Female-specific reliance on endothelial FoxO1 governs vascular resilience and metabolic adaptation to obesity

Abstract Sex differences in adipose tissue vascular remodeling critically influence susceptibility to obesity-associated metabolic disease, yet the underlying mechanisms remain unclear. Here we identify Forkhead box O1 (FoxO1) as a sex-dependent regulator of endothelial function, with female endothelial cells (EC) expressing higher levels of FoxO1 and depending on it to maintain vascular remodeling and metabolic homeostasis. Accordingly, FoxO1 loss in females disrupted angiogenesis, and promoted adipocyte hypertrophy, weight gain and glucose dysregulation, whereas opposite effects have been reported in males. This phenotype was associated with a shift in the endothelial transcriptome toward a male-like state, consistent with loss of female protection against diet-induced metabolic dysfunction. Mechanistically, FoxO1 inhibition exerted time-dependent effects, with short-term suppression promoting proliferation and sustained inhibition reducing proliferation and inducing metabolic dysfunction. Although also observed in males, these effects were more pronounced in female EC, which also selectively exhibited mitochondrial dysfunction, increased oxidative stress and DNA damage accumulation, culminating in a senescence-like arrest. Antioxidant treatment partially rescued this phenotype, implicating oxidative stress as a driver of female-specific vulnerability. These findings reveal a sex-dependent divergence in FoxO1 function and identify endothelial FoxO1 as a determinant of opposing vascular and metabolic responses to obesogenic stress.