PPAR /RXR Heterodimers Control Human Trophoblast Invasion

The ligand-dependent nuclear receptors PPAR and RXR / were recently determined to be essential for murine placental development and trophoblast differentiation. In the current study we examined the expression and role of the PPAR / RXR heterodimers in human invasive trophoblasts. We first report that in human first trimester placenta, PPAR and RXR are highly expressed in cytotrophoblasts at the fetomaternal interface, especially in the extravillous cytotrophoblasts involved in uterus invasion. The coexpression of PPAR and RXR genes in extravillous cytotrophoblast nuclei were then confirmed by immunocytochemistry, immunoblot, and real-time quantitative PCR using cultured purified primary extravillous cytotrophoblasts. We next examined, using the extravillous cytotrophoblast culture model, the biological role of PPAR /RXR heterodimers in vitro, and we showed that both synthetic (rosiglitazone) and natural [15-deoxy-(12,14)PGJ2] PPAR agonists inhibit extravillous cytotrophoblast invasion in a concentration-dependent manner and synergize with pan-RXR agonists. Conversely, PPAR or pan-RXR antagonists promoted extravillous cytotrophoblast invasion. Furthermore, the pan-RXR antagonist abolished the inhibitory effect of the PPAR agonists. Together these data underscore an important function of PPAR / RXR heterodimers in the modulation of trophoblast invasion. (J Clin Endocrinol Metab 86: 5017–5024, 2001)