High Glycemia and Soluble Epoxide Hydrolase in Females: Differential Multiomics in Murine Brain Microvasculature

Abstract

The effect of a high glycemic diet (HGD) on brain microvasculature is a crucial, yet understudied research topic, especially in females. This study aimed to determine the transcriptomic changes in female brain hippocampal microvasculature induced by a HGD and characterize the response to a soluble epoxide hydrolase inhibitor (sEHI) as a mechanism for increased epoxyeicosatrienoic acids (EETs) levels shown to be protective in prior models of brain injury. We fed mice a HGD or a low glycemic diet (LGD), with/without the sEHI (t-AUCB), for 12 weeks. Using microarray, we assessed differentially expressed protein-coding and noncoding genes, functional pathways, and transcription factors from laser-captured hippocampal microvessels. We demonstrated for the first time in females that the HGD had an opposite gene expression profile compared to the LGD and differentially expressed 506 genes, primarily downregulated, with functions related to cell signaling, cell adhesion, cellular metabolism, and neurodegenerative diseases. The sEHI modified the transcriptome of female mice consuming the LGD more than the HGD by modulating genes involved in metabolic pathways that synthesize neuroprotective EETs and associated with a higher EETs/dihydroxyeicosatrienoic acids (DHETs) ratio. Our findings have implications for sEHIs as promising therapeutic targets for the microvascular dysfunction that accompanies vascular dementia.

Sex-Specific Response of the Brain Free Oxylipin Profile to Soluble Epoxide Hydrolase Inhibition

“…The t-AUCB was provided in the drinking water using polyethylene glycol 400 (PEG400) (Millipore, Burlington, MA, USA) as a vehicle from 20 weeks of age until sacrifice at 32 weeks of age (Figure 1B). We chose this timeline of treatment and sacrifice to align with our previous publications regarding sEHI, which found this length of treatment sufficient to induce changes in the brain microvascular transcriptome [54,56,57]. Consistent with prior protocols, the final contents of the drinking water were 1% (by volume) PEG400 and 10 mg/L t-AUCB [58,59].…”

How cy pres promotes transdisciplinary convergence science: an academic health center for women’s cardiovascular and brain health

“…To date, the work of the Basic Science and Animal Modeling core has demonstrated that both hyperlipidemic and hyperglycemic stress induces sex-specific expression of protein coding and non-coding genes [85][86][87][88][89][90]. Interestingly, the functional cellular pathways are primarily associated with neurodegeneration in male [89], and neuroprotection in female mice [88].…”