Sex Differences In Endothelial FoxO1 Response To Nutrient And Oxidative Stress

Endothelial cells (ECs) are vital for vascular homeostasis, regulating blood flow, nutrient exchange, and immune responses. EC dysfunction contributes to diseases such as type 2 diabetes, atherosclerosis, and hypertension, with sex-specific differences in disease progression. Our lab previously observed sex differences in the response of adipose tissue ECs (ATECs) to high-fat diet-induced metabolic and oxidative stress, with females showing more favorable outcomes. Female ECs express higher Forkhead Box O1 (FoxO1) levels than males, suggesting sex-specific FoxO1 regulation. To explore this, male and female ECs were exposed to metabolic and oxidative stress, and FoxO1 subcellular localization and post-translational modifications were assessed. Male ECs showed increased FoxO1 phosphorylation and cytoplasmic localization, while females retained FoxO1 in the nucleus, supporting enhanced transcriptional potential. These findings highlight sex-dependent FoxO1 regulation, offering insights into molecular mechanisms driving sex differences in vascular health.