New Regulator of Ovulation Identified

Cornell researchers have discovered a new cell signaling pathway involved in ovulation, a potential target for future research on infertility, contraception and ovarian disease.

Semaphorin proteins have been shown to be critical players in the vascular, nervous and immune systems, and in cancer development. Semaphorin 3E (Sema3E) also plays a role in facilitating ovulation in mice, according to a paper published May 20 in Advanced Science and co-authored by 10 Cornell researchers and two colleagues from Baylor College of Medicine. First author is Hanxue Zhang, postdoctoral associate in the lab of Yi Athena Ren, assistant professor of animal science in the College of Agriculture and Life Sciences.

“Female reproductive tissues, such as the uterus and the ovary, are unique: No other tissue in adult life goes through a similar cycle of drastic construction and deconstruction – every month in women and every four days in mice,” Ren said. “We wanted to understand how different types of cells in the ovary communicate and coordinate with each other to enable such changes under the control of reproductive hormones.”

During ovulation, eggs are released from a fully-grown ovarian follicle. But before the start of ovulation, the interior of the follicles is one of only a few places in the body that don’t have a direct blood supply or vascular network (others include the tubules inside the testes and the cornea of the eye). For an egg to be released, the follicle essentially “creates a wound” in itself on the surface of the ovary, Ren said. Once the egg is released, the follicle begins producing progesterone and developing an elaborate network of blood vessels to support a potential pregnancy.

“So before ovulation, there’s no vasculature, and then once the egg is released, we see one of the highest densities of vasculature in the body – comparable to that in the most aggressive tumors,” Ren said. “And all of this happens within 24 to 48 hours in mice. We want to understand what enables this switch.”

In their research with mice, Zhang, Ren and their colleagues found that when they manipulated Sema3E, it impaired ovulation itself and damaged the ovarian vascular remodeling critical to maintaining a pregnancy. Impeding the protein had negative impacts upstream, as well, by hampering the expression of genes important for multiple biological processes indispensable for ovulation.

This basic discovery opens new lines of research that could be relevant in myriad ways. Animal scientists could target the Sema3E pathway to improve reproductive performance in dairy cows. Researchers of human health could explore the pathway to design contraceptives or treat infertility.

“Because reproductive hormones act on other tissues in the body, discoveries in ovarian function could also translate to other biological processes, such as how hormones impact cardiovascular health and tumor development,” Ren said, “We have this whole world to explore.”

Reference: Zhang H, Dhillon J, Soloway PD, et al. Semaphorin 3E-plexin-D1 pathway downstream of the luteinizing hormone surge regulates ovulation, granulosa cell luteinization, and ovarian angiogenesis in mice. Advanced Science. 2025:e17163. doi: 10.1002/advs.202417163

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