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

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

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±nm, surface area: 81.36m2/ g) by intratracheal instillation, intravenous injection, or gastric gavage. Mesenteric arterioles were harvested 24h postexposure 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.

Original languageEnglish (US)
Pages (from-to)77-89
Number of pages13
JournalToxicological Sciences
Volume144
Issue number1
DOIs
StatePublished - Mar 1 2015

All Science Journal Classification (ASJC) codes

  • Toxicology

Keywords

  • Cerium dioxide nanoparticles
  • Mesentery
  • Microvascular function
  • Nitric oxide

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