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Physiological premature aging of ovarian blood vessels leads to decline in fertility in middle-aged mice

Author

Listed:
  • Lu Mu

    (China Agricultural University)

  • Ge Wang

    (China Agricultural University)

  • Xuebing Yang

    (China Agricultural University)

  • Jing Liang

    (China Agricultural University)

  • Huan Tong

    (China Agricultural University)

  • Lingyu Li

    (China Agricultural University)

  • Kaiying Geng

    (China Agricultural University)

  • Yingnan Bo

    (China Agricultural University)

  • Xindi Hu

    (China Agricultural University)

  • Ruobing Yang

    (China Agricultural University)

  • Xueqiang Xu

    (China Agricultural University
    Peking University)

  • Yan Zhang

    (China Agricultural University)

  • Hua Zhang

    (China Agricultural University)

Abstract

Ovarian function declines significantly as females enter middle-age, but the mechanisms underlying this decline remain unclear. Here, we utilize whole-organ imaging to observe a notable decrease in ovarian blood vessel (oBV) density and angiogenesis intensity of middle-aged mice. This leads to a diminished blood supply to the ovaries, resulting in inadequate development and maturation of ovarian follicles. Utilizing genetic-modified mouse models, we demonstrate that granulosa cell secreted VEGFA governs ovarian angiogenesis, but the physiological decline in oBV is not attributed to VEGFA insufficiency. Instead, through single-cell sequencing, we identify the aging of the ovarian vascular endothelium as the primary factor contributing to oBV decline. Consequently, the administration of salidroside, a natural compound that is functional to reverse oBV aging and promote ovarian angiogenesis, significantly enhances ovarian blood supply and improve fertility in older females. Our findings highlight that enhancing oBV function is a promising strategy to boost fertility in females.

Suggested Citation

  • Lu Mu & Ge Wang & Xuebing Yang & Jing Liang & Huan Tong & Lingyu Li & Kaiying Geng & Yingnan Bo & Xindi Hu & Ruobing Yang & Xueqiang Xu & Yan Zhang & Hua Zhang, 2025. "Physiological premature aging of ovarian blood vessels leads to decline in fertility in middle-aged mice," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-024-55509-y
    DOI: 10.1038/s41467-024-55509-y
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    References listed on IDEAS

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    1. Tapsi Kumar & Kevin Nee & Runmin Wei & Siyuan He & Quy H. Nguyen & Shanshan Bai & Kerrigan Blake & Maren Pein & Yanwen Gong & Emi Sei & Min Hu & Anna K. Casasent & Aatish Thennavan & Jianzhuo Li & Tua, 2023. "A spatially resolved single-cell genomic atlas of the adult human breast," Nature, Nature, vol. 620(7972), pages 181-191, August.
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