Diet is a modifiable risk factor for
cardiovascular disease (CVD) and
dementia, yet relatively little is known about the effect of a high glycemic diet (HGD) on the brain's microvasculature. The objective of our study was to determine the molecular effects of an HGD on hippocampal microvessels and cognitive function and determine if a soluble
epoxide hydrolase (sEH) inhibitor (sEHI), known to be vasculoprotective and anti-inflammatory, modulates these effects. Wild type male mice were fed a low glycemic diet (LGD, 12%
sucrose/weight) or an HGD (34%
sucrose/weight) with/without the sEHI, trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-
benzoic acid (
t-AUCB), for 12 weeks. Brain hippocampal microvascular gene expression was assessed by microarray and data analyzed using a multi-omic approach for differential expression of
protein and non-
protein-coding genes, gene networks, functional pathways, and
transcription factors. Global hippocampal microvascular gene expression was fundamentally different for mice fed the HGD vs. the LGD. The HGD response was characterized by differential expression of 608 genes involved in cell signaling, neurodegeneration, metabolism, and cell adhesion/
inflammation/oxidation effects reversible by
t-AUCB and hence sEH inhibitor correlated with protection against Alzheimer's
dementia. Ours is the first study to demonstrate that high dietary glycemia contributes to brain hippocampal microvascular
inflammation through sEH.