Xanthine Oxidase Mediates Cerebrovascular Function Impairment in Chronically Stressed Mice

Abstract

Chronic stress‐induced depression is a major cerebrovascular risk factor, and the link between obesity and depression is strong. We have previously shown that chronic stress in obese rats significantly reduces cerebrovascular function, mediated by an increase in oxidative stress. Xanthine oxidase (XO) is a major source of oxidative stress, thus, we examined the effects of Febuxostat (XO inhibitor) on improving cerebrovascular function after the development of depressive like symptoms.Diet induced obesity (60 kcal% fat) started at 6 weeks of age in C57BL/6 mice (n=12) lasting for a total of twenty weeks. During the final eight weeks, 6 mice underwent the unpredictable chronic mild stress (UCMS; 5 days/week for 7 Hrs/day) model to elicit a depressive phenotype. On week twenty, the mice were euthanized and the middle cerebral arteries (MCA) were removed and positioned in a pressurize myobath. To test for vessel health, the MCA was exposed it to increasing concentrations of acetylcholine (Ach; 10−9M to 10−4M) in the presence or absence of Febuxostat (40μM), XO (40μM), and L‐NAME (10−4M).MCA dilation to Ach was impaired in obese mice that underwent UCMS compared to obese control mice (7±1% vs. 23±3%, p<0.05). Incubating the MCA with Febuxostat for 30 minutes in the chamber did not improve MCA dilation to Ach in the obese control mice but restored MCA dilation in the UCMS obese mice (26±2% vs. 25±3%, p<0.05, respectively). Incubating the MCA with XO or L‐NAME had the same affect and reduced MCA dilation to Ach to 6% and 5%, respectively, in the obese control mice. Further, in the UCMS obese mice, max Ach dilation did not differ to the Ach dilation in the presence of L‐NAME. These data suggest that a depressive phenotype generates an increased production of reactive oxygen species possibly via increased activity of xanthine oxidase.Support or Funding InformationNIH Cobra Grant 5P20GM109098This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.