Abstract Body: Introduction: Hypertension (HTN) is a leading cause of vascular cognitive impairment and blood pressure (BP) control is linked with improved brain health. Angiotensin-II (Ang-II) infusion in mice has been used to model HTN induced end-organ dysfunction including cerebrovascular dysfunction. However, Ang-II induced HTN effects on the different cerebral metabolic processes are not well studied yet.
Hypothesis: Since Ang-II induced HTN leads to cerebrovascular oxidative stress, we hypothesized that it would significantly alter the brain metabolic pathways involving energy production, neurotransmitter synthesis, and inflammatory responses.
Methods: 10–13 week-old male C57BL/6J mice were infused with Ang-II (N=3) at 600 ng/kg/min or saline as control (N=3) via subcutaneous osmotic mini-pumps for 14 days. Liquid Chromatography-Mass Spectrometry (LC-MS) was used for non-targeted metabolomics analysis of the brain tissue at the end of treatment. The LC-MS data were analyzed using MetaboAnalyst 6 online tool for functional analysis. Differentially changed compounds with P-value < 0.05 were used for pathway enrichment analysis using metabolic pathways library from Kyoto Encyclopedia of Genes and Genomes (KEGG).
Results: Ang II infusion caused sustained systolic BP elevation at 2 weeks (Ang-II: 144±5.6 vs saline: 108±4.2 mmHg, P=0.0009). 590 metabolic compounds were identified from the positive and negative ion modes. Enrichment analysis revealed that Ang-II induced HTN causes significant metabolic shift in the brain by altering the pathways which are involved in glycolysis/gluconeogenesis (false discovery rate (FDR)=0.004), pentose phosphate pathway (FDR=0.002), and purine metabolism (FDR=0.004). Additionally, key amino acid metabolic pathways, including alanine, aspartate and glutamate metabolism (FDR=0.003), and arginine and proline metabolism (FDR=0.002), were disrupted. Furthermore, lipid metabolism, particularly arachidonic acid metabolism (FDR=0.007), was altered, suggesting an impact on neuroinflammatory processes.
Conclusions: Our results indicate that Ang-II induced HTN impairs the cerebral metabolism affecting crucial pathways regulating energy balance, neurotransmitter production, and cellular signaling. This study provides new avenues for mechanistic interventions targeting cerebral metabolism to develop specific therapeutics for Ang-II induced HTN aiming to improve brain health and HTN induced cerebrovascular disorders.