Mechanism of Shoutai Wan against recurrent spontaneous abortion: regulation of decidual vascular remodeling via ERβ-ANGPT2 signaling axis.

Abstract

Shoutai Wan (STW), a classic traditional Chinese medicine formula used to tonify the kidney and prevent miscarriage, has been widely applied in the clinical management of recurrent spontaneous abortion (RSA). Increasing clinical evidence supports its efficacy in reducing miscarriage rates and improving pregnancy outcomes. However, the molecular basis by which STW alleviates defective decidual vascular remodeling in unexplained RSA remains insufficiently understood. Clinically, decidual ERβ and ANGPT2 expression, as well as serum estradiol, ANGPT2 and VEGFA levels were significantly decreased in RSA patients, accompanied by reduced decidual microvascular density. Furthermore, ERβ expression was positively correlated with ANGPT2 and microvascular density. In vivo, STW dose-dependently reduced embryo loss in RSA mice, repaired the damaged decidual-placental interface structure, and improved vascular maturation, structural stability and endothelial-pericyte ultrastructural connections. Mechanistically, STW upregulated ERβ expression. We demonstrated that ERβ binds to the ANGPT2 promoter, suggesting transcriptional upregulation of ANGPT2, thereby activating Tie2 and the downstream PI3K/AKT pathway and increasing NO and VEGFA secretion. In vitro, hypoxia inhibited ERβ nuclear translocation and ANGPT2 secretion in mDSCs, while STW-containing serum reversed these abnormalities. ERβ knockdown impaired the pro-angiogenic capacity of mDSCs, which was partially rescued by exogenous ANGPT2 supplementation. Network pharmacology predicted that STW targets were mainly enriched in PI3K-Akt, estrogen, VEGF and angiogenesis-related pathways. Transcriptomic GSEA further revealed that the gene signatures of angiogenesis and PI3K-Akt signaling were markedly suppressed in the RSA model, and STW treatment significantly normalized these transcriptional signatures.