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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.
Citation
Qin, Yushu (2023). A Novel PPARΓ-B-Catenin Signaling in Placenta Development, Regarding Preeclampsia. Doctoral dissertation, Texas A&M University. Available electronically from https : / /hdl .handle .net /1969 .1 /199102.