The mechanism(s) through which engineered nanomaterial (ENM) inhalation disrupts normal extrapulmonary cardiovascular function remains to be fully defined. One of the better studied links that mediates exposure and effect is inflammatory mediator activation. We have reported that ENM inhalation (nano-titanium dioxide, count mode aerodynamic diameter &lt;150 nm, 5-10 mg/m<sup>3</sup>, 4-5 hrs) leads to focalized alveolitis, in a dose-dependent manner (pulmonary deposition 10-150 μg), and this initiates a series of plasma-borne mediators that ultimately activate systemic neutrophils and stimulate their adhesion and rolling. To gain further insight into these pathways/mechanisms, comprehensive comparative proteomic analyses on plasma, aorta, and small resistance vasculature were performed. 30 aortic proteins, 21 plasma proteins, and 23 resistance vasculature proteins were significantly altered after ENM inhalation. In the aorta and plasma, biopathway analysis revealed: acute phase response signaling, LXR/RXR activation, and FXR/RXR activation. Whereas, in the resistance vasculature, biopathway analysis revealed alterations in: ILK signaling, D-myo-inositol (1,3,4)-trisphosphate biosynthesis, and 1D-myo-inositol hexakisphosphate biosynthesis. One of the revealing consequences of these alterations is the generation of reactive species in the microvascular wall. Microvascular oxidative and nitrosative stress was assessed with fluorescent biomarkers, and functionally verified with various agonists and antagonists. The functional impact of ENM exposure exists in both arterioles and venules, and inter-vessel signaling is typically disrupted. The principal consequence of this disruption is an inability to match capillary inflow and outflow, and altered leukocyte-endothelium trafficking. Physiologically, this alters mechanotransduction and volume blood flow; which in turn compromise the ability to maintain cardiovascular homeostasis. The impact of these microvascular toxicities will be discussed from a cardiovascular health perspective.

Plasma proteomics, the link between engineered nanomaterial inhalation and systemic microvascular dysfunction?

254th National Meeting (2017)

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