PSG2 Impairs Human Trophoblast Function in Preeclampsia by Activating TGF-β/Smad3 to Suppress EMT and MMP2/9...

Preeclampsia (PE) is a severe pregnancy-specific disorder featured by insufficient extravillous trophoblast (EVT) invasion and impaired spiral artery remodeling. Pregnancy-specific beta-1-glycoprotein 2 (PSG2), a placenta-derived protein, is significantly elevated in the serum of PE patients, yet its exact role and underlying mechanism in trophoblast function remain largely unknown. We demonstrated that PSG2 was remarkably upregulated in PE placentas and its expression correlated positively with blood pressure and proteinuria, and negatively with gestational age and birth weight. In HTR-8/SVneo trophoblast cells, PSG2 overexpression suppressed proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT), downregulated MMP2 and MMP9 expression, and induced S-phase cell cycle arrest and late apoptosis. Conversely, PSG2 knockdown exerted opposing effects without influencing cell cycle distribution or apoptosis. Immunofluorescence staining verified the co-localization of PSG2 and TGF-β1 in trophoblasts and placental tissues. Mechanistically, PSG2 activated the TGF-β/Smad3 signaling pathway, and the TGFBR1 inhibitor SB431542 effectively reversed PSG2-mediated inhibition of EMT, MMP2/MMP9 expression, and trophoblast functional impairment. In conclusion, highly expressed PSG2 in PE placentas contributes to PE pathogenesis by activating the TGF-β/Smad3 pathway, thereby inhibiting EMT and MMPs expression and attenuating trophoblast proliferation, migration, and invasion. These findings provide a novel molecular basis for understanding PE pathogenesis.