PPARγ and Early Human Placental Development

During pregnancy, the placenta ensures multiple functions, which are directly involved in the initiation, outcome of gestation and fetal growth. Human implantation involves a major invasion of the uterus wall and a complete remodeling of the uterine arteries by the extravillous cytotrophoblasts (EVCT) during the first trimester of pregnancy. Abnormality of these early steps of placental development leads to poor placentation, fetal growth defects and is very often associated with preeclampsia, a major and frequent complication of human pregnancy. Unexpectedly, genetic studies performed in mice established that the peroxisome proliferator-activated receptor-gamma (PPARgamma) is essential for placental development. In the human placenta, PPARgamma is specifically expressed in the villous cytotrophoblast (VCT) and the syncytiotrophoblast (ST) as well as in the EVCT along their invasive pathway. To study the mechanisms that control human trophoblast invasion during early placental development and to provide new insight in the understanding of preeclampsia, we have developed in vitro models of human invasive trophoblasts. We observed that activation of the ligand-activated nuclear receptor PPARgamma agonists inhibits the trophoblastic invasion process in a concentration-dependent manner. Analysis of PPARgamma-target genes revealed that placental growth hormone, the protease PAPP-A and the human chorionic gonadotropin hormone (hCG) might be involved in the PPARgamma-mediated effect in an autocrine manner. The presence of oxidized-LDLs at the maternofetal interface suggests that oxidized-LDLs from maternal sera might be a source of potential PPARgamma ligands for the trophoblasts. Indeed, oxidized-LDLs decrease trophoblast invasion in vitro and analysis of their content revealed that they contain potent PPARgamma agonists such as eicosanoids, but also oxysterols, which are ligands for another nuclear receptor, the liver X Receptor (LXR). LXRbeta was found to be expressed in trophoblast and LXR agonists shown to inhibit trophoblast invasion. Together, these data underscore a major role for PPARgamma in the control of human trophoblast invasion during early placental development and suggest that ligands such as oxidized-LDLs at the implantation site might contribute to the modulation of trophoblast invasion through activation of PPARgamma and LXRbeta, two nuclear receptors that modulate the human trophoblastic cell invasion process.