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.

Links

Publisher Full Text

Authors

Stefulj J, Panzenboeck U, Becker T, Hirschmugl B, Schweinzer C, Lang I, Marsche G, Sadjak A, Lang U, Desoye G, Wadsack C

Institution

Institute of Pathophysiology and Immunology, Center of Molecular Medicine, Medical University Graz, Graz, Austria.

Source

Circulation research 104:5 2009 Mar 13 pg 600-8

MeSH

ATP-Binding Cassette Transporters
Apolipoprotein A-I
Cell Membrane
Cells, Cultured
Cholesterol
DNA-Binding Proteins
Endothelial Cells
Female
Glyburide
Humans
Lipoproteins, HDL3
Maternal-Fetal Exchange
Orphan Nuclear Receptors
Placenta
Pregnancy
Probucol
RNA Interference
RNA, Small Interfering
Receptors, Cytoplasmic and Nuclear
Scavenger Receptors, Class B
Time Factors

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19168441