Role of nuclear receptors and their ligands in human trophoblast invasion

Human implantation involves a major invasion of the uterine wall and complete remodelling of uterine arteries by extravillous cytotrophoblasts (EVCT). Abnormality in these early steps of placental development leads to poor placentation, fetal growth defects and is often associated with preeclampsia, a major and frequent complication of human pregnancy. To study the mechanisms that control trophoblast invasion during early placental development and provide new insight in the understanding of preeclampsia, we have developed in vitro models of human invasive trophoblasts. We have shown that activation of the ligand-activated nuclear receptor PPARγ with synthetic (rosiglitazone) or natural (15deoxyPGJ2) agonists inhibits the trophoblastic invasion process. Analysis of PPARγ-target genes revealed that placental growth hormone and the protease PAPP-A might be involved in the PPARγ-mediated effect in an autocrine manner. We next investigated PPARγ ligands at the materno-fetal interface and have shown that oxidized LDLs are present in EVCT in situ and decrease trophoblast invasion in vitro. Analysis of oxidized LDLs revealed that they contain potent PPARγ agonists such as eicosanoids and also high levels of oxysterols, which are specific ligands for the liver X receptor (LXR). The isoform β of LXR was found in EVCT in situ, and activation of LXRβ with synthetic or natural ligands inhibits trophoblast invasion in vitro. Together, our data underscore a major role for PPARγ and LXRβ in the control of human trophoblast invasion and suggest that excess ligands such as oxidized LDLs at the implantation site might contribute to the development of preeclampsia.