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Biological sex and a high glycemic diet (HGD) contribute to dementia, yet little is known about the operative molecular mechanisms. Our goal was to understand the differences between males and females in the multi-genomic response of the hippocampal microvasculature to the HGD, and whether there was vasculoprotection via the inhibition of soluble epoxide hydrolase (sEHI). Adult wild type mice fed high or low glycemic diets for 12 weeks, with or without an sEHI inhibitor (t-AUCB), had hippocampal microvessels isolated by laser-capture microdissection. Differential gene expression was determined by microarray and integrated multi-omic bioinformatic analyses. The HGD induced opposite effects in males and females: the HGD-upregulated genes were involved in neurodegeneration or neuroinflammation in males, whereas in females they downregulated the same pathways, favoring neuroprotection. In males, the HGD was associated with a greater number of clinical diseases than in females, the sEHI downregulated genes involved in neurodegenerative diseases to a greater extent with the HGD and compared to females. In females, the sEHI downregulated genes involved in endothelial cell functions to a greater extent with the LGD and compared to males. Our work has potentially important implications for sex-specific therapeutic targets for vascular dementia and cardiovascular diseases in males and females.

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.

International audience; Dysfunction of blood-brain barrier formed by endothelial cells of cerebral blood vessels, plays a key role in development of neurodegenerative disorders. Epicatechin exerts vasculo-protective effects through genomic modifications, however molecular mechanisms of action, particularly on brain endothelial cells, are largely unknow. This study aimed to use a multi-omic approach (transcriptomics of mRNA, miRNAs and lncRNAs, and proteomics), to provide novel in-depth insights into molecular mechanisms of how metabolites affect brain endothelial cells under lipid-stressed (as a model of BBB dysfunction) at physiological concentrations. We showed that metabolites can simultaneously modulate expression of protein-coding, non-coding genes and proteins. Integrative analysis revealed interactions between different types of RNAs and form functional groups of genes involved in regulation of processing like VEGF-related functions, cell signaling, cell adhesion and permeability. Molecular modeling of genomics data predicted that metabolites decrease endothelial cell permeability, increased by lipotoxic stress. Correlation analysis between genomic modifications observed and genomic signature of patients with vascular dementia and Alzheimer's diseases showed opposite gene expression changes. Taken together, this study describes for the first time a multi-omic mechanism of action by which (-)-epicatechin metabolites could preserve brain vascular endothelial cell integrity and reduce the risk of neurodegenerative diseases. Significance: Dysfunction of the blood-brain barrier (BBB), characterized by dysfunction of endothelial cells of cerebral blood vessels, result in an increase in permeability and neuroinflammation which constitute a key factor in the development neurodegenerative disorders. Even though it is suggested that polyphenols can prevent or delay the development of these disorders, their impact on brain endothelial cells and underlying mechanisms of actions are unknow. This study aimed to use a multi-omic approach including analysis of expression of mRNA, microRNA, long non-coding RNAs, and proteins to provide novel global in-depth insights into molecular mechanisms of how (-)-epicatechin metabolites affect brain microvascular endothelial cells under lipid-stressed (as a model of BBB dysfunction) at physiological relevant conditions. The results provide basis of knowledge on the capacity of polyphenols to prevent brain endothelial dysfunction and consequently neurodegenerative disorders.

Summary: Increased lipid accumulation in the artery wall and atherosclerotic lesion development are two hallmarks of atherosclerotic cardiovascular disease. Atheroma quantification and characterization assesses neutral lipid accumulation in the vessel wall, percentage of lesions per aortic segment (quantitative) and lesion morphology, complexity, and severity (qualitative). Modified from: Villablanca AC, et.al. J Cardiovasc Transl Res. 2009 Sep;2(3):289-99.