Intravenous and gastric cerium dioxide nanoparticle exposure disrupts microvascular smooth muscle signaling

Valerie C Minarchick; Phoebe A Stapleton; Natalie R Fix; Stephen S Leonard; Edward M Sabolsky; Timothy R Nurkiewicz

doi:10.1093/toxsci/kfu256

Intravenous and gastric cerium dioxide nanoparticle exposure disrupts microvascular smooth muscle signaling

Toxicol Sci. 2015 Mar;144(1):77-89. doi: 10.1093/toxsci/kfu256. Epub 2014 Dec 5.

Authors

Valerie C Minarchick¹, Phoebe A Stapleton¹, Natalie R Fix², Stephen S Leonard², Edward M Sabolsky², Timothy R Nurkiewicz³

Affiliations

¹ *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.
² *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.
³ *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.

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.

Keywords: cerium dioxide nanoparticles; microvascular function; nitric oxide; mesentery.

Publication types

Comparative Study
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Administration, Inhalation
Administration, Oral
Animals
Arterioles / drug effects*
Arterioles / metabolism
Cerium / toxicity*
Cyclic GMP / metabolism
Dose-Response Relationship, Drug
Epithelial Cells / drug effects
Epithelial Cells / metabolism
Guanylate Cyclase / metabolism
Injections, Intravenous
Intubation, Gastrointestinal
Male
Mesentery / blood supply*
Muscle, Smooth, Vascular / drug effects*
Muscle, Smooth, Vascular / metabolism
Myocytes, Smooth Muscle / drug effects*
Myocytes, Smooth Muscle / metabolism
Nanoparticles*
Nitric Oxide / metabolism
Particle Size
Rats, Sprague-Dawley
Reactive Oxygen Species / metabolism
Receptors, Cytoplasmic and Nuclear / metabolism
Signal Transduction / drug effects*
Soluble Guanylyl Cyclase
Vasodilation / drug effects*

Substances

Reactive Oxygen Species
Receptors, Cytoplasmic and Nuclear
Cerium
Nitric Oxide
ceric oxide
Guanylate Cyclase
Soluble Guanylyl Cyclase
Cyclic GMP

Abstract

Publication types

MeSH terms

Substances

Grants and funding