Cerebrovascular function is protected in hepatic xanthine oxidase knockout mice under chronic stress

Abstract

Americans have been facing a mental health crisis that is predicted to impact and yield long-term psychological and physiological consequences negatively. We have shown that exposure to chronic stress can induce a pro-oxidative environment leading to cerebrovascular dysfunction and cognitive impairment. Xanthine oxidoreductase (XOR) is an enzyme that generates xanthine oxidase (XO) and xanthine dehydrogenase (XDH). Under hypoxic or pro-inflammatory conditions, XO produces excessive amounts of hydrogen peroxide and superoxide, which plays an important role in this stress-induced cerebrovascular dysfunction. Pharmacologically inhibiting XO with Febuxostat (50 mg/L) prevented stress-induced cerebrovascular dysfunction. XO is found in multiple tissues/organs; however, the liver is the major source of XO. Thus, this study aimed to understand how XO produced from the liver impacted cerebrovascular function during chronic stress. We hypothesize that liver XO production mediates stress-induced cerebrovascular dysfunction. To test our hypothesis, we exposed wild-type (WT) and hepatic XO knockout mice (HXO) to eight weeks of unpredictable chronic mild stress (UCMS) with or without Febuxostat (Feb). Groups were separated by HXO-control, HXO-UCMS, HXO-UCMS+Feb, WT-con, WT-UCMS, and WT-UCMS+Feb. During terminal procedures, the middle cerebral artery (MCA) was isolated and assessed using pressure myography to test the endothelial-dependent (EDD) and endothelium-independent dilation (EID) to acetylcholine (ACh) and sodium nitroprusside (SNP). The isolated MCA was kept under physiological conditions (pH 7.4±0.2; 70±2 mmHg, 37±1℃). In WT mice, UCMS decreased by 50% EDD (p<0.0001) and did not affect EID compared to WT-con, whereas the WT-UCMS+Feb group was fully protected, with similar EDD and EID values compared to WT-con. In contrast, HXO mice were partially protected from UCMS, reflected by only a 24% decrease (p<0.0001) in EDD and no change in EID. However, the HXO-UCMS+Feb group was fully protected with similar EDD and EID values to control mice. Our data shows that the liver significantly contributes to stress-induced cerebrovascular dysfunction. However, additional sources of XO circulation within the cerebrovasculature need further investigation. NIH, NINDS BINP R01 NS1117754, Psychosocial Stress-Induced Vascular Contributions to Cognitive Impairment and Alzheimer's. Disease: The Role of Xanthine Oxidase, NIH F31 Diversity Award, US DHHS-NIH-National Institute on Aging, Role of Xanthine Oxidase on Vascular Contributions to Cognitive Impairment This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.