G protein-coupled estrogen receptor promotes human extravillous trophoblast invasion via YAP-Snail-mediated CYR61 expression.

Preeclampsia (PE) is a pregnancy-related disorder characterized by impaired extravillous trophoblast (EVT) invasion, leading to defective placental development. The G protein-coupled estrogen receptor (GPER) is expressed in human EVT cells and has been implicated in promoting cell invasion. Cysteine-rich angiogenic inducer 61 (CYR61), also known as CCN1, is a matricellular protein that facilitates cell migration and invasion; however, whether GPER activation regulates CYR61 expression in EVT cells remains undefined. In this study, we investigated the molecular mechanisms underlying GPER-mediated regulation of CYR61 in human EVT cells. We demonstrated that activation of GPER by its selective agonist G1 upregulated CYR61 expression in both HTR-8/SVneo and primary human EVT cells. Mechanistically, GPER activation enhanced YAP signaling, leading to the upregulation of Snail, which was required for CYR61 expression. Functional assays revealed that CYR61 was essential for EVT cell invasion, as its knockdown significantly reduced G1-stimulated cell invasion. Furthermore, analysis of publicly available single-cell RNA sequencing (scRNA-seq) data showed that CYR61 expression was significantly downregulated in EVT cells from PE placentas. Our findings identify a novel GPER-YAP-Snail-CYR61 signaling axis that regulates EVT invasion and suggest that dysregulation of this pathway may contribute to defective trophoblast invasion in PE.