Circulation. 2026 Apr 9. doi: 10.1161/CIRCULATIONAHA.125.076218. Online ahead of print.
ABSTRACT
BACKGROUND: Preeclampsia affects approximately 1 in 10 pregnancies, leading to severe complications and long-term health risks for both mother and offspring. While the etiology remains unclear, preeclampsia has been linked to both autoimmunity and the timing of menarche.
METHODS: Through human single-cell and spatial analyses, coupled with in vitro, in vivo, and ex vivo models, we demonstrate that VGLL3, a transcription coregulator in the Hippo pathway, is upregulated in preeclamptic placentas.
RESULTS: VGLL3 promotes immune activation, impairs trophoblast differentiation, and induces endothelial dysfunction, all of which contribute to pregnancy-related hypertension, fetal growth restriction, and offspring mortality. Our data reveal that VGLL3 acts upstream of preeclampsia-associated processes, including the production of sFLT1 (soluble fms-like tyrosine kinase 1), a key biomarker of the disease. Notably, targeting VGLL3, either by genetic deletion in mouse placentas or through therapeutic inhibition in human placentas, protects against preeclampsia and alleviates disease pathology.
CONCLUSIONS: These findings position VGLL3 as a promising novel therapeutic target for preeclampsia.
PMID:41953989 | DOI:10.1161/CIRCULATIONAHA.125.076218
