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Sex-dependent Effects of AHR Activation in Endothelial Cells in Hypoxic Conditions

ABSTRACT: Chronic kidney disease (CKD) is a risk factor for peripheral arterial disease, however the molecular mechanisms linking the pathobiologies are ill-defined. The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor, has been previously shown to regulate angiogenesis. Notably, CKD results in the accumulation of metabolites that are endogenous ligands for the AHR. Results from animal work showed in male mice with CKD, AHRecKO lead to improvements in limb perfusion without improvements in muscle contractile or mitochondrial function. There was no effect of genotype observed in female mice. To assess these sex-dependent effects we cultured hypoxic endothelial cells from male and female mice and found inherent sex differences in AHR activating potential. Further to this, we performed bulk RNA sequencing and identified several angiogenic genes that were differentially expressed. In summaryn mice with CKD, endothelium-specific deletion of the AHR improved blood perfusion in muscle but did not confer improvement in mitochondrial function or muscle strength. Interestingly, these changes were observed in male, but not female, mice. Cell culture experiments revealed inherent sex-differences in gene expression.

ORGANISM(S): Mus musculus

PROVIDER: GSE234508 | GEO | 2024/02/14

REPOSITORIES: GEO

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Project description:Aims: This study aimed to identify and characterize the intrinsic properties of locus coeruleus (LC) noradrenergic neurons in male and female mice using a genetic approach. We also sought to investigate sex-specific differences in membrane properties, action potential generation, and protein expression profiles to understand the mechanisms underlying neuronal excitability variations. Methods: Utilizing a genetic mouse model by crossing Dbhcre knock-in mice with tdTomato Ai14 transgenic mice, LC neurons were identified using fluorescence microscopy. Neuronal properties, including capacitance, action potential frequency, and rheobase, were assessed using patch-clamp recordings. Spontaneous and evoked activity between sexes was compared. Proteomic analyses of individual LC neuron soma was conducted using mass-spectrometry to discern protein expression profiles. Results: Female LC noradrenergic neurons displayed greater membrane capacitance than those in male mice. Male LC neurons demonstrated greater spontaneous and evoked action potential generation compared to females. Male LC neurons exhibited a lower rheobase and achieved higher peak frequencies with similar current injections. Proteomic analysis revealed inherent differences in protein expression profiles between sexes, with male mice displaying a notably larger unique protein set compared to females. Notably, pathways pertinent to protein synthesis, degradation, and recycling, such as EIF2 and glucocorticoid receptor signaling, showed reduced expression in females. Conclusions: Male LC noradrenergic neurons exhibit higher intrinsic excitability compared to those from females. The discernible sex-based differences in excitability could be ascribed to varying protein expression profiles, especially within pathways that regulate protein synthesis and degradation. This study lays the groundwork for future studies focusing on the interplay between proteomics and neuronal function examined in individual cells.

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Sex-dependent Effects of AHR Activation in Endothelial Cells in Hypoxic Conditions

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