Molecular mechanisms of ligustilide in the treatment of low endometrial receptivity: involvement of desmoglein-2.

Abstract

We have previously shown that ligustilide (LIG) treatment can restore endometrial receptivity and promote implantation in pregnant rats with low endometrial receptivity (LER). Using mRNA sequencing technology, we found that desmoglein-2 (Dsg2) is one of the differentially expressed genes, which is downregulated in rats with LER but elevated after LIG treatment. DSG2 is an adhesion protein that exists in epithelial tissues and serves as a crucial component of the junction complex for intercellular adhesion. The ability to adhere between cells is considered essential for successful embryo implantation. Hence, we speculated that DSG2 might be involved in the mechanism by which LIG treats LER. Immunofluorescence staining, western blots, and immunohistochemical staining were performed to confirm the restored expression of DSG2 by LIG treatment in the endometrial tissues of LER rats. Then, we investigated the effect of DSG2 on endometrial receptivity by injecting small interfering (si)Dsg2 (for silencing Dsg2 expression) into one uterine horn of a pregnant rat and siNC (for a normal control) into the other. It was found that the side of the endometrium injected with siDsg2 showed significant changes in the expression of multiple receptivity-related molecules and obvious embryo loss. In addition, we found that these receptivity-related molecules were affected by siDsg2 in Ishikawa (an endometrial cell line) cells. Dsg2 knockdown reduced the ability of Ishikawa cells to adhere to trophoblastic spheroids. Furthermore, the effect of LIG on endometrial cell-trophoblast adhesion was partially abolished by Dsg2 silencing. In conclusion, our findings suggest that the protective effect of LIG against LER might be achieved by increasing DSG2 expression. DSG2 enhancement might become a novel strategy for the development of LIG-inspired treatments to improve endometrial receptivity.