Henry-Berger Joëlle, Mouzat Kevin, Baron Silvère, Bernabeu Carmelo, Marceau Geoffroy, Saru Jean-Paul, Sapin Vincent, Lobaccaro Jean-Marc A, Caira Françoise
CNRS UMR6247-GreD, Centre de Recherche en Nutrition Humaine d'Auvergne, Clermont Université, 63177 Aubière, France.
Biol Reprod. 2008 Jun;78(6):968-75. doi: 10.1095/biolreprod.107.066498. Epub 2008 Feb 14.
Human implantation involves invasion of the uterine wall and remodeling of uterine arteries by extravillous cytotrophoblasts. Defects in these early steps of placental development lead to poor placentation and are often associated with preeclampsia, a frequent complication of human pregnancy. One of the complex mechanisms controlling trophoblast invasion involves the activation of the liver X receptor beta (or NR1H2, more commonly known as LXRbeta) by oxysterols known as potent LXR activators. This activation of LXRbeta leads to a decrease of trophoblast invasion. The identification of new target genes of LXR in the placenta could aid in the understanding of their physiological roles in trophoblast invasion. In the present study, we show that the endoglin (ENG) gene is a direct target of the liver X receptor alpha (NR1H3, also known as LXRalpha). ENG, whose gene is highly expressed in syncytiotrophoblasts, is part of the transforming growth factor (TGF) receptor complex that binds several members of the TGFbeta superfamily. In the human placenta, ENG has been shown to be involved in the inhibition of trophoblast invasion. Treatment of human choriocarcinoma JAR cells with T0901317, a synthetic LXR-selective agonist, leads to a significant increase in ENG mRNA and protein levels. Using transfection and electrophoretic mobility shift assays, we demonstrate that LXR (as a heterodimer with the retinoid X receptor) is able to bind the ENG promoter on an LXR response element and mediates the activation of ENG gene expression by LXRalpha in JAR cells. This study suggests a novel mechanism by which LXR may regulate trophoblast invasion in pathological pregnancy such as preeclampsia.
人类着床涉及到子宫壁的侵入以及绒毛外细胞滋养层细胞对子宫动脉的重塑。胎盘发育这些早期步骤中的缺陷会导致胎盘形成不良，并且常常与子痫前期相关，子痫前期是人类妊娠常见的并发症。控制滋养层细胞侵入的复杂机制之一涉及到被称为强效肝X受体激活剂的氧化甾醇对肝X受体β（或NR1H2，通常称为LXRβ）的激活。LXRβ的这种激活会导致滋养层细胞侵入减少。鉴定胎盘中LXR的新靶基因有助于理解它们在滋养层细胞侵入中的生理作用。在本研究中，我们表明内皮糖蛋白（ENG）基因是肝X受体α（NR1H3，也称为LXRα）的直接靶基因。ENG基因在合体滋养层细胞中高度表达，它是转化生长因子（TGF）受体复合物的一部分，该复合物可结合TGFβ超家族的多个成员。在人类胎盘中，ENG已被证明参与抑制滋养层细胞侵入。用合成的LXR选择性激动剂T0901317处理人绒毛膜癌细胞JAR，会导致ENG mRNA和蛋白水平显著增加。通过转染和电泳迁移率变动分析，我们证明LXR（作为与视黄酸X受体的异二聚体）能够在LXR反应元件上结合ENG启动子，并介导LXRα在JAR细胞中激活ENG基因表达。本研究提示了一种新机制，通过该机制LXR可能在子痫前期等病理性妊娠中调节滋养层细胞侵入。
