title: PPARγ controls pregnancy outcome through activation of EG-VEGF: new insights into the mechanism of placental development.
abstract: 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.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité 1036, Grenoble, France; Université Grenoble-Alpes, Grenoble, France; iRTSV-Biology of Cancer and Infection, Commissariat à l'Energie Atomique, Grenoble, France;
authors.forename: Vanessa
authors.initials: V
authors.lastname: Garnier
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité 1036, Grenoble, France; Université Grenoble-Alpes, Grenoble, France; iRTSV-Biology of Cancer and Infection, Commissariat à l'Energie Atomique, Grenoble, France;
authors.forename: Wael
authors.initials: W
authors.lastname: Traboulsi
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité 1036, Grenoble, France; Université Grenoble-Alpes, Grenoble, France; iRTSV-Biology of Cancer and Infection, Commissariat à l'Energie Atomique, Grenoble, France;
authors.forename: Aude
authors.initials: A
authors.lastname: Salomon
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité 1036, Grenoble, France; Université Grenoble-Alpes, Grenoble, France; iRTSV-Biology of Cancer and Infection, Commissariat à l'Energie Atomique, Grenoble, France; Department of Life and Environmental Sciences, University of Cagliari, Cagliari, Italy;
authors.forename: Sophie
authors.initials: S
authors.lastname: Brouillet
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, UMR-S 1139, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France; PremUP Foundation, Paris, France;
authors.forename: Thierry
authors.initials: T
authors.lastname: Fournier
authors.affiliation: Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland;
authors.forename: Carine
authors.initials: C
authors.lastname: Winkler
authors.affiliation: Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland;
authors.forename: Beatrice
authors.initials: B
authors.lastname: Desvergne
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité 1036, Grenoble, France; Université Grenoble-Alpes, Grenoble, France; iRTSV-Biology of Cancer and Infection, Commissariat à l'Energie Atomique, Grenoble, France; Department of Obstetrics and Gynaecology, University Hospital of Grenoble, La Tronche, France; and.
authors.forename: Pascale
authors.initials: P
authors.lastname: Hoffmann
authors.affiliation: Department of Pharmacology, University of California-Irvine, Irvine, California;
authors.forename: Qun-Yong
authors.initials: QY
authors.lastname: Zhou
authors.affiliation: Department of Life and Environmental Sciences, University of Cagliari, Cagliari, Italy;
authors.forename: Cenzo
authors.initials: C
authors.lastname: Congiu
authors.affiliation: Department of Life and Environmental Sciences, University of Cagliari, Cagliari, Italy;
authors.forename: Valentina
authors.initials: V
authors.lastname: Onnis
authors.affiliation: Laboratoire de Chimie et Biologie des Métaux, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5249, Grenoble, France.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Benharouga
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité 1036, Grenoble, France; Université Grenoble-Alpes, Grenoble, France; iRTSV-Biology of Cancer and Infection, Commissariat à l'Energie Atomique, Grenoble, France;
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Feige
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité 1036, Grenoble, France; Université Grenoble-Alpes, Grenoble, France; iRTSV-Biology of Cancer and Infection, Commissariat à l'Energie Atomique, Grenoble, France; nadia.alfaidy-benharouga@cea.fr.
authors.forename: Nadia
authors.initials: N
authors.lastname: Alfaidy
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D002478:Cells, Cultured; D006224:Cricetinae; D010064:Embryo Implantation / Q000187:drug effects / Q000235:genetics; D004622:Embryo, Mammalian; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D047495:PPAR gamma / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D010920:Placenta / Q000378:metabolism; D010929:Placentation; D011247:Pregnancy; D011256:Pregnancy Outcome / Q000235:genetics*; D011725:Pyridines / Q000494:pharmacology; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology; D015533:Transcriptional Activation / Q000187:drug effects; D042662:Vascular Endothelial Growth Factor, Endocrine-Gland-Derived / Q000235:genetics* / Q000378:metabolism
chemical_list: D001549:Benzamides; D047495:PPAR gamma; D011725:Pyridines; C458508:T 0070907; D045162:Thiazolidinediones; D042662:Vascular Endothelial Growth Factor, Endocrine-Gland-Derived; D000077154:Rosiglitazone
keywords: endocrine gland-derived vascular endothelial growth factor, trophoblast invasion; human pregnancy; peroxisome proliferator-activated receptor-γ knockout