Journal
TOXICOLOGICAL SCIENCES
Volume 170, Issue 2, Pages 525-535Publisher
OXFORD UNIV PRESS
DOI: 10.1093/toxsci/kfz121
Keywords
traffic pollution; angiotensin II; AT1 receptor; cerebral microvasculature; tight junction proteins
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Funding
- National Institute of Environmental Health Sciences at the National Institute of Health [R15ES026795]
- University of North Texas Research Initiation Grant (RIG) [GA93601]
- Environmental Protection Agency Center [RD83479601]
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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 (AT(1)) 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-AT(1) 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 mu g/m(3) PM) 6 h/d for 30 days. Exposure to HF+MVE resulted in a significant increase in plasma Ang II and expression of AT(1) 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 AT(1) antagonist, Losartan. Our BBB coculture showed increased levels of astrocyte AT(1) and decreased expression of aryl hydrocarbon receptor and glutathione peroxidase-1, associated with increased interleukin-6 and transforming growth factor-beta 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-AT(1) signaling and inflammation, which is exacerbated by an HF diet.
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