Metabolomic Analysis Reveals Dysregulated Lipid Signaling and Glycolytic Reprogramming in Carotid Arteries Following Long-Term High-Altitude Hypoxia

Long term hypoxic stress causes structural and functional adaptations to the carotid artery, which leads to dysregulation in cerebral blood flow. While the physiological impact of hypoxia on cerebral vascular function is well-known, the dysregulation that occurs at the cellular and molecular level is not yet completely understood for adult carotid arteries. Exploring the effects of long-term hypoxia (LTH) using a metabolomic approach is advantageous in deciphering the etiology associated with the development of disease. LTH is well regarded for inducing oxidative stress and causing inflammation. A number of possible regulators associated with LTH stress include oxylipins and endocannabinoids, products of polyunsaturated fatty acid (PUFA) oxidation. We hypothesized that high-altitude LTH would reduce the levels of key oxylipins and endocannabinoids in carotid arteries of adult sheep and give rise to an increase in reactive oxygen species (ROS) generation. To investigate this, we obtained carotid arteries from adult normoxic and hypoxic sheep that resided at 3,800 meters above sea level for ~ 110 days. Metabolite levels were quantified using ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). Chemical similarity enrichment analyses and visualization by complex pathway analyses was performed on the datasets. Enrichment analysis revealed changes in key metabolic pathways such as glycolysis, purine metabolism, polyol metabolism, and lipid metabolism. Crucial anti-inflammatory oxylipins known for being downstream of inflammatory molecules such as 12(13)-EpOME experienced downregulation under hypoxic stress. A glycolytic shift was also observed, indicative that aerobic respiration was impacted due to the reduced oxygen availability at altitude. These included metabolites involved in glycolysis and polyol metabolism, with mannitol, lyxitol, glycerol-alpha-phosphate all being increased under hypoxic stress conditions. Our results support the hypothesis that chronic hypoxia initiates redox stress-mediated metabolic reprogramming, leading to impaired glycolytic flux and subsequent carotid vascular dysfunction, a mechanism that warrants continued investigation. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.