Soluble endoglin induces trophoblast apoptosis and dysfunction via the CD39-ATP signaling axis: a potential pathogenic mechanism of preeclampsia

Objective Excessive trophoblast apoptosis and dysfunction are critical events in the pathogenesis of preeclampsia (PE). Soluble endoglin (sENG) is elevated in PE; however, its direct role in regulating trophoblast biology remains incompletely understood. In this study, we investigated whether sENG promotes trophoblast apoptosis and impairs trophoblast function, and further explored the underlying molecular mechanisms. Methods Placenta-targeted sENG overexpression was induced in pregnant mice via an AAV6 vector driven by the FLT1 promoter, and PE-like phenotypes including hypertension and proteinuria were evaluated. Transforming growth factor-β (TGF-β)-Smad2/3 signaling, CD39 expression, extracellular ATP (eATP) levels, and P2X7 receptor (P2X7R) expression were analyzed in placental tissues and maternal serum. In vitro, HTR-8/SVneo trophoblasts were treated with recombinant sENG, and trophoblast biological functions and signaling protein expression were assessed by CCK-8, wound healing, Transwell, immunofluorescence, and western blotting. Rescue experiments were performed using exogenous TGF-β1 and a P2 × 7R inhibitor. Key signaling changes were further validated in placental tissues from patients with PE and healthy controls. Results In mice, sENG overexpression triggered hypertension, proteinuria, fetal growth restriction, and placental apoptosis, accompanied by inhibition of the TGF-β1-Smad2/3-CD39 pathway. In vitro, sENG induced dose-dependent apoptosis by suppressing Smad2/3 phosphorylation, downregulating CD39, and elevating eATP levels; these effects were reversed by exogenous TGF-β1. BzATP-mediated P2X7R activation contributed to trophoblast dysfunction and apoptosis. In human PE placentas, reduced phosphorylation of Smad2/3 and decreased CD39 expression, together with increased P2X7R expression, were associated with enhanced apoptotic signaling. Conclusion sENG induces trophoblast apoptosis and dysfunction through the TGF-β-Smad2/3-CD39-eATP-P2 × 7R signaling axis, contributing to PE pathogenesis and representing a promising molecular candidate for future therapeutic research into PE.