, West Virginia University School of Medicine, Pathology and Physiology Research Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health and Department of Mechanical and Aerospace Engineering, West Virginia University, Morgantown, West Virginia 26506.
authors.forename: Phoebe A
authors.initials: PA
authors.lastname: Stapleton
authors.affiliation: *Center for Cardiovascular and Respiratory Sciences and Department of Physiology and Pharmacology, West Virginia University School of Medicine, Pathology and Physiology Research Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health and Department of Mechanical and Aerospace Engineering, West Virginia University, Morgantown, West Virginia 26506.
authors.forename: Natalie R
authors.initials: NR
authors.lastname: Fix
authors.affiliation: *Center for Cardiovascular and Respiratory Sciences and Department of Physiology and Pharmacology, West Virginia University School of Medicine, Pathology and Physiology Research Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health and Department of Mechanical and Aerospace Engineering, West Virginia University, Morgantown, West Virginia 26506.
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Leonard
authors.affiliation: *Center for Cardiovascular and Respiratory Sciences and Department of Physiology and Pharmacology, West Virginia University School of Medicine, Pathology and Physiology Research Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health and Department of Mechanical and Aerospace Engineering, West Virginia University, Morgantown, West Virginia 26506.
authors.forename: Edward M
authors.initials: EM
authors.lastname: Sabolsky
authors.affiliation: *Center for Cardiovascular and Respiratory Sciences and Department of Physiology and Pharmacology, West Virginia University School of Medicine, Pathology and Physiology Research Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health and Department of Mechanical and Aerospace Engineering, West Virginia University, Morgantown, West Virginia 26506 *Center for Cardiovascular and Respiratory Sciences and Department of Physiology and Pharmacology, West Virginia University School of Medicine, Pathology and Physiology Research Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health and Department of Mechanical and Aerospace Engineering, West Virginia University, Morgantown, West Virginia 26506 *Center for Cardiovascular and Respiratory Sciences and Department of Physiology and Pharmacology, West Virginia University School of Medicine, Pathology and Physiology Research Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health and Department of Mechanical and Aerospace Engineering, West Virginia University, Morgantown, West Virginia 26506 tnurkiewicz@hsc.wvu.edu.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Nurkiewicz
mesh_terms: D000280:Administration, Inhalation; D000284:Administration, Oral; D000818:Animals; D001160:Arterioles / Q000187:drug effects* / Q000378:metabolism; D002563:Cerium / Q000633:toxicity*; D006152:Cyclic GMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D006162:Guanylate Cyclase / Q000378:metabolism; D007275:Injections, Intravenous; D007441:Intubation, Gastrointestinal; D008297:Male; D008643:Mesentery / Q000098:blood supply*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism; D053758:Nanoparticles; D009569:Nitric Oxide / Q000378:metabolism; D010316:Particle Size; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D000071756:Soluble Guanylyl Cyclase; D014664:Vasodilation / Q000187:drug effects*
chemical_list: D017382:Reactive Oxygen Species; D018160:Receptors, Cytoplasmic and Nuclear; D002563:Cerium; D009569:Nitric Oxide; C030583:ceric oxide; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP
keywords: cerium dioxide nanoparticles; microvascular function; nitric oxide; mesentery