Xanthine oxidase mediates chronic stress-induced cerebrovascular dysfunction and cognitive impairment.

Xanthine oxidase (XO) mediates vascular function. Chronic stress impairs cerebrovascular function and increases the risk of stroke and cognitive decline. Our study determined the role of XO on stress-induced cerebrovascular dysfunction and cognitive decline. We measured middle cerebral artery (MCA) function, free radical formation, and working memory in 6-month-old C57BL/6 mice who underwent 8 weeks of control conditions or unpredictable chronic mild stress (UCMS) with or without febuxostat (50 mg/L), a XO inhibitor. UCMS mice had an impaired MCA dilation to acetylcholine vs. controls (p < 0.0001), and increased total free radical formation, XOR protein levels, and hydrogen peroxide production in the liver compared to controls. UCMS increased hydrogen peroxide production in the brain and cerebrovasculature compared to controls. Working memory, using the y-maze test, was impaired (p < 0.05) in UCMS mice compared to control mice. However, blocking XO using febuxostat prevented the UCMS-induced impaired MCA response, while free radical production and hydrogen peroxide levels were similar to controls in the liver and brain of UCMS mice treated with febuxostat. Further, UCMS + Feb mice did not have a significant reduction in working memory. These data suggest that the cerebrovascular dysfunction associated with chronic stress may be driven by XO, which leads to a reduction in working memory.

Left Ventricular Segmental Strain Identifies Unique Myocardial Deformation Patterns After Intrinsic and Extrinsic Stressors in Mice.

We used segmental strain analysis to evaluate whether intrinsic (diet-induced obesity [DIO]) and extrinsic (unpredictable chronic mild stress [UCMS]) stressors can alter deformational patterns of the left ventricle. Six-week-old male C57BL/6J mice were randomized into the lean or obese group (n = 24/group). Mice underwent 12 wk of DIO with a high-fat diet (HFD). At 18 wk, lean and obese mice were further randomized into UCMS and non-UCMS groups (UCMS, 7 h/d, 5 d/wk, for 8 wk). Echocardiography was performed at baseline (6 wk), post-HFD (18 wk) and post-UCMS (26 wk). Machine learning was applied to the DIO and UCMS groups. There was robust predictive accuracy (area under the receiver operating characteristic curve [AUC] = 0.921) when comparing obese with lean mice, with radial strain changes in the lateral (-64%, p ≤ 0.001) and anterior free (-53%, p < 0.001) walls being most informative. The ability to predict mice that underwent UCMS, irrespective of diet, was assessed (AUC = 0.886), revealing longitudinal strain rate of the anterior midwall and radial strain of the posterior septal wall as the top features. The wall segments indicate a predilection for changes in deformation patterns to the free wall (DIO) and septal wall (UCMS), indicating disease-specific alterations to the myocardium.