Lipids from oxidized low-density lipoprotein modulate human trophoblast invasion:: Involvement of nuclear liver X receptors
Lipids from oxidized low-density lipoprotein modulate human trophoblast invasion:: Involvement of nuclear liver X receptors
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DOI：
10.1210/en.2003-1747
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发表时间：
2004-10-01
期刊：
影响因子：
4.8
通讯作者：
Fournier, T
中科院分区：
文献类型：
--
作者：
Pavan, L;Hermouet, A;Fournier, T
人类胚胎着床涉及绒毛外细胞滋养层细胞(EVCT)对子宫壁的主要侵袭和子宫动脉的重塑。胎盘发育的这些早期阶段的异常会导致胎盘不良和胎儿生长缺陷，并经常与先兆子痫有关，先兆子痫是人类妊娠的主要并发症。我们最近发现氧化型低密度脂蛋白(OxLDL)存在于EVCT中，并以浓度依赖的方式抑制细胞侵袭。本研究的目的是为了更好地了解oxLDL调节滋养层细胞侵袭的机制。因此，我们研究了我们的人侵袭性原发EVCT细胞培养模型中oxLDL受体的存在。通过免疫细胞化学和免疫印迹实验，我们发现凝集素样oxLDL受体-1是EVCT中主要表达的清道夫受体，可能参与了oxLDL的摄取。接下来，我们利用Matrigel涂层Transwell上培养的EVCT，研究了低密度脂蛋白氧化状态对滋养层细胞体外侵袭的影响。我们证明，只有分别为肝X受体(LXR)和过氧化氢受体(PPARGamma)提供配体的oxLDL含有高比例的氧固醇和磷脂酰胆碱氢过氧化氢衍生物，才能减少滋养层的侵袭。接下来，我们研究了这些核受体的存在和作用，发现除了PPARγ外，人侵袭性滋养层细胞还表达LXRβ，通过特定的合成或天然配体激活这些核受体可以抑制滋养层细胞的侵袭。最后，使用PPARGamma拮抗剂，我们认为LXRbeta而不是PPARGamma参与了oxLDL介导的体外抑制人滋养层细胞侵袭的过程。
Human embryonic implantation involves major invasion of the uterine wall and remodeling of the uterine arteries by extravillous cytotrophoblast cells (EVCT). Abnormalities in these early steps of placental development lead to poor placentation and fetal growth defects and are frequently associated with preeclampsia, a major complication of human pregnancy. We recently showed that oxidized low-density lipoproteins (oxLDLs) are present in situ in EVCT and inhibit cell invasion in a concentration-dependent manner. The aim of the present study was to better understand the mechanisms by which oxLDL modulate trophoblast invasion. We therefore investigated the presence of oxLDL receptors in our cell culture model of human invasive primary EVCT. We found using immunocytochemistry and immunoblotting that the lectin-like oxLDL receptor-1 was the scavenger receptor mainly expressed in EVCT and was probably involved in oxLDL uptake. We next examined the effect of low-density lipoprotein oxidative state on trophoblast invasion in vitro using EVCT cultured on Matrigel-coated Transwell. We demonstrated that only oxLDL containing a high proportion of oxysterols and phosphatidylcholine hydroperoxide derivatives that provide ligands for liver X receptor (LXR) and peroxisomal proliferator-activated receptor gamma (PPARgamma), respectively, reduced trophoblast invasion. We next investigated the presence and the role of these nuclear receptors and found that in addition to PPARgamma, human invasive trophoblasts express LXRbeta, and activation of these nuclear receptors by specific synthetic or natural ligands inhibited trophoblast invasion. Finally, using a PPARgamma antagonist, we suggest that LXRbeta, rather than PPARgamma, is involved in oxLDL-mediated inhibition of human trophoblast invasion in vitro.