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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 PPAR\u03b3, suggesting potential regulation of EG-VEGF by PPAR\u03b3. EG-VEGF exerts its functions via prokineticin receptor 1 (PROKR1) and 2 (PROKR2). This study sought to investigate whether EG-VEGF mediates part of PPAR\u03b3 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 PPAR\u03b3<jats:sup>+\/\u2212<\/jats:sup> and PPAR\u03b3<jats:sup>\u2212\/\u2212<\/jats:sup> mice. Major processes of placental development that are known to be controlled by PPAR\u03b3, 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 PPAR\u03b3 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 PPAR\u03b3<jats:sup>\u2212\/\u2212<\/jats:sup> 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 PPAR\u03b3 effects during pregnancy and bring new insights into the fine mechanism of trophoblast invasion. <\/jats:p>","DOI":"10.1152\/ajpendo.00093.2015","type":"journal-article","created":{"date-parts":[[2015,6,16]],"date-time":"2015-06-16T23:55:55Z","timestamp":1434498955000},"page":"E357-E369","source":"Crossref","is-referenced-by-count":30,"title":["PPAR\u03b3 controls pregnancy outcome through activation of EG-VEGF: new insights into the mechanism of placental development"],"prefix":"10.1152","volume":"309","author":[{"given":"Vanessa","family":"Garnier","sequence":"first","affiliation":[{"name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale, Unit\u00e9 1036, Grenoble, France;"},{"name":"Universit\u00e9 Grenoble-Alpes, Grenoble, France;"},{"name":"iRTSV-Biology of Cancer and Infection, Commissariat \u00e0 l'Energie Atomique, Grenoble, 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