Reversal of air pollution exposure restores vascular homeostasis via transcriptional regulation of chromatin remodelers

Air pollution exposure is a major modifiable risk factor for atherosclerotic cardiovascular disease (ASCVD). However, the mechanistic reasons for the reduction in events following cessation of fine particulate matter (PM2.5) exposure remain poorly understood. We hypothesized that removal from chronic PM2.5 exposure would reverse maladaptive vascular transcriptional programs driving atherogenesis. Male ApoE - / - mice were exposed to filtered air (FA), concentrated PM2.5 (PM2.5), or transitioned from PM2.5 to FA (REV) using a Versatile Aerosol Concentration and Enrichment System (VACES) that provides exposure to real-world levels of air pollution (mean PM2.5 concentration: ~101 μg/m³). Endothelial-dependent relaxation and contractility were measured in thoracic aortic rings by pin myography, and atheroma burden was quantified in brachiocephalic arteries and aortic roots by histology. Single-cell RNA sequencing (10x Genomics) was performed on aortic tissues to identify cell-specific transcriptional signatures across exposure groups. PM2.5 exposure significantly impaired acetylcholine-mediated relaxation (maximum response decreased 40%, p< 0.05) and enhanced phenylephrine-induced constriction (p=0.0011) compared with FA. REV mice demonstrated partial restoration of relaxation and decreased constriction, indicating functional reversibility. Atheroma area was decreased in REV vs. PM2.5 (p< 0.01) in the brachiocephalic artery, with no difference in the aortic root, consistent with site-specific vulnerability. Transcriptomic profiling revealed distinct molecular reversal signatures. In endothelial cells (ECs), PM2.5 exposure upregulated genes involved in chromatin remodeling and nitric oxide substrate handling (Kmt2a, Rab14, Slc7a2) and suppressed cAMP signaling (Popdc2), whereas reversal restored Popdc2, while downregulating mitochondrial stress (Uqcrh) and inflammatory (Ebi3) transcripts. In vascular smooth muscle cells (VSMCs), PM exposure increased metabolic and matrix remodeling mediators (Wnk2, Csnk2b, Timp3), which were reduced after reversal alongside induction of homeostatic and anti-fibrotic regulators (Tmeff2, Cnksr3). These findings indicate REV restores broad transcriptional programs through pathways involving chromatin remodeling master regulators involved in redox homeostasis, inflammation and matrix remodeling. Together, this integrative physiologic and single-cell transcriptomic analysis demonstrates that air pollution–induced vascular injury is dynamically reversible, highlighting the cardiovascular benefits of exposure reduction and mechanistic pathways underlying vascular resilience to environmental exposures. This work was supported by the National Institutes of Health (R35ES031702-S.R.) and the Burroughs Wellcome Fund Postdoctoral Diversity Enrichment Program (1060485-J.E-G.) This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.