Immune‐mediated vasomotor dysfunction and ROS production during hypercholesterolemia occurs through an IFN‐γ‐dependent signaling pathway

Hypercholesterolemia (HC), a risk factor for the development of atherosclerosis, elicits a systemic inflammatory response that is accompanied by endothelium‐dependent vasomotor dysfunction. Although immune‐derived cytokines and the production of reactive oxygen species (ROS) have been implicated in atherogenesis, it remains unclear how these factors contribute to HC‐induced vasomotor dysfunction. We tested the hypothesis that HC elicits immune‐mediated ROS production and endothelial dysfunction through IFN‐γ signaling. Wire myography was employed to assess vasomotor responses and a cytochrome C reduction assay was used to assess ROS production in aortic rings harvested from wild type (WT) or mutant mice placed on either a normal (ND) or cholesterol‐enriched (HC) diet. Bone marrow chimeras (BMC) were produced by marrow transplantation between WT and IFN‐γ‐deficient (IFN‐γ−/−) mice. Endothelium‐dependent vasodilation to Ach was impaired and ROS production was increased in WT and WT→WT BMC mice on HC. The impaired vasodilation and increased ROS production were absent in IFN‐γ−/−, IFN‐γ−/−→WT BMC, and IFN‐γ receptor‐deficient mice on HC diet. Our findings indicate that immune‐mediated endothelium‐dependent vasomotor dysfunction and increased ROS production caused by HC occurs through an IFN‐γ signaling pathway.