Senolytics Reverse PM<sub>2.5</sub> - Induced Cell and Vascular Dysfunction.

Exposure to fine airborne particulate matter (PM_2.5) is associated with cardiovascular disease and increased atherogenesis. While some prior studies provided mechanistic insights linking exposure to lesion progression, instability, and rupture, a complete definition of cellular events contributing to early vascular inflammation is lacking. Here we show that C57BL/6J mice exposed to concentrated ambient PM_2.5 (CAP), as opposed to control mice inhaling filtered air, displayed endothelial activation, as evidenced by the increased number of leukocytes rolling on, and adhering to, the intact vasculature in vivo. As CAP exposure also induced the senescence(definition) of peripheral blood mononuclear cells (MNCs) and endothelial progenitor cells (EPCs), we further assessed the role of this outcome in PM_2.5-induced vascular dysfunction. We observed that treatment with the senolytics(definition) Dasatinib and Quercetin (DQ), which eliminate senescent cells, was effective in reversing the CAP-induced senescence of both of MNCs and EPCs as demonstrated by reductions in β-galactosidase activity and the expression of genes characteristic of the senescence activated secretory phenotype (SASP). Furthermore, we found that DQ treatment was effective in reversing CAP-induced defects in in vitro EPC function (tube forming capacity) and limited in vivo endothelial activation as well. These results provide strong evidence for a role of PM_2.5 in the early stages of atherogenesis by inducing endothelial activation leading to leukocyte recruitment. Our results further suggest that senolytic treatment may be efficacious in combatting adverse cardiovascular outcomes in those chronically exposed to high levels of PM_2.5.