Abstract 16056: Pulmonary Oxidative Stress Contributes to Ambient Fine Particulate Matter (PM2.5)-Induced Vascular VEGF Resistance and Endothelial Progenitor Cell Retention
Background and Rationale: Epidemiological evidence suggests that exposure to ambient fine particulate matter (PM2.5) is associated with increased cardiovascular disease (CVD) risk. Previous studies in our laboratory have shown that in both humans and mice, endothelial progenitor cells (EPCs) are early and sensitive targets of air pollution. EPC depletion has been suggested to be a significant contributor to cardiovascular injury and disease and circulating EPC levels predict CVD risk and mortality. Nevertheless the mechanisms by which PM2.5 exposure decreases EPC levels remain unknown. We tested the hypothesis that PM2.5 exposure decreases EPC levels by inducing pulmonary oxidative stress.
Methods and Results: Exposure to concentrated air PM2.5 particulate matter (CAP) for 9 days induced vascular hypercontractility and impaired aortic VEGF signaling in young adult mice. Flow cytometry analysis showed that CAP exposure decreased circulating EPC (Flk-1+/Sca-1+-cells) levels (52±7% of control; p=0.002) and increased in bone marrow EPCs (141±9% of control; p=0.007). Glutathione levels, measured by flow cytometry in the Flk-1+/Sca-1+-cell-populations, were decreased upon CAP exposure. CAP exposure also enhanced the abundance of protein-acrolein adducts in the lung, indicating increased oxidative stress. To test the role of pulmonary oxidative stress, we exposed mice transgenic for lung-specific extracellular superoxide dismutase (ecSOD) to CAP. In contrast with WT mice no increase in protein acrolein adducts was observed in the lung of CAP-exposed ecSOD-transgenic mice. No differences in EPC abundance or GSH levels were found in the blood or the bone marrow isolated from air- or CAP-exposed ecSOD transgenic mice. Pulmonary overexpression of ecSOD also preserved aortic VEGF-stimulated Akt phosphorylation after CAP exposure.
Conclusions: Exposure to PM2.5 depletes circulating EPC levels by inducing oxidative stress in the lungs, which also impairs VEGF signaling. These findings suggest that the antioxidant capacity of the lung may be an important determinant of PM2.5-induced cardiovascular injury and that increasing pulmonary antioxidant defense could attenuate cardiovascular injury induced by exposure to fine air pollution.
Author Disclosures: P. Haberzettl: None. J. McCracken: None. R. Folz: None. I. Zelko: None. A. Bhatnagar: None. D.J. Conklin: None.
- © 2014 by American Heart Association, Inc.