PPARγ/RXRα heterodimers control human trophoblast invasion

The ligand-dependent nuclear receptors PPAR gamma and RXR alpha/beta 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 gamma/ RXR alpha heterodimers in hum an invasive trophoblasts. We first report that in human first trimester placenta, PPAR gamma and RXR alpha are highly expressed in cytotrophoblasts at the fetomaternal interface, especially in the extravillous cytotrophoblasts involved in uterus invasion. The coexpression of PPAR gamma and RXR alpha 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 gamma /RXR alpha heterodimers in vitro, and we showed that both synthetic (rosiglitazone) and natural [15-deoxy-delta-(12,14)PGJ(2)] PPAR gamma agonists inhibit extravillous cytotrophoblast invasion in a concentration-dependent manner and synergize with pan-RXR agonists. Conversely, PPAR gamma or pan-RXR antagonists promoted extravillous cytotrophoblast invasion. Furthermore, the pan-RXR antagonist abolished the inhibitory effect of the PPAR gamma agonists. Together these data underscore an important function of PPAR gamma/ RXR alpha heterodimers in the modulation of trophoblast invasion.