PPAR /RXR  Heterodimers Control Human Trophoblast Invasion

Abstract

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

Peroxisome proliferator-activated receptors in the regulation of female reproductive functions

“…Tarrade et al [95] reported that PPARg is highly expressed in human cytotrophoblasts at the feto-maternal interface, particularly in the extravillous cytotrophoblasts involved in uterus invasion. They also showed that both synthetic and natural PPARg agonists inhibited extravillous cytotrophoblast invasion and the treatment with PPARg antagonist facilitated the invasion process [95]. Recently, the analysis of PPARg-target genes in human trophoblast led to characterization of new factors engaged in the regulation of trophoblast invasion [82,83,96].…”

Preterm and infection-driven preterm labor: the role of peroxisome proliferator-activated receptors and retinoid X receptor

“…Peroxisome proliferator-activated receptors (PPARs) have been implicated in several aspects of early pregnancy development including implantation, placentation, and trophoblast differentiation (Barak et al 1999, Lim & Dey 2000, Tarrade et al 2001. We and others have presented data implicating PPARs in the inflammatory events that contribute to normal labor at term (Lim & Dey 2000, Lappas et al 2002b, Berry et al 2003, Dunn-Albanese et al 2004, Ackerman et al 2005, Lindstrom & Bennett 2005, Froment et al 2006, Schaiff et al 2006, Fournier et al 2007, Holdsworth-Carson et al 2009).…”

“…PPAR-associated inflammatory mediator suppression suggests that a breakdown in PPAR expression or activity may be apparent during periods of preterm intra-amniotic infection, as seen in non-gestational tissue infections (Kielian et al 2008, Perez et al 2008. While some groups have investigated PPAR expression in first (Tarrade et al 2001, Capparuccia et al 2002, Rodie et al 2005 and second trimester placenta (Waite et al 2000, Rodie et al 2005 and serum samples throughout the course of pregnancy (Wieser et al 2008), data are lacking regarding the expression and activity of PPAR isoforms in association with preterm delivery, with and without infection. The aim of this study was to compare the expression and DNA binding activity patterns of PPAR isoforms and the expression of RXRA in human gestational tissues from term and preterm vaginal deliveries, and to determine the effect of infectionassociated preterm delivery on PPAR isoforms and RXRA expression.…”

Expression patterns and role of prostaglandin-endoperoxide synthases, prostaglandin E synthases, prostacyclin synthase, prostacyclin receptor, peroxisome proliferator-activated receptor delta and retinoid x receptor alpha in rat endometrium during artificially-induced decidualization

“…During our study, the three bands observed for RXRA disappeared when the primary antibody was incubated in the presence of its own blocking peptide (data not shown) suggesting that the bands could represent different isoforms from the same protein that are present specifically in rat endometrium. To investigate changes in the expression of RXRA protein during initiation of decidualization, we quantified only the 54 kDa band for RXRA for several reasons; this is the band reported by the supplier; it is the only isoform found it in the human placenta ( Tarrade et al 2001); according to the literature, it is the only full-length 540 C Gillio-Meina and others form; and is the most abundant form of the protein that is present in most tissues and cell lines studied (Matsushima-Nishiwaki et al 1996, Dufour & Kim 1999, Zhong et al 2003. RXRA protein levels significantly increased (P!0.05) at 16 h and remained high at 32 h as compared with 0 and 2 h (Fig.…”