Article: article from journal or magazin.
PPARγ controls pregnancy outcome through activation of EG-VEGF: new insights into the mechanism of placental development.
American Journal of Physiology. Endocrinology and Metabolism
PPARγ-deficient mice die at E9.5 due to placental abnormalities. The mechanism by which this occurs is unknown. We demonstrated that the new endocrine factor EG-VEGF controls the same processes as those described for PPARγ, suggesting potential regulation of EG-VEGF by PPARγ. EG-VEGF exerts its functions via prokineticin receptor 1 (PROKR1) and 2 (PROKR2). This study sought to investigate whether EG-VEGF mediates part of PPARγ effects on placental development. Three approaches were used: 1) in vitro, using human primary isolated cytotrophoblasts and the extravillous trophoblast cell line (HTR-8/SVneo); 2) ex vivo, using human placental explants (n = 46 placentas); and 3) in vivo, using gravid wild-type PPARγ(+/-) and PPARγ(-/-) mice. Major processes of placental development that are known to be controlled by PPARγ, such as trophoblast proliferation, migration, and invasion, were assessed in the absence or presence of PROKR1 and PROKR2 antagonists. In both human trophoblast cell and placental explants, we demonstrated that rosiglitazone, a PPARγ agonist, 1) increased EG-VEGF secretion, 2) increased EG-VEGF and its receptors mRNA and protein expression, 3) increased placental vascularization via PROKR1 and PROKR2, and 4) inhibited trophoblast migration and invasion via PROKR2. In the PPARγ(-/-) mouse placentas, EG-VEGF levels were significantly decreased, supporting an in vivo control of EG-VEGF/PROKRs system during pregnancy. The present data reveal EG-VEGF as a new mediator of PPARγ effects during pregnancy and bring new insights into the fine mechanism of trophoblast invasion.
Animals, Benzamides/pharmacology, Cells, Cultured, Cricetinae, Embryo Implantation/drug effects, Embryo Implantation/genetics, Embryo, Mammalian, Female, Humans, Male, Mice, Mice, Transgenic, PPAR gamma/agonists, PPAR gamma/antagonists & inhibitors, Placenta/metabolism, Placentation, Pregnancy, Pregnancy Outcome/genetics, Pyridines/pharmacology, Thiazolidinediones/pharmacology, Transcriptional Activation/drug effects, Vascular Endothelial Growth Factor, Endocrine-Gland-Derived/genetics, Vascular Endothelial Growth Factor, Endocrine-Gland-Derived/metabolism
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