Long-Term PM2.5 Exposure Promoted Vascular Calcification through XBP1s-Associated Osteogenic Switching and Inflammatory Crosstalk

Fine particulate matter (PM2.5) is a major environmental risk factor for cardiovascular disease, yet the mechanisms underlying long-term exposure-induced vascular calcification remain incompletely understood. Whether PM2.5 directly participates in mineral nucleation remains unclear. We found that PM2.5 accelerated the transformation of amorphous calcium phosphate (ACP) into crystalline hydroxyapatite (HAP) and may act as a heterogeneous nucleation interface under simulated physiological conditions. Mice were exposed to environmentally relevant PM2.5 concentrations (5 or 35 μg/m3) for 180 days using a whole-body inhalation system. Long-term PM2.5 exposure increased arterial stiffness and promoted vascular remodeling and calcification. Mechanistically, PM2.5 increased XBP1s expression in mouse aortic smooth muscle cells (MOVAS), promoting proliferative and osteogenic phenotypic switching. Genetic deletion of Xbp1 markedly attenuated PM2.5-induced MOVAS proliferation, migration, osteogenic transformation, and mineralization. In addition, PM2.5-stimulated MOVAS acquired a pro-inflammatory secretory phenotype that promoted macrophage recruitment and M1 polarization, whereas Xbp1 deficiency attenuated these effects. We also established a human iPSC-derived blood vessel organoid (BVO)-macrophage coculture system and found that macrophages substantially amplified PM2.5-induced osteogenic remodeling and calcification. Collectively, these findings revealed the involvement of both physicochemical mineralization and XBP1-associated osteogenic and inflammatory responses in PM2.5-induced vascular calcification, providing new insights into the mechanisms underlying PM2.5-associated vascular injury.