Female-specific reliance on endothelial FoxO1 governs vascular resilience and metabolic adaptation to obesity.
9 affiliations
- 1Department of Biology, York University, Toronto, M3J 1P3, Canada.
- 2School of Kinesiology and Health Science & Muscle Health Research Centre, York University, Toronto, M3J 1P3, Canada.
- 3Department of Biomedicine, Aarhus University, Høegh-Guldbergsgade 10, 8000, Aarhus C, Denmark.
- 4Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark.
- 5Department Laboratory Medicine, Clinical Physiology, Karolinska Institutet and Department of Clinical Physiology, Karolinska University Hospital, Stockholm, Sweden.
- 6School of Kinesiology and Health Science & Muscle Health Research Centre, York University, Toronto, M3J 1P3, Canada. [email protected].
- 7UCL Institute of Ophthalmology, 11-43 Bath Street London EC1V 9EL, London, UK. [email protected].
- 8Department of Biology, York University, Toronto, M3J 1P3, Canada. [email protected].
- 9School of Kinesiology and Health Science & Muscle Health Research Centre, York University, Toronto, M3J 1P3, Canada. [email protected].
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.
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BibTeX
@article{pislaru2026femalespecific,
title = {{Female-specific reliance on endothelial FoxO1 governs vascular resilience and metabolic adaptation to obesity.}},
author = {Alexandra Pislaru and Emilie Roudier and Omid Rezvan and Connor Breadmore and Minoosh Fathi and George Nader and Ibrahim AlZaim and Emmanuel Nwadozi and Gisang Lee and Ehsan Yavari and Aly Fawzy and Eric Rullman and Joanna Kalucka and Thomas Gustafsson and Martina Rudnicki and Tara L Haas},
journal = {Angiogenesis},
year = {2026},
month = oct,
doi = {10.1007/s10456-026-10093-1},
url = {https://europepmc.org/article/MED/42911289},
note = {CC BY},
}
RIS
TY - JOUR
TI - Female-specific reliance on endothelial FoxO1 governs vascular resilience and metabolic adaptation to obesity.
AU - Alexandra Pislaru
AU - Emilie Roudier
AU - Omid Rezvan
AU - Connor Breadmore
AU - Minoosh Fathi
AU - George Nader
AU - Ibrahim AlZaim
AU - Emmanuel Nwadozi
AU - Gisang Lee
AU - Ehsan Yavari
AU - Aly Fawzy
AU - Eric Rullman
AU - Joanna Kalucka
AU - Thomas Gustafsson
AU - Martina Rudnicki
AU - Tara L Haas
PY - 2026
DA - 2026/10/22
JO - Angiogenesis
DO - 10.1007/s10456-026-10093-1
UR - https://europepmc.org/article/MED/42911289
AB - 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.
SN - 0969-6970
SN - 1573-7209
ER -