PPARγ/RXRα Heterodimers Control Human Trophoblast Invasion

The ligand-dependent nuclear receptors PPARγ and RXRα/β 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 PPARγ/RXRα heterodimers in human invasive trophoblasts. We first report that in human first trimester placenta, PPARγ and RXRα are highly expressed in cytotrophoblasts at the feto-maternal interface, especially in the extravillous cytotrophoblasts involved in uterus invasion. The coexpression of PPARγ and RXRα 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 PPARγ/RXRα heterodimers in vitro, and we showed that both synthetic (rosiglitazone) and natural [15-deoxy-δ-(12,14)PGJ2] PPARγ agonists inhibit extravillous cytotrophoblast invasion in a concentration-dependent manner and synergize with pan-RXR agonists. Conversely, PPARγ or pan-RXR antagonists promoted extravillous cytotrophoblast invasion. Furthermore, the pan-RXR antagonist abolished the inhibitory effect of the PPARγ agonists. Together these data underscore an important function of PPARγ/RXRα heterodimers in the modulation of trophoblast invasion.