Ovarian vascular aging: a hidden driver of mid-age female fertility decline

Abstract

Although ovarian reserve remains sufficient, ovarian function declines in mid-age, leading to reduced fertility around age 35, with the causes remaining unclear. Recent studies highlight vascular aging as a key factor in this decline, with age-related reductions in ovarian vascular remodeling disrupting oocyte development. Salidroside, a natural compound that reverses ovarian vascular aging and promotes ovarian angiogenesis, presents a promising strategy to rejuvenate ovarian health and enhance fertility, offering potential for preserving reproductive function in aged women.

The ovary, a cornerstone of the female reproductive system, plays a dual role in generating oocytes and secreting essential reproductive hormones. Central to its function are ovarian follicles, which harbor developing oocytes. Notably, the ovary is one of the earliest aging organs in women, showing signs of decline well before other tissues exhibit significant aging¹. Despite advancements that have pushed female life expectancy beyond 80 years in many countries², ovarian aging persists, typically beginning at age 35, with menopause occurring around age 50³. As a result, women spend more than half of their lives in a state of reduced fertility, with approximately one-third of their lifespan devoid of reproductive capability. This early deterioration has far-reaching consequences, including hormonal imbalances, osteoporosis, and increased risks of cardiovascular disease^4–6. Furthermore, it elevates the likelihood of neurodegenerative and neoplastic diseases^5,7. Addressing ovarian aging is, therefore, critical not only to extend reproductive potential but also to safeguard overall health.

The decline in fertility associated with aging is often attributed to the loss and diminished quality of ovarian follicles, which are the functional units responsible for oocyte development. Consequently, much research has focused on improving oocyte maturation in aging females. Strategies such as mitochondrial enhancement, including mitochondrial transfer and mitochondrial-targeted antioxidants like Coenzyme Q10, aim to restore energy balance and improve oocyte viability⁸. Similarly, reversing age-related epigenetic changes, such as DNA methylation and histone modifications, has shown promise for improving oocyte developmental competence^9,10. For instance, Zhang et al. identified spermidine as a critical metabolite for preserving oocyte quality during aging, using ovarian metabolomic data combined with in vivo and in vitro experiments¹¹. Bertoldo et al. demonstrated that oocyte levels of NAD(P)H decline with age, and supplementation with the metabolic precursor nicotinamide mononucleotide (NMN) restores oocyte quality and enhances fertility¹². These studies provide valuable insights into addressing the decline in oocyte quality associated with ovarian aging.

However, oocyte maturation is only the final step in oocyte development. For middle-aged women and many infertile patients, a significant number of early-stage oocytes and follicles remain in aging ovaries but fail to develop effectively. Thus, the core challenge is not the absence of early-stage follicles but rather the inability to nurture and utilize these resources — the oocytes within the incompletely developed follicles. Recognizing this, researchers have shifted their focus to the development of ovarian follicles in aged ovaries. Wu et al. mapped the spatiotemporal single-cell transcriptomic landscape of human ovarian aging, identifying FOXP1 (Forkhead Box Protein1) in granulosa cells as a key regulator of ovarian reserve that becomes deregulated with age¹³. Yang et al. linked inflammation-induced CD38 (Cluster of Differentiation 38) accumulation in middle-aged ovaries to declining NAD+ (Nicotinamide Adenine Dinucleotide) levels¹⁴, while Liu et al. highlighted the role of the mevalonate pathway in granulosa cells in promoting oocyte meiotic maturation¹⁵. Furthermore, Wang et al. demonstrated that exposing aged oocytes to a young follicle microenvironment could rejuvenate them and preserve quality¹⁶. These studies illuminate the intricate mechanisms of follicle development driving ovarian aging and provide a foundation for identifying biomarkers and therapeutic targets.

While intra-follicle strategies show promise, they often overlook the broader ovarian microenvironment, which plays a pivotal role in supporting follicle and oocyte development. The ovarian microenvironment, composed of non-ovarian somatic cells, has been increasingly recognized as a key regulator of ovarian aging. Thanks to technological advances such as omics analysis and high-resolution imaging, recent studies have uncovered molecular and cellular insights into the ovarian microenvironment. For example, Wang et al. created a comprehensive single-cell transcriptomic atlas of ovaries in young and aged non-human primates¹⁷, while Isola et al., Umehara et al. and McCloskey et al. demonstrated that ovarian aging promotes chronic inflammation and fibrosis in mice^18–20. Additionally, Converse et al. indicated that multinucleated giant cells (MNGCs) in the ovarian stroma play a key role in ovary aging²¹.

Our own research has highlighted the critical role of ovarian stromal cells in maintaining follicle health²². By identifying platelet-derived growth factor receptor α (PDGFRα) as a biomarker of ovarian stromal cells, we were able to isolate and analyze differences between young and aged ovarian stroma. Our findings revealed that the loss of several key stromal cell components in aged ovaries significantly contributes to reduced fertility. Remarkably, the introduction of young stromal cells into aged ovaries improved both the quantity and quality of ovulated oocytes. These results underscore the crucial role of stromal cells in regulating follicle development and suggest that aging-related changes in the ovarian stroma are a key driver of ovarian aging.

Among the diverse cells in the ovarian stroma, endothelial cells form the ovarian vascular system, which is critical for supporting ovarian survival and development. As a dynamic endocrine organ, the ovary relies on systemic factors—such as hormones and nutrients—delivered through its vascular network. Unlike most tissues, the maintenance of adult ovarian function depends on continuous vascular remodeling to accommodate the fluctuating demands of follicle growth and ovulation. This remodeling is driven by angiogenesis, the process by which new blood vessels are formed from existing ones²³. While angiogenesis is generally absent in most adult organs, its activity in the ovary especially in the corpus luteum²⁴ and uterus, two key organs of the female reproductive system, has been recognized for over 30 years²⁵. However, the lack of comprehensive studies on the spatial and temporal patterns of ovarian angiogenesis, along with its physiological role in adults, has limited the potential to manipulate angiogenesis for controlling female fertility. To address this gap, our previous study developed advanced three-dimensional (3D) whole-mount imaging with subcellular resolution, enabling us to reconstruct the spatial and temporal patterns of angiogenesis and vascular remodeling in adult ovaries. Combined with cell lineage tracing of blood vessels in ovarian follicles, we found that angiogenesis is primarily active in growing follicles, where dynamic vascular networks regulate follicle development and maturation (Fig. 1, left; Fig. 2, left frame). Furthermore, we demonstrated that these newly formed blood vessels in the follicles are temporary structures that must be eliminated upon the completion of follicle development²⁶. In addition to these findings, we also showed that temporarily suppressing angiogenesis with Axitinib could preserve the ovarian reserve, delay ovarian aging, and extend the reproductive lifespan. These findings highlight vascular remodeling as a promising fertility-enhancing strategy.

Fig. 1. The schematic model illustrates aging-related differences in oocyte and follicle development between young and middle-aged ovaries.

In young ovaries, active angiogenesis supports abundant blood vessel formation and a healthy stromal environment, ensuring an adequate supply of nutrients and hormones for follicle growth and the maintenance of high-quality oocytes (left). In contrast, reduced angiogenesis in middle-aged ovaries leads to poor vascularization and an unhealthy stromal environment, resulting in insufficient nutrient and hormone supply and subsequently lower-quality oocytes (right). Pink dots represent nutrients, and purple dots represent hormones.

Fig. 2. Salidroside rebuilds ovarian vasculature to enhance fertility in aged females.

In illustrations resembling a traditional Chinese three-frame screen, the left frame depicted a healthy and active blood supply (depicted as a river) facilitating the transportation of nutrients and hormones (represented by colorful fishes) to support the high-quality development of ovarian follicles (depicted as a Ruan, a Chinese traditional instrument, in the lady’s hand). These well-developed follicles secrete adequate sexual hormones (depicted as flowers) to sustain active fertility. In middle-aged females, the aging of ovarian blood vessels (depicted as a frozen river) results in a reduction of upstream hormones reaching the ovaries, causing a blockage in follicle development and ultimately resulting in a decline in female reproduction (illustrated in the middle frame). However, the administration of Salidroside (depicted as red grass on the mountains) has been proven effective in restoring ovarian angiogenesis, enhancing blood supply to middle-aged ovaries, thereby promoting follicle development and restoring fertility in aging females (illustrated in the right frame). (Designed by Hua Zhang, illustrated by Ruobing Yang.).

Building on this foundation, our recent research identified premature aging of ovarian blood vessels as a critical factor in mid-age fertility decline²⁷. Unlike the general decline in vessel density observed in multiple organs, which is associated with the aging of non-reproductive organs in later life²⁸, our study observed a pronounced reduction in ovarian blood vessel density and angiogenesis intensity as early as in middle-aged mice, impairing follicle development (Fig. 1, right; Fig. 2, middle frame). Although vascular endothelial growth factor A (VEGFA), secreted by granulosa cells, governs ovarian angiogenesis, we found increased VEGFA expression in aged ovaries, suggesting that vascular decline was not due to VEGFA insufficiency. Instead, single-cell sequencing revealed aging and oxidative stress accumulation in ovarian vascular endothelium as the primary driver of ovarian vascular aging and angiogenesis decline. As we previously mentioned, the functional maintenance of adult ovaries depends on blood vessels that transport hormones from upstream organs, such as the pituitary. Clearly, the decline in ovarian blood vessels in mid-age significantly reduces the efficiency of upstream hormones in stimulating follicle development since these factors cannot be effectively transported to the ovaries. Indeed, our study found that even when exogenous hormones were supplied, the follicles still failed to respond to the hormones for fast growth in middle-aged females. Notably, the natural compound salidroside (2-[4-hydroxyphenyl] ethyl β-D-glucopyranoside), derived from Rhodiola rosea L, has been reported to counteract ischemia in various organs by stimulating angiogenesis and reducing oxidative stress^29,30. It was found to reverse vascular aging, enhance angiogenesis, and restore ovarian blood supply, significantly improving follicle development and fertility in aged female mice. Salidroside-treated follicles cultured in vitro exhibited enhanced vascular growth, while in vivo treatment improved ovarian function, follicle development, and oocyte quality. Remarkably, salidroside treatment also resulted in significantly higher natural pregnancy and birth rates in aged mice, underscoring its potential as a fertility-preserving intervention (Fig. 2, right frame).

These findings highlight the critical role of ovarian vascular aging in fertility decline, revealing the ovarian vasculature as an overlooked yet vital therapeutic target. Enhancing ovarian blood vessel function not only supports follicle and oocyte development but also amplifies the efficacy of anti-ovarian aging therapies by ensuring effective delivery of systemic treatments. Salidroside, with its dual ability to rejuvenate vascular health and enhance ovarian function, represents a transformative approach that could be used alone or in combination with other therapies.

In conclusion, ovarian aging is a complex process involving molecular, cellular, and systemic dimensions. While most interventions focus on oocytes and granulosa cells, the ovarian microenvironment, including vascular, stromal components and the interplay between endothelial cells and stromal-cells producing extracellular matrix, is increasingly recognized as a critical factor in maintaining ovarian function. Targeting ovarian vascular aging offers a holistic strategy for preserving fertility and improving women’s quality of life as they age. Further exploration of vascular dynamics and systemic interventions promises to revolutionize approaches for combating ovarian aging, paving the way for extended reproductive windows and healthier aging trajectories.

Author contributions

G.W. and H.Z. wrote the paper. R.Y. and H.Z. draw the graphic model. All authors have seen and approved the final version.

Data availability

No datasets were generated or analyzed during the current study.

Competing interests

The authors declare no competing interests.