Role of the trophoblastic BMP7-TGM2 axis in the pathogenesis and prevention of preeclampsia

Preeclampsia (PE) is a major hypertensive disorder of pregnancy and a leading cause of maternal and perinatal mortality and morbidity worldwide. Aberrant placental development, characterized by shallow trophoblast invasion and incomplete remodeling of maternal spiral arteries, remains central to PE pathogenesis. In PE, tissue transglutaminase (TGM2) is dysregulated in the placenta, contributing to vascular dysfunction, inflammation, and impaired trophoblast differentiation, yet the upstream regulatory signals remain unknown. Bone morphogenetic protein 7 (BMP7) is abundantly expressed at the maternal-fetal interface and implicated in vascular homeostasis, but its role in regulating trophoblast function, especially related to PE pathogenesis, remains undefined. Here, single-cell transcriptomic profiling of placental tissues revealed coordinated downregulation of BMP7 and upregulation of TGM2 in PE relative to normotensive controls. Functional assays in immortalized and primary human trophoblasts demonstrated that BMP7 promotes trophoblast migration and invasion by suppressing TGM2 expression through the ALK2/3-SMAD1/5/9-SMAD4 pathway. Trophoblast organoid models further demonstrated the anti-invasive role of TGM2 in trophoblast differentiation during early placentation. In vivo, an adenovirus-expressing sFlt-1 (Ad sFlt-1)-induced PE mouse model showed increased placental Tgm2 expression, while recombinant BMP7 administration ameliorated PE-like symptoms. Although the protective effects of BMP7 in vivo are likely mediated by mechanisms beyond TGM2 alone, together these findings identify the BMP7-TGM2 axis as an important trophoblast-regulatory mechanism in PE and support BMP7 as a potential therapeutic candidate.