Degree

Doctor of Philosophy (PhD)

Department

Comparative Biomedical Sciences

Document Type

Dissertation

Abstract

Air pollution is consistently linked with elevations in cardiovascular disease (CVD) and its mortality. Particulate matter (PM) is a pivotal factor in air pollution-associated CVD. PM containing environmentally persistent free radicals (EPFR) forms from the incomplete combustion of organic wastes. These products adhere to particulate matter carrying redox-active transition metals on its surface. To enable systematic research of the health impacts of EPFR, our colleagues developed a combustion method to produce EPFR-containing PM that closely resemble urban PM and validated their use for typical laboratory settings. We exposed mice to laboratory generated EPFR through whole-body inhalation and investigated their dose-dependent impact on vascular function. These studies revealed that EPFR leads to endothelial dysfunction, impairing vascular function in an endothelium- and radical-dependent manner. Further, aryl hydrocarbon receptor (AhR) activation was observed in alveolar type-II (AT-II) cells that make up the air-blood interface in the lung. We hypothesized that AhR activation in AT-II cells at the air-blood interface may stimulate the release of systemic factors that provoke endothelial dysfunction in arteries peripheral to the lungs. To test this hypothesis, we deleted AhR from AT-II cells of male and female mice, and mice were subjected to EFPR inhalation. Deletion of AhR from AT-II cells mitigated impairment in endothelium-dependent vasodilation and plasma biomarkers of endothelial dysfunction. Our findings suggest that at a transcriptional level, AhR activation governs endothelial function in a paracrine fashion. AhR is a recognized regulator of microRNA (miRNA) biogenesis, and miRNA control diverse signaling pathways. We thus hypothesized that miRNA are systemic mediators of EPFR-induced endothelial dysfunction. Studies using transgenic mice revealed that EPFR-induced AhR activation in AT-II cells in the lungs altered 17 miRNA in plasma. Utilizing Ingenuity Pathway Analysis, we found that 7 of these miRNA may have roles in modulating endothelin-1 and endothelial nitric oxide signaling, thus governing endothelial dysfunction, suggesting that miRNA may be systemic mediators linking EPFR inhalation with vascular injury observed peripheral to the lung The findings from my study enhance our understanding of the mechanisms of EPFR-induced endothelial dysfunction, ultimately aiding human risk assessment and suggesting interventions to reduce the impacts of EPFR exposure.

Date

11-14-2023

Committee Chair

Dugas, Tammy R.

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