{
  "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.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Biology, York University, Toronto, M3J 1P3, Canada.",
    "School of Kinesiology and Health Science & Muscle Health Research Centre, York University, Toronto, M3J 1P3, Canada.",
    "Department of Biomedicine, Aarhus University, Høegh-Guldbergsgade 10, 8000, Aarhus C, Denmark.",
    "Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark.",
    "Department Laboratory Medicine, Clinical Physiology, Karolinska Institutet and Department of Clinical Physiology, Karolinska University Hospital, Stockholm, Sweden.",
    "School of Kinesiology and Health Science & Muscle Health Research Centre, York University, Toronto, M3J 1P3, Canada. m.rudnicki@ucl.ac.uk.",
    "UCL Institute of Ophthalmology, 11-43 Bath Street London EC1V 9EL, London, UK. m.rudnicki@ucl.ac.uk.",
    "Department of Biology, York University, Toronto, M3J 1P3, Canada. thaas@yorku.ca.",
    "School of Kinesiology and Health Science & Muscle Health Research Centre, York University, Toronto, M3J 1P3, Canada. thaas@yorku.ca."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 16,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Alexandra Pislaru"
    },
    {
      "affs": [
        1
      ],
      "name": "Emilie Roudier"
    },
    {
      "affs": [
        1
      ],
      "name": "Omid Rezvan"
    },
    {
      "affs": [
        0
      ],
      "name": "Connor Breadmore"
    },
    {
      "affs": [
        0
      ],
      "name": "Minoosh Fathi"
    },
    {
      "affs": [
        1
      ],
      "name": "George Nader"
    },
    {
      "affs": [
        2,
        3
      ],
      "name": "Ibrahim AlZaim"
    },
    {
      "affs": [
        1
      ],
      "name": "Emmanuel Nwadozi"
    },
    {
      "affs": [
        1
      ],
      "name": "Gisang Lee"
    },
    {
      "affs": [
        1
      ],
      "name": "Ehsan Yavari"
    },
    {
      "affs": [
        1
      ],
      "name": "Aly Fawzy"
    },
    {
      "affs": [
        4
      ],
      "name": "Eric Rullman"
    },
    {
      "affs": [
        2,
        3
      ],
      "name": "Joanna Kalucka"
    },
    {
      "affs": [
        4
      ],
      "name": "Thomas Gustafsson"
    },
    {
      "affs": [
        5,
        6
      ],
      "name": "Martina Rudnicki",
      "orcid": "0000-0002-7863-5044"
    },
    {
      "affs": [
        7,
        8
      ],
      "name": "Tara L Haas",
      "orcid": "0000-0001-8559-9574"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/5jts0e1g6k67q.bib",
  "cited_by": 0,
  "doi": "10.1007/s10456-026-10093-1",
  "fulltext_url": "https://europepmc.org/articles/PMC13690923",
  "id": "5jts0e1g6k67q",
  "issns": [
    "0969-6970",
    "1573-7209"
  ],
  "landing_url": "https://europepmc.org/article/MED/42911289",
  "language": "eng",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1312|FOXO transcription factor regulation"
    ]
  ],
  "openalex": "W7223185001",
  "pdf_url": "https://europepmc.org/articles/PMC13690923?pdf=render",
  "pmcid": "PMC13690923",
  "pmid": "42911289",
  "published": "2026-10-22",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/5jts0e1g6k67q.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:20:10Z",
      "native_id": "MED:42911289",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42911289"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|FOXO transcription factor regulation",
      "subfield": "molecular-biology"
    }
  ],
  "title": "Female-specific reliance on endothelial FoxO1 governs vascular resilience and metabolic adaptation to obesity.",
  "title_text": "Female-specific reliance on endothelial FoxO1 governs vascular resilience and metabolic adaptation to obesity.",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:20:10Z",
  "url": "https://research.draconitic.com/paper/5jts0e1g6k67q",
  "venue": "Angiogenesis",
  "versions": []
}