PPAR gamma/RXR alpha heterodimers control human trophoblast invasion

The ligand-dependent nuclear receptors PPAR gamma and RXR alpha/beta were r ecently determined to be essential for murine placental development and tro phoblast differentiation. In the current study we examined the expression a nd role of the PPAR gamma/ RXR alpha heterodimers in hum an invasive tropho blasts. 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 uter us invasion. The coexpression of PPAR gamma and RXR alpha genes in extravil lous cytotrophoblast nuclei were then confirmed by immunocytochemistry, imm unoblot, and real-time quantitative PCR using cultured purified primary ext ravillous cytotrophoblasts. We next examined, using the extravillous cytotr ophoblast culture model, the biological role of PPAR gamma /RXR alpha heter odimers in vitro, and we showed that both synthetic (rosiglitazone) and nat ural [15-deoxy-delta-(12,14)PGJ(2)] PPAR gamma agonists inhibit extravillou s cytotrophoblast invasion in a concentration-dependent manner and synergiz e with pan-RXR agonists. Conversely, PPAR gamma or pan-RXR antagonists prom oted extravillous cytotrophoblast invasion. Furthermore, the pan-RXR antago nist abolished the inhibitory effect of the PPAR gamma agonists. Together t hese data underscore an important function of PPAR gamma/ RXR alpha heterod imers in the modulation of trophoblast invasion.