PM2.5 is a known cardiovascular risk factor, yet its specific pathways to vascular dysfunction-particularly the roles of mitochondrial homeostasis, mtDNA integrity, and energy metabolism in endothelial impairment-are poorly understood. To address this, we adopted an integrated approach combining a controlled exposure trial with cellular experiments. The randomized, double-blind crossover trial demonstrated that short-term PM2.5 exposure significantly increases serum levels of EGF, VEGFA, and D-dimer, while decreasing levels of PDGF, PON1, GSH-Px, and mtDNAcn. Causal mediation modeling revealed that PM2.5-triggered endothelial dysfunction is partially mediated through oxidative stress response (decreased PON1 activity, and reduced GSH-Px levels), accounting for 40.30-71.80 % of the total effect. In Vitro, PM2.5 treatment induces damage to human umbilical vein endothelial cells (HUVECs) in a time- and concentration-dependent manner. Mechanistically, PM2.5 exposure elevated mitochondrial ROS generation, enhanced intracellular ROS levels, and suppressed eNOS expression, ultimately impairing NO bioavailability. PM2.5-exposed endothelial cells exhibited mitochondrial dysfunction, manifested by structural abnormalities (mitochondrial swelling and rupture) and functional impairment (a significant reduction in mitochondrial membrane potential). Metabolic profiling further demonstrated that PM2.5 disrupts endothelial bioenergetics by inhibiting glycolysis inhibition, suppressing fatty acid oxidation suppression, and inducing an energy crisis marked by reduced ATP production. These synergistic effects disrupt vascular homeostasis by critically compromising endothelial integrity and function. Our findings demonstrate that PM2.5 exposure elevates cardiovascular risk via an oxidative stress/mitochondrial dysfunction/endothelial impairment axis, revealing a key mechanistic pathway for its population health impacts.
Jiang et al. (Thu,) studied this question.