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

Lu Mu, Ge Wang, Xuebing Yang, Jing Liang, Huan Tong, Lingyu Li, Kaiying Geng, Yingnan Bo, Xindi Hu, Ruobing Yang, Xueqiang Xu, Yan Zhang and Hua Zhang ()
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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
Yan Zhang: China Agricultural University
Hua Zhang: China Agricultural University

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-024-55509-y

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