title: Human endothelial cells of the placental barrier efficiently deliver cholesterol to the fetal circulation via ABCA1 and ABCG1.
abstract: Although maternal-fetal cholesterol transfer may serve to compensate for insufficient fetal cholesterol biosynthesis under pathological conditions, it may have detrimental consequences under conditions of maternal hypercholesterolemia leading to preatherosclerotic lesion development in fetal aortas. Maternal cholesterol may enter fetal circulation by traversing syncytiotrophoblast and endothelial layers of the placenta. We hypothesized that endothelial cells (ECs) of the fetoplacental vasculature display a high and tightly regulated capacity for cholesterol release. Using ECs isolated from human term placenta (HPECs), we investigated cholesterol release capacity and examined transporters involved in cholesterol efflux pathways controlled by liver-X-receptors (LXRs). HPECs demonstrated 2.5-fold higher cholesterol release to lipid-free apolipoprotein (apo)A-I than human umbilical vein ECs (HUVECs), whereas both cell types showed similar cholesterol efflux to high-density lipoproteins (HDLs). Interestingly, treatment of HPECs with LXR activators increased cholesterol efflux to both types of acceptors, whereas no such response could be observed for HUVECs. In line with enhanced cholesterol efflux, LXR activation in HPECs increased expression of ATP-binding cassette transporters ABCA1 and ABCG1, while not altering expression of ABCG4 and scavenger receptor class B type I (SR-BI). Inhibition of ABCA1 or silencing of ABCG1 decreased cholesterol efflux to apoA-I (-70%) and HDL(3) (-57%), respectively. Immunohistochemistry localized both transporters predominantly to the apical membranes of placental ECs in situ. Thus, ECs of human term placenta exhibit unique, efficient and LXR-regulated cholesterol efflux mechanisms. We propose a sequential pathway mediated by ABCA1 and ABCG1, respectively, by which HPECs participate in forming mature HDL in the fetal blood.
authors.affiliation: Institute of Pathophysiology and Immunology, Center of Molecular Medicine, Medical University Graz, Graz, Austria.
authors.forename: Jasminka
authors.initials: J
authors.lastname: Stefulj
authors.forename: Ute
authors.initials: U
authors.lastname: Panzenboeck
authors.forename: Tatjana
authors.initials: T
authors.lastname: Becker
authors.forename: Birgit
authors.initials: B
authors.lastname: Hirschmugl
authors.forename: Cornelia
authors.initials: C
authors.lastname: Schweinzer
authors.forename: Ingrid
authors.initials: I
authors.lastname: Lang
authors.forename: Gunther
authors.initials: G
authors.lastname: Marsche
authors.forename: Anton
authors.initials: A
authors.lastname: Sadjak
authors.forename: Uwe
authors.initials: U
authors.lastname: Lang
authors.forename: Gernot
authors.initials: G
authors.lastname: Desoye
authors.forename: Christian
authors.initials: C
authors.lastname: Wadsack
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D000070996:ATP Binding Cassette Transporter, Subfamily G; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016632:Apolipoprotein A-I / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D005905:Glyburide / Q000494:pharmacology; D006801:Humans; D053440:Lipoproteins, HDL3 / Q000378:metabolism; D000071518:Liver X Receptors; D008431:Maternal-Fetal Exchange; D057093:Orphan Nuclear Receptors; D010920:Placenta / Q000098:blood supply*; D011247:Pregnancy; D011341:Probucol / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D051122:Scavenger Receptors, Class B / Q000378:metabolism; D013997:Time Factors
chemical_list: C577836:ABCA1 protein, human; C419353:ABCG1 protein, human; C439766:ABCG4 protein, human; D064286:ATP Binding Cassette Transporter 1; D000070996:ATP Binding Cassette Transporter, Subfamily G; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D004268:DNA-Binding Proteins; D053440:Lipoproteins, HDL3; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D034741:RNA, Small Interfering; D018160:Receptors, Cytoplasmic and Nuclear; C495124:SCARB1 protein, human; D051122:Scavenger Receptors, Class B; D002784:Cholesterol; D011341:Probucol; D005905:Glyburide