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

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.