Pulmonary cerium dioxide nanoparticle exposure differentially impairs coronary and mesenteric arteriolar reactivity

Abstract

Cerium dioxide nanoparticles (CeO2 NPs) are an engineered nanomaterial (ENM) that possesses unique catalytic, oxidative, and reductive properties. Currently, CeO2 NPs are being used as a fuel catalyst but these properties are also utilized in the development of potential drug treatments for radiation and stroke protection. These uses of CeO2 NPs present a risk for human exposure; however, to date, no studies have investigated the effects of CeO2 NPs on the microcirculation following pulmonary exposure. Previous studies in our laboratory with other nanomaterials have shown impairments in normal microvascular function after pulmonary exposures. Therefore, we predicted that CeO2 NP exposure would cause microvascular dysfunction that is dependent on the tissue bed and dose. Twenty-four-hour post-exposure to CeO2 NPs (0-400 μg), mesenteric, and coronary arterioles was isolated and microvascular function was assessed. Our results provided evidence that pulmonary CeO2 NP exposure impairs endothelium-dependent and endothelium-independent arteriolar dilation in a dose-dependent manner. The CeO2 NP exposure dose which causes a 50 % impairment in arteriolar function (EC50) was calculated and ranged from 15 to 100 μg depending on the chemical agonist and microvascular bed. Microvascular assessments with acetylcholine revealed a 33-75 % reduction in function following exposure. Additionally, there was a greater sensitivity to CeO2 NP exposure in the mesenteric microvasculature due to the 40 % decrease in the calculated EC50 compared to the coronary microvasculature EC50. CeO2 NP exposure increased mean arterial pressure in some groups. Taken together, these observed microvascular changes may likely have detrimental effects on local blood flow regulation and contribute to cardiovascular dysfunction associated with particle exposure.

Figure 1

TEM Images of CeO₂ nanoparticles at A) low magnification B) high magnification. Red dashes indicate individual particles that were estimated to be 4–6 nm. C) DLS distribution curve of the suspended CeO₂ NPs with an average agglomerate size for peak 1: 191 ± 77 nm; peak 1: 901 ± 391 nm; peak 3: 5081 ± 566 nm.

Figure 2

XPS Spectra of the hydrothermally synthesized and dried CeO₂ nanoparticles with deconvoluted peaks using a Gaussian fit A) C 1s B) O 1s.

Figure 3

Pulmonary inflammation was altered after exposure to CeO₂ NPs. There was a significant increase in LDH (A), AM activation (C), and PNM inflitration (D). However, there was no change in albumin (B) levels after exposure. Values are means ± SE. † p ≤ 0.05 vs. control; ^ p ≤ 0.05 vs. 100 μg CeO₂ NPs.

Figure 4

ACh-induced vasodilation was impaired in mesenteric (A; n=8–13) and coronary (B; n=7–9) arterioles from groups 24 hr post-exposure to CeO₂ NPs. Values are means ± SE. † p ≤ 0.05 vs. control; * p ≤ 0.05 vs. 10 μg CeO₂ NPs. The right panel represents the responses of the various doses of CeO₂ NPs and was analyzed by nonlinear regression. The left panel highlights the point-to-point differences between the control and CeO₂ NP exposed group.

Figure 5

The Ca²⁺ iontophore (A23187)-induced vasodilation was impaired in mesenteric (A; n=6–11) and coronary (B; n=6–8) arterioles from groups 24 hr post-exposure to CeO₂ NPs. Values are means ± SE. † p ≤ 0.05 vs. control. The right panel represents the responses of the various doses of CeO₂ NPs and was analyzed by nonlinear regression. The left panel highlights the point-to-point differences between the control and CeO₂ NP exposed group.

Figure 6

SNP-induced vasodilation was impaired in mesenteric (A; n=9–11) and coronary (B; n=6–13) arterioles from groups 24 hr post-exposure to CeO₂ NPs. Values are means ± SE. † p ≤ 0.05 vs. control.

Figure 7

SPR-induced vasodilation was impaired in mesenteric (A; n=6–12) and coronary (B; n=6–8) arterioles from groups 24 hr post-exposure to CeO₂ NPs. Values are means ± SE. † p ≤ 0.05 vs. control; * p ≤ 0.05 vs. 10 μg CeO₂ NPs; ‡ p ≤ 0.05 vs. 50 μg CeO₂ NPs; ^ p ≤ 0.05 vs. 100 μg CeO₂ NPs. The right panel represents the responses of the various doses of CeO₂ NPs and was analyzed by nonlinear regression. The left panel highlights the point-to-point differences between the control and CeO₂ NP exposed group.

Figure 8

PE-induced vasoconstriction was not significantly impaired in mesenteric (A; n=5–13) and coronary (B; n=6–9) arterioles from groups 24 hr post-exposure to CeO₂ NPs. Values are means ± SE. The right panel represents the responses of the various doses of CeO₂ NPs and was analyzed by nonlinear regression. The left panel highlights the point-to-point differences between the control and CeO₂ NP exposed group.

Figure 9

5-HT-induced vasoconstriction was not significantly impaired in mesenteric (A; n=6–10) arterioles. An attenuated response was observed only in coronary (B; n=6–8) arterioles from groups 24 hr post-exposure to 400 μg CeO₂ NPs. Values are means SE. ‡ p ≤ 0.05 vs. 50 μg CeO₂ NPs; ^ p ≤ 0.05 vs. 100 μgCeO₂ NPs. The right panel represents the responses of the various doses ofCeO₂ NPs and was analyzed by nonlinear regression. The left panel highlights the point-to-point differences between the control and CeO₂ NP exposed group.

Figure 10

Myogenic responsiveness was not impaired in mesenteric (A; n=10–15) and coronary (B; n=6–9) arterioles from groups 24 hr post-exposure to CeO₂ NPs. Values are means ± SE. The right panel represents the responses of the various doses of CeO₂ NPs and was analyzed by nonlinear regression. The left panel highlights the point-to-point differences between the control and CeO₂ NP exposed group.