Tanshinone IIA improved psychological stress-induced embryo implantation disorders by inhibiting GC/GR signaling and promoting angiogenesis.

BACKGROUND

The exact mechanism by which psychological stress leads to embryo implantation disorders remains unclear. Studies have shown that psychological stress is associated with elevated levels of glucocorticoids (GC). Successful embryo implantation is closely related to normal endometrial angiogenesis, a key process in the creation of a conducive environment for embryo implantation. Tanshinone IIA (Tan IIA), a compound derived from traditional Chinese medicine, promotes angiogenesis. This study aimed to elucidate how psychological stress impairs embryo implantation and explore the potential therapeutic effects of Tan IIA.

METHODS

Female mice were randomly divided into seven groups: control, restraint stress, CORT125134 antagonizing glucocorticoid receptor (GR), 7.5, 15, 30 mg/kg Tan IIA, and aspirin. Open-field and elevated plus maze tests were employed to evaluate behavioral changes. The embryo implantation sites were quantified using trypan blue injection. Endometrial GC levels by ELISA, GR expression by RT-qPCR and WB, angiogenesis by HE and IHC, and angiogenic factors (VEGF, ANG2) by IF were measured. JC-1, ATP, p-DRP1, and transmission electron microscopy were used to detect endometrial mitochondrial damage. Oxidative stress was determined through ROS, MDA, catalase, and GPX4 assays, and IF co-staining of CD31 with 4-HNE examined vascular oxidative injury. Endometrial receptivity was evaluated by LIF and integrin αvβ3 expression.

RESULTS

Psychological stress significantly induced anxiety-like behavior, reduced implantation sites, impaired endometrial angiogenesis, triggered mitochondrial dysfunction and oxidative stress, and compromised endometrial receptivity via GC/GR signaling activation. Administration of Tan IIA effectively alleviated these stress-induced impairments in a dose-dependent manner, primarily by inhibiting GC/GR activation and GR nuclear translocation. Specifically, Tan IIA alleviated anxiety-like behavior, reduced the p-DRP1/DRP1 ratio, restored MMP and ATP production, and attenuated mitochondrial vacuolization and crista disruption. In addition, Tan IIA markedly decreased the levels of ROS, MDA, and CAT, while enhancing the expression of GPX4, VEGF, ANG2, LIF, and integrin αvβ3.

CONCLUSION

Psychological stress disrupted embryo implantation by activating the GC/GR signaling. Tan IIA effectively alleviated stress-induced implantation disorders by inhibiting the GC/GR signaling. This study highlights the therapeutic potential of Tan IIA as a promising candidate for stress-related implantation disorders.