Title: Mixed Vehicle Emissions Induces Angiotensin II and Cerebral Microvascular Angiotensin Receptor Expression in C57Bl/6 Mice and Promotes Alterations in Integrity in a Blood-Brain Barrier Coculture Model.
Authors: Suwannasual, Usa; Lucero, JoAnn; Davis, Griffith; McDonald, Jacob D; Lund, Amie K
Published In Toxicol Sci, (2019 08 01)
Abstract: Exposure to traffic-generated pollution is associated with alterations in blood-brain barrier (BBB) integrity and exacerbation of cerebrovascular disorders. Angiotensin (Ang) II signaling through the Ang II type 1 (AT1) receptor is known to promote BBB disruption. We have previously reported that exposure to a mixture of gasoline and diesel vehicle engine emissions (MVE) mediates alterations in cerebral microvasculature of C57Bl/6 mice, which is exacerbated through consumption of a high-fat (HF) diet. Thus, we investigated the hypothesis that inhalation exposure to MVE results in altered central nervous system microvascular integrity mediated by Ang II-AT1 signaling. Three-month-old male C57Bl/6 mice were placed on an HF or low-fat diet and exposed via inhalation to either filtered air (FA) or MVE (100 μg/m3 PM) 6 h/d for 30 days. Exposure to HF+MVE resulted in a significant increase in plasma Ang II and expression of AT1 in the cerebral microvasculature. Results from a BBB coculture study showed that transendothelial electrical resistance was decreased, associated with reduced expression of claudin-5 and occludin when treated with plasma from MVE+HF animals. These effects were attenuated through pretreatment with the AT1 antagonist, Losartan. Our BBB coculture showed increased levels of astrocyte AT1 and decreased expression of aryl hydrocarbon receptor and glutathione peroxidase-1, associated with increased interleukin-6 and transforming growth factor-β in the astrocyte media, when treated with plasma from MVE-exposed groups. Our results indicate that inhalation exposure to traffic-generated pollutants results in altered BBB integrity, mediated through Ang II-AT1 signaling and inflammation, which is exacerbated by an HF diet.
PubMed ID: 31132127
MeSH Terms: Air Pollutants/toxicity; Angiotensin II/drug effects*; Angiotensin II/metabolism; Animals; Astrocytes/drug effects; Blood-Brain Barrier/drug effects*; Central Nervous System/drug effects*; Cerebrovascular Circulation; Coculture Techniques; Diet, High-Fat; Gene Expression/drug effects; Inflammation; Inhalation Exposure/adverse effects; Male; Mice; Mice, Inbred C57BL; Microvessels/metabolism; Receptor, Angiotensin, Type 1/drug effects*; Receptor, Angiotensin, Type 1/metabolism; Renin-Angiotensin System/drug effects*; Tight Junction Proteins/metabolism; Vehicle Emissions/toxicity*