Mechanistic Insight into Airborne Particulate Matter PM10 As an Environmental Hazard for Hemorrhagic Stroke: Evidence from in Vitro and in Vivo Studies

Airborne particulate matter less than 10 µm in diameter (PM10) is recognized as a significant environmental risk factor for hemorrhagic stroke (HS), as evidenced by epidemiological studies that link PM10 with the heightened cerebrovascular mortality related to HS. Nonetheless, the molecular mechanisms underlying this association remain unknown. Cerebral aneurysm (CA), an etiological factor of HS, is characterized by a bulge resulting from the abnormal loss of the muscular layer of a cerebral artery, comprising brain vascular endothelial cell (BVEC) and vascular smooth muscle cell (VSMC). BVEC exhibiting an inflammatory phenotype is critical for VSMC death within the cerebrovasculature. Here, we elucidate a molecular mechanism by which PM10 augments necroptotic death of VSMC as a consequence of intercellular effects arising from FasL inflammatory cytokine, which is derived from BVEC. Notably, BVEC exposed to PM10 upregulates FasL through ATM-NF-κB signaling, in response to oxidative DNA damage. This genotoxic stress is attributed to pro-oxidant action of aluminum, the prevalent element in PM10. Furthermore, respiratory exposure to PM10 in mice precipitates early onset of CA development through necroptotic VSMC death in cerebral artery, by activating FasL expression in BVEC. In conclusion, this study provides molecular evidence establishing a direct association between PM10 pollution and an elevated risk of stroke, particularly HS.