A Novel PPARΓ-B-Catenin Signaling in Placenta Development, Regarding Preeclampsia

Abstract

Abnormal placenta development has been recognized in pre-eclampsia (PE) and gestational diabetes (GDM), which are both leading causes of maternal death during pregnancy. GDM is recognized as a risk factor for PE. Peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-dependent transcription factor, strongly expressed in both human and mouse placentas. In placentas from our GDM mouse model, we observed an impaired migration ability of spiral artery-associated trophoblast giant cells (SpA-TGCs) with a decreased expression of PPARγ. To further explore the function of PPARγ in placenta development, we utilized a PPARγ+/- mice model, which replicates human PPARγ insufficiency. In the PPARγ+/- pregnant mice, defective SpA remodeling is observed, accompanied by elevated blood pressure during mid-gestation, which resolved after delivery. Importantly, PE-like symptoms (elevated BP and proteinuria) were noted in the PPARγ+/- pregnant mice under hyperglycemia. Interestingly, SpA-TGCs progenitor-specific knockdown of PPARγ did not develop elevated BP. To understand the molecular mechanism that leads to defective SpA remodeling, we performed Mass-Spec Pull-down Analysis using anti-PPARγ and identified potential interaction with β-catenin. β-catenin maintains intercellular tight junctions in forming the membranous E-cadherin/β-catenin complex and facilitates the transcription of migratory genes of Wnt signaling when translocated to the nucleus. Insufficient PPARγ in the placenta repressed β-catenin translocation and degradation resulting in the retention of β-catenin in the cytoplasm. Increased membrane-bound β-catenin indicated a stronger formation of E-cadherin/β-catenin complex which enhanced cell-cell adhesion, while less nuclear translocation of β-catenin supports the reduced expression of migratory genes. In summary, the study disclosed the role of PPARγ in SpA remodeling, contributing to the etiology of elevated blood pressure in pregnancy.