BMP6 as a therapeutic target for preeclampsia: enhancing trophoblast invasion and vascular mimicry

Shallow trophoblast invasion and improper maternal spiral artery remodeling are the primary mechanisms underlying the development of preeclampsia (PE). Bone morphogenetic protein 6 (BMP6) is a proinvasive and proangiogenic factor in vitro; however, its regulatory mechanisms in trophoblast behavior and its role in PE development remain unclear. In this study, primary human trophoblasts and the HTR8/SVneo cell line were utilized asin vitrostudy models. Bulk RNA sequencing (RNA-seq) and single-cell RNA sequencing (scRNA-seq) data were analyzed to explore the expression patterns of BMP6-regulated genes. We found that BMP6 treatment significantly upregulated inhibitor of DNA-binding 1 (ID1) in human trophoblasts. ID1 depletion abolished both basal and BMP6-induced trophoblast invasion and vascular mimicry. Mechanistically, ID1-mediated upregulation of serpin family E member 2 (SERPINE2) and placental growth factor (PlGF) was essential for BMP6-induced trophoblast invasion. In third-trimester placentas, BMP6 mRNA and protein levels were significantly elevated in PE compared with controls. In the adenovirus-expressing fms-like tyrosine kinase-1 (Ad Flt1)-induced rat model of PE, both circulating BMP6 and placental Bmp6 expression were increased in PE rats in late pregnancy. Significantly, BMP6 supplementation during early pregnancy (gestational days 10-13) alleviated maternal hypertension and fetal growth restriction in the PE model. These findings suggest BMP6 promotes trophoblast invasion through ID1-mediated upregulation of SERPINE2 and PlGF. The late-gestation upregulation of BMP6 may represent a compensatory response to shallow trophoblast invasion in PE. Early BMP6 supplementation mitigates PE-related phenotypes in a rat model, highlighting BMP6 as a potential therapeutic target for the prevention and management of PE.