Spatiotemporal heterogeneity of PPARγ expression in porcine uteroplacenta for regulating of placental angiogenesis through VEGF‐mediated signalling

Abstract

Non-infectious prenatal mortality severely affects the porcine industry, with pathological placentation as a likely key reason. Previous studies have demonstrated that peroxisome proliferator-activated receptor gamma (PPARγ) deficiency causes defects in the uteroplacental vasculature and induces embryonic losses in mice. However, its role in porcine placental angiogenesis remains unclear. In the present study, PPARγ expression was investigated in porcine uteroplacental tissues at gestational day (GD) 25, GD40 and GD70 via quantitative polymerase chain reaction (qPCR), Western blot and immunohistochemistry (IHC). Moreover, the roles of PPARγ in porcine placental angiogenesis were investigated using a cell model of porcine umbilical vein endothelial cells (PUVECs) to conduct proliferation, migration and tube formation assays in vitro and a mouse xenograft model to assess capillary formation in vivo. The results showed that PPARγ was mainly located in the glandular epithelium, trophoblast, amniotic chorion epithelium and vascular endothelium, as indicated by the higher expression levels at GD25 and GD40 than at GD70 in endometrium and by higher expression levels at GD40 and GD70 than at GD25 in placenta. Moreover, PPARγ expression was significantly downregulated in placenta with dead foetus. In PUVECs, knocking out PPARγ significantly inhibited proliferation, migration and tube formation in vitro and inhibited capillary formation in mouse xenografts in vivo by blocking S-phase, promoting apoptosis and downregulating the angiogenic factors of VEGF and its receptors. Overall, the spatiotemporal heterogeneity of PPARγ expression in porcine uteroplacental tissue suggests its vital role in endometrial remodelling and placental angiogenesis, and PPARγ regulates placental angiogenesis through VEGFmediated signalling.

Placental vascularization in middle and late gestation in the pig

“…During early gestation, the greatest increase in placenta weight occurs between 37 and 42 days ( Wright et al 2016 ). In fact, when the trophoblast-endometrial bilayer fully develops at day 40, increased vascularization occurs in the chorion ( Zhang et al 2020 ), whereas the unoccupied areas of the uterus develop folds with changes in endometrial cell size and morphology ( Wright et al 2016 ).…”

“…The placental vascularization, as indicated by the number and size of placental blood vessels, also increases markedly during this period. The endometrium is remodelled and requires a large amount of nutrients, while fetal growth is slow ( Wright et al 2016 , Wu et al 2017 , Zhang et al 2020 ).…”

“…In late-middle gestation, around day 70 of gestation, endometrial remodelling is almost complete, and the fetal placenta unit grows steadily, requiring abundant nutritional supplements to meet the maternal–fetal exchange ( Zhang et al 2020 ). Studies have shown a greater vascular development in the middle third of gestation, while after day 80 of gestation the vascular network tends to stabilize, and only the diameter of the vessels increases ( Guimarães et al 2017 ).…”

The Role of Peroxisome Proliferator-Activated Receptors in Preeclampsia

“…In porcine umbilical vein endothelial cells, PPARγ knock-out significantly repressed proliferation, migration and tube formation in vitro. In vivo, capillary formation in mouse xenograft models was hindered by blocking S-phase, promoting apoptosis and down-regulating the VEGF angiogenic factors along with its receptors [79].…”