PM2.5 impairs gliovascular coupling via endothelial AHR-mitochondrial signaling in mice

Abstract

Particulate matter (PM2.5) is a pervasive air pollutant increasingly linked to neurovascular dysfunction, but the cellular mechanisms remain unclear. We identify the aryl hydrocarbon receptor (AHR) as a key endothelial sensor of PM2.5 that initiates mitochondrial stress and Parkin-dependent mitophagy. Across complementary inhalation and intratracheal instillation models, integrated with spatial transcriptomics, high-resolution imaging, and in vitro assays, endothelial mitochondrial injury and oxidative stress constricted cerebral vessels and reduced perfusion. These vascular insults propagated to astrocytes, where calmodulin-dependent mislocalization of aquaporin-4 (AQP4) disrupted perivascular water homeostasis and glymphatic exchange. System-level consequences included dendritic degeneration, microglial activation, and hypoxic stress, with the hippocampus showing heightened vulnerability. Spatial transcriptomics resolved region-and cell type-specific injury and synaptic remodeling that bulk RNA sequencing failed to detect, while endothelial readouts evidenced canonical AHR engagement. Collectively, the data establish endothelial mitophagy as a metabolic checkpoint linking environmental particulate exposure to gliovascular dysfunction and impaired brain clearance, and nominate AHR signaling as a potential therapeutic target to preserve brain homeostasis under chronic air pollution. These mechanistic links provide a framework for interpreting epidemiological associations between PM2.5 exposure and neurodegenerative disease risk.