Research Grants Program Office

BackgroundDioxins are persistent environmental pollutants found in industrial emissions, tobacco smoke, and air pollution. Chronic exposure is associated with cardiovascular disease, but how dioxins act within the vessel wall to promote atherosclerosis remains unclear. We aimed to determine how dioxin exposure alters vascular smooth muscle cell behavior and whether smooth muscle cell aryl hydrocarbon receptor signaling modifies plaque progression.MethodsWe studied atherosclerotic mouse models exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin and complementary cultures of human coronary artery smooth muscle cells. We used single-cell gene-expression profiling, single-cell chromatin-accessibility profiling, smooth muscle cell lineage tracing, histology, cell migration and proliferation assays, and chromatin binding analysis.ResultsHere we show that dioxin exposure accelerates atherosclerosis, increases plaque size, promotes early smooth muscle cell phenotypic transitions, and enhances inflammatory cell recruitment. Modulated smooth muscle cells emerge as the most transcriptionally responsive vascular cell type to dioxin and important inflammatory mediators within plaques. Dioxin-induced gene programs overlap with tobacco-associated responses and are enriched for migration, inflammation, and cell-death pathways. Dioxin also increases chromatin accessibility at vascular remodeling and immune activation genes and reduces genomic binding of TCF21, a regulator of smooth muscle cell stability. Loss of aryl hydrocarbon receptor signaling specifically in smooth muscle cells worsens dioxin-induced plaque growth, oxidative stress, and loss of smooth muscle cell-derived fibrous cap cells.ConclusionsThese findings identify smooth muscle cell reprogramming as a mechanism by which dioxin promotes atherosclerosis and vascular inflammation. They also reveal that endogenous smooth muscle cell aryl hydrocarbon receptor signaling protects against oxidative stress and helps preserve plaque-stabilizing fibrous cap structure.