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Lipids from Oxidized Low-Density Lipoprotein Modulate Human Trophoblast Invasion: Involvement of Nuclear Liver X Receptors

Institut National de la Santé et de la Recherche Médicale, Unité 427, Faculté des Sciences Pharmaceutiques et Biologiques, Université René Descartes (L.P., A.H., V.T., D.E.-B., T.F.); Maternité Port-Royal, Hôpital Cochin, Université René Descartes (V.T.); Laboratoire de Biochimie Clinique et Métabolique, Faculté des Sciences Pharmaceutiques et Biologiques, Université René Descartes (P.T.), 75006 Paris, France; and Department of Bioscience, National Cardiovascular Center Research Institute (T.S.), Suita, Osaka 565-8565, Japan

Address all correspondence and requests for reprints to: Dr. Thierry Fournier, Institut National de la Santé et de la Recherche Médicale, Unité 427, Faculté de Pharmacie, 75006 Paris, France. E-mail: thierry.fournier{at}univ-paris5.fr.

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 (PPAR), respectively, reduced trophoblast invasion. We next investigated the presence and the role of these nuclear receptors and found that in addition to PPAR, human invasive trophoblasts express LXRß, and activation of these nuclear receptors by specific synthetic or natural ligands inhibited trophoblast invasion. Finally, using a PPAR antagonist, we suggest that LXRß, rather than PPAR, is involved in oxLDL-mediated inhibition of human trophoblast invasion in vitro.

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