Introduction: Poor air quality has become a growing health concern. Ultrafine particles (UFP), a component of air pollution, has been associated with cardiovascular disease/ events, establishing a critical need to understand the cellular mechanisms involved. Using a model UFP we have shown elevated vascular oxidant production, and inflammation. However, the underlying mechanisms were unexplored. Xanthine oxidoreductase (XOR), increases in circulation following various insults, which we recently established is actively derived from hepatocytes. The binding of endothelial cells (EC) and the mechanisms by which EC bound XOR mediates impairment are not fully understood. Bound XOR produces almost exclusively H 2 O 2 , which can across the membrane and influence cellular signaling and gene expression. We hypothesize that UFP inhalation elevates hepatic XOR release into circulation and XOR binds to EC initiating redox signaling pathways leading to epigenetic-mediated inflammatory gene upregulation. Methods & Results: Male (M) and female (F) rats and mice (8 wk) were exposed to sham air or UFP for 3 days. Plasma XOR activity increased 5-fold M and 3-fold F exposed to UFP (both p<0.05). We then determined that UFP activation of PKC (rat liver 2.4-fold, mouse liver 2.3-fold, AML12 cells 1.7-fold, all p<0.05) leads to G9a-dependent upregulation and release of XOR in hepatocytes (Control 2± 0.3 vs PMA 8± 1 vs PMA G9a siRNA 2± 2 μU/ml, p<0.05). In arterioles, UFP arterioles showed greater XOR binding when perfused with Alexaflur tagged XOR (69±6 vs 51±4 AFU, p<0.05) and impaired dilation, which was prevented in hepatocyte XOR knockouts mice (KO) (max dilation sham 62± 3 vs UFP 35± 4 vs UFP KO 50± 4, p<0.05). In culture EC were treated with XOR for 1h (for binding) then washed with PBS and cultured for 24 h (XOR-EC). XOR-EC increased demethylase KDM4a expression (1.7-fold, p<0.05) and inflammatory markers ICAM, VCAM, TNF, and TLR4 (p<0.05), leading to enhanced leukocyte adhesion (~2-fold, p<0.05). KDM4a loss of function (iKDM4a) prevented ICAM expression (XOR-EC 8-fold vs iKDM4a 2-fold, p<0.05) and diminished leukocyte adhesion (p<0.05). Conclusion: These findings suggest that vascular inflammation caused by UFP inhalation is mediated in part by an EC bound XOR- KDM4a pathway.