Published online before print January 22, 2009, doi: 10.1161/CIRCRESAHA.108.185066
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© 2009 American Heart Association, Inc.
Molecular Medicine |
Human Endothelial Cells of the Placental Barrier Efficiently Deliver Cholesterol to the Fetal Circulation via ABCA1 and ABCG1
From the Institute of Pathophysiology and Immunology (J.S., U.P., T.B., C.S., A.S.); Clinic of Obstetrics and Gynecology (B.H., U.L., G.D., C.W.); Institute of Cell Biology, Histology and Embryology (I.L.); and Institute of Experimental and Clinical Pharmacology (G.M.), Medical University Graz, Austria; and Department of Molecular Biology (J.S.), Rudjer Boskovic Institute, Zagreb, Croatia.
Correspondence to Ute Panzenboeck, Institute of Pathophysiology and Immunology, Center of Molecular Medicine, Medical University Graz, Heinrichstrasse 31a, 8010 Graz, Austria. E-mail ute.panzenboeck{at}meduni-graz.at
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Abstract |
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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 HDL3 (–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.
Key Words: maternal–fetal cholesterol transfer • endothelial cells • HDL • liver X receptors
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Introduction |
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Cholesterol is indispensable during fetal development.1 It has been long assumed that most, if not all, cholesterol required for fetal growth is synthesized de novo by the fetus itself, thus making it autonomous from maternal or placental cholesterol supply. However, several lines of evidence have cast doubt on this notion.2,3 Fetuses that lack the ability to synthesize cholesterol, such as those with the Smith–Lemli–Opitz syndrome, are, nevertheless, born with low levels of tissue and plasma cholesterol, indicating that they have acquired maternal cholesterol in utero.4 Recent exciting studies demonstrated a strong correlation between the size and number of atherosclerotic lesions in human fetal arteries with maternal cholesterol levels.5,6 Moreover, maternal hypercholesterolemia also modified early predictors of cardiovascular disease in the offspring, thus corroborating the concept of developmental programming of adult disease in human.7 Considering that progression of atherosclerosis in adults takes ages, these striking results support the assumption of a strong maternal impact on the comparatively short period of fetal development.
These results have sparked strong interest in delineating the mechanism of maternal-to-fetal cholesterol transfer, because identifying molecular targets might offer options for therapeutic intervention. Maternal cholesterol destined to enter the fetal circulation has to traverse the syncytiotrophoblast layer and the endothelium of the fetoplacental circulation. In vitro studies on human syncytiotrophoblast membranes and on human primary trophoblasts8–10 demonstrated the presence and functional role of low-density lipoprotein (LDL) receptor and the high-density lipoprotein (HDL) receptor scavenger receptor class B type 1 (SR-BI) in cholesterol uptake and subsequent transport across the syncytiotrophoblast layer. To date, no reports are available on the mechanisms of cholesterol transfer across the second layer, ie, ECs of fetal vessels in the placenta.
In general, ECs are resistant to excess cholesterol/lipid accumulation. In fact, they are the only cell type in the vascular wall not becoming foam cells during atherosclerosis. The biochemical pathways for sterol synthesis and endocytosis of lipoproteins, as well as for cholesterol efflux, all appear to be active in ECs.11 However, unlike for macrophages,12 the mechanisms responsible for the efflux of cellular cholesterol from ECs are still poorly characterized.
The majority of cholesterol in fetal blood is transported by HDL, which makes up to 44% of total lipoproteins in cord blood.13 A major function of HDL is its role during reverse cholesterol transport, the protective pathway that prevents the excess accumulation of cholesterol.14 This process involves different pathways of cholesterol efflux from peripheral cells, including transport mediated by specific membrane proteins. The ATP-binding cassette transporters ABCA1 and ABCG1 have been identified as primary gatekeepers for eliminating tissue cholesterol and for the biogenesis of HDL. ABCA1 stimulates cholesterol efflux to lipid-poor apolipoproteins, predominantly to apoA-I,15,16 whereas ABCG1 promotes efflux of cholesterol and oxysterols to HDL.17 SR-BI also promotes cholesterol efflux from peripheral cells to HDL but not to lipid-free apoA-I.18
Liver-X-receptors (LXRs) are key transcriptional regulators of cholesterol storage, transport, and catabolism. On activation by oxysterols, LXRs induce transcription of specific target genes that in concert regulate feed-forward pathways in HDL-mediated reverse cholesterol transport.19 These include cellular cholesterol efflux pathways mediated by ABCA1,20,21 ABCG1,17 and ABCG4.22
The principal objective of our study was to identify cholesterol efflux mechanisms and the transporters involved in fetal ECs of human placenta (HPECs) at term of gestation to test the hypothesis that these cells have a strong and carefully regulated ability to efflux cellular cholesterol to different acceptors.
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Materials and Methods |
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The procedures for isolation and culture of HPECs and HUVECs, cellular cholesterol efflux assays, protein extraction, Western blot analyses, RNA isolation, gene-specific mRNA quantification, small interfering (si)RNA-mediated cellular RNA interference (RNAi), immunohistochemistry, light microscopy, and statistical analyses are described in detail in the expanded Materials and Methods section in the online data supplement, available at http://circres.ahajournals.org.
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Results |
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High Capacity of HPECs to Efflux Cholesterol
Despite the existence of inconsistent reports on the prevailing mechanism(s) for cellular cholesterol export,23 HDL-dependent reverse cholesterol transport appears to be the common major mechanism for the removal of cholesterol from ECs. Both, lipid-free and lipid-associated apoA-I promote different cholesterol efflux pathways in this process.
The first series of experiments was conducted to analyze the efficiency of cholesterol release from cultured HPECs and HUVECs to lipid-free apoA-I and to HDL3 (Figure 1). To analyze effects of LXR activation, cholesterol efflux was studied using [3H]-cholesterol–labeled ECs, preincubated in the absence or presence of the endogenous LXR agonist 24(S)OH-cholesterol for 16 hours before the addition of cholesterol acceptors to the culture media.
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ApoA-I at saturating concentrations of 20 µg/mL24 (Figure 1A) induced a time-dependent release of cellular [3H]-cholesterol from HPECs, reaching 4±0.7% of total radiolabel detected in medium at 3 hours. 24(S)OH-Cholesterol treatment significantly enhanced apoA-I–dependent cholesterol efflux at all time points investigated by 1.7- up to 2.3-fold (1.5 hour). These studies suggest that the LXR-regulated lipid transporter ABCA1, which promotes lipid efflux to apoA-I (and other lipid-free apolipoproteins), is functional in HPECs. In contrast to HPECs, HUVECs displayed negligible (1.5±0.1% at 3 hours) apoA-I–dependent cholesterol release, which was only marginally (2.0±0.04% at 3 hours) inducible by 24(S)OH-cholesterol (Figure 1B).
HDL3 (100 µg/mL), the main cholesterol acceptor in fetal blood, strongly induced [3H]-cholesterol release from HPECs, reaching 10.0±0.6% of [3H]-cholesterol in medium after 3 hours (Figure 1C). LXR activation by 24(S)OH-cholesterol significantly enhanced cholesterol efflux to HDL3 by 1.9-fold (3 hours). Notably, the capacity of HUVECs for HDL3-dependent cholesterol release in the absence of LXR agonist was almost identical to that observed for HPECs (11.5±1.0% and 10.0±0.6% of [3H]-cholesterol was released to HDL3 during 3 hours by HUVECs and HPECs, respectively), but in contrast to HPECs, this pathway in HUVECs was not responsive to 24(S)OH-cholesterol treatment (Figure 1D). This clearly indicates that LXR-regulated pathways are less important for cholesterol transport/homeostasis in HUVECs.
Similar results for HDL3 mediated cholesterol efflux were obtained when a synthetic, nonsteroidal LXR agonist (TO901317, 2 µmol/L) was used instead of 24(S)OH-cholesterol (data not shown). These studies indicate that HPECs possess an efficient, LXR-regulated mechanism for efflux of cholesterol to HDL.
LXR Activation Increases Expression of ABCA1 and ABCG1 in HPECs
Having demonstrated efficient and LXR-regulated cholesterol efflux from HPECs to both lipid-free apoA-I and lipid-associated HDL, we next analyzed expression of known cellular lipid transporters. Using real-time quantitative RT-PCR and immunoblotting, we examined effects of LXR activation on the expression levels of ABCA1, ABCG1, ABCG4, and SR-BI.
Exposure of HPECs to the endogenous agonist of LXRs [24(S)OH-cholesterol, 10 µmol/L] for 24 hours induced upregulation of ABCA1 and ABCG1 mRNA (6- and 4-fold, respectively; Figure 2A) and protein (5- and 3-fold, respectively; Figure 2B) levels. Similar results were obtained also with a synthetic, nonsteroidal LXR activator (TO901317, 2 µmol/L; Figure 2A). ABCA1 mRNA levels in HPECs were found to be approximately 3-fold higher than in HUVECs (Figure I, A, in the online data supplement), whereas, under basal conditions, ABCG1 mRNA levels in HPECs were approximately the same as in HUVECs (supplemental Figure I, B). As expected, expression of SR-BI, which is not a direct target gene of LXR, was not affected by LXR activation (Figure 2). Interestingly, LXR agonists did not influence expression of the proposed LXR target gene ABCG4, which was found to be present at negligible levels (Figure 2).
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Inhibitors of ABCA1, but Not SR-BI, Decrease Cellular Cholesterol Release
To obtain more direct evidence for the functional relevance of ABCA1 in HPECs, we next analyzed apoA-I–dependent cholesterol efflux in the presence of 2 pharmacological inhibitors of ABCA1, glyburide25 and probucol.26
Probucol and glyburide significantly diminished basal (by 72% and 75%, respectively) and LXR-activated (by 69% and 64%, respectively) apoA-I–dependent [3H]-cholesterol release from HPECs (Figure 3A), demonstrating a major involvement of ABCA1 in this process. Neither of the 2 inhibitors showed any effect on HDL3-mediated cholesterol efflux (data not shown).
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Another chemical inhibitor, BLT-1,27 was used to examine the role of SR-BI in HDL-dependent efflux of cholesterol from HPECs. HEK cells overexpressing SR-BI (HEK-SR-BI) served as a positive control in these experiments. In contrast to HEK-SR-BI cells, which displayed diminished (50%) cholesterol release to HDL3 (50 µg/mL) in the presence of BLT-1 (10 µmol/L), HPECs did not respond to BLT-1 treatment (Figure 3B). These data clearly show that SR-BI does not contribute to HDL-mediated cholesterol release from HPECs.
Reduction of ABCG1 Expression by RNAi Decreases Cholesterol Release to HDL3
Having ruled out a role for SR-BI, the most plausible candidate responsible for HDL-mediated cholesterol release from HPECs that remained was ABCG1. No specific inhibitor for ABCG1 is presently available. Therefore, to confirm our hypothesis, we aimed at reducing ABCG1 expression by applying RNAi before conducting cholesterol efflux assays. A strong significant reduction (76±5.4%) of ABCG1 mRNA by ABCG1-siRNA, as compared to scrambled siRNA (Figure 4A), resulted in a 49±2.0% to 56±2.2% reduction in time-dependent cholesterol release to 50 µg/ ml of HDL3 (Figure 4B), in line with (
45%) diminished ABCG1 protein levels (Figure 4B, inset). Neither SR-BI nor ABCA1 mRNA levels were significantly influenced by the RNA-silencing procedure (data not shown). We, therefore, conclude that HDL3-mediated cholesterol efflux from HPECs is mainly mediated by ABCG1.
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Cholesterol Enrichment of HPECs Increases Acceptor-Mediated Cholesterol Efflux
Cellular cholesterol enrichment with increasing concentrations of LDL or cholesterol (Figure 5C) enhanced apoA-I–mediated cholesterol efflux (Figure 5A) by up to 5.8±0.8-fold (100 µg/mL LDL, 3 hours) as compared to BSA-treated (1 mg/mL) HPECs independent of external and cellular cholesterol concentration. In contrast to apoA-I, HDL3 (Figure 5B) elicited a dose-dependent increase in cholesterol release from HPECs pretreated with LDL (up to 7.5±1.3-fold) or cholesterol (up to 9.9±0.3-fold). Despite the pronounced induction of cholesterol efflux, protein levels of ABCA1 remained unchanged on treatment with either LDL or cholesterol (Figure 5A). Similarly, ABCG1 expression (Figure 5B) remained unchanged on LDL treatment but was induced by cholesterol. These data clearly support a physiological role for acceptor mediated cholesterol release from HPECs. In addition, the induction of the cholesterol efflux activity of HPECs appears not to rely on increasing cellular protein levels of ABCA1 and/or ABCG1 but may involve other features of the mechanism(s) that are changed on cholesterol enrichment, possibly membrane translocation of the transporter(s) and/or increased accessibility of the cholesterol pool determined for efflux to apoA-I and/or HDL3.
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Enrichment of HDL3 With ApoE Enhances Its Acceptor Capacity
ApoE is prominent in cord blood, and, in contrast to adults, more than 80% of it is associated with HDL.13 ABCA1 is known to efflux cholesterol to different lipid-free apolipoproteins, including apoE,28 whereas ABCG1 promotes cholesterol efflux only to lipid-associated particles, ie, HDL.17 In view of these findings, we aimed to investigate the influence of apoE on cholesterol efflux from HPECs, using lipid-free apoE, HDL3, and apoE-enriched HDL3 as acceptor particles (Figure 6). ApoE (20 µg/mL) was similarly efficient as apoA-I in promoting [3H]-cholesterol release from HPECs (Figures 6 and 1
A, respectively). Interestingly, apoE-enriched HDL3 elicited a moderate, but significant, increase in cholesterol release as compared to apoE-free HDL3, to almost the same extent (1.3-fold) with (Figure 6) or without (data not shown) LXR activation. For all acceptors tested, LXR activation significantly enhanced cellular cholesterol efflux as compared to basal conditions (data not shown).
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ABCA1 and ABCG1 Are Located at the Apical Surface of HPECs In Vivo
To define the location of ABCA1 and ABCG1 in HPECs in situ, immunohistochemical analyses of term placental cryosections were performed (Figure 7). Both ABCG1 (Figure 7A) and ABCA1 (Figure 7B) were detected predominantly at the apical surface of the fetal endothelium facing the fetal circulation, thus supporting our hypothesis of cholesterol efflux in the maternal-to-fetal direction.
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Discussion |
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The significance of maternal cholesterol in developmental programming of atherosclerosis and the presence of severe developmental defects in offspring with inborn errors of cholesterol synthesis have prompted interest in delineating the distinct processes involved in cholesterol transfer across the placenta. Although the major mechanisms accounting for the uptake of maternal cholesterol into the placental syncytiotrophoblast have been identified, its subsequent release from the ECs has awaited investigation.
We have recently succeeded in culturing highly purified primary ECs isolated from the human placental vasculature at the end of gestation.29 This enabled us to demonstrate differences in cholesterol efflux from ECs obtained from different sites within one organ, ie, ECs from the placental "barrier" (HPECs) and from the umbilical cord (HUVECs). The present study provides the first evidence for efficient cholesterol efflux at the end of gestation from human ECs of the placenta to lipid-free apolipoproteins and to HDL and identifies contributing mechanisms. Our key findings demonstrate that: (1) ABCA1 and ABCG1, respectively, accomplish these 2 pathways of acceptor-mediated cholesterol efflux; and (2) both pathways can be induced in HPECs by LXR activation using endogenous or synthetic agonists. In addition, our results exclude a major contribution of SR-BI and ABCG4 to HDL-mediated cholesterol efflux from HPECs. However, a contribution of additional, but still unknown, cholesterol efflux transporters cannot be ruled out. The absence of a significant contribution of ABCG4 concurs with the present notion that this transporter is predominantly active in the brain.30
Whereas efflux from HPECs to apo-AI and HDL3 was stimulated by LXR agonists, the same effect was only moderately present or virtually absent in HUVECs. It may be hypothesized that the function of HPECs as a cellular constituent of the maternal–fetal cholesterol transport system requires careful regulation different from the less elaborate function of HUVECs as vascular lining. Stimulation of cholesterol efflux from HPECs via LXR activation may have important physiological, and potentially pharmacotherapeutic, implications. Both major natural LXR activators, 24S- and 27-OH-cholesterol, are present in the fetal circulation,31 and their concentrations are elevated in inborn errors of cholesterol biosynthesis, such as Smith–Lemli–Opitz.32,33 It is tempting to speculate that oxysterols are taken up by HPECs from the fetal and/or maternal circulation and stimulate transport of maternal cholesterol into the fetal circulation to compensate, at least in part, for the absence of endogenous fetal cholesterol biosynthesis.
Observations that placental ABCA1 expression is reduced in primary antiphospholipid syndrome, a pregnancy pathology characterized by recurrent pregnancy loss,34 and that functional loss of ABCA1 in mice causes severe placental malformation35 highlight the functional importance of ABCA1 in the placenta. Therefore, the expression of functional ABCA1 on HPECs at term of gestation, as observed in our study, might be fundamental for fetal development.
ABCA1 is the best-characterized transporter of active, ATP-dependent cellular cholesterol efflux to lipid-free or lipid-poor apolipoproteins.15,16 We have demonstrated a major contribution of ABCA1 to cholesterol release from HPECs by: (1) basal expression of ABCA1 mRNA and protein, (2) induction of ABCA1 expression levels along with an increase of cholesterol efflux to apoA-I and apoE, and (3) decreasing effects of ABCA1 inhibitors on cholesterol efflux. Interestingly, our previous studies demonstrated that the apoA-I/ABCA1 pathway is also operative and inducible by LXR activation in porcine brain capillary ECs (pBCECs), which constitute the blood–brain barrier.36,37 In contrast ECs from other vascular beds such as HUVECs (as confirmed the present study; Figure 1B) and/or human aortic ECs (HAECs) show only a poor ability to efflux cholesterol to lipid-free apoA-I.23,38,39 Therefore, the apoA-I/ABCA1 pathway appears to be prominently active and regulated by LXR in ECs constituting blood–tissue and blood–blood barriers, ie, blood–brain and placental "barrier." These findings may reflect different functions of HUVECs/HAECs as compared to ECs from barriers. Despite differences in junctional connections, both fetal placental ECs and brain capillary ECs are specialized ECs that, in addition to maintaining the integrity of blood vessels, restrict the passage of toxic and immunogenic factors while ensuring efficient solute and nutrient exchange.
In macrophages, ABCG1 promotes efflux of cholesterol and phospholipids onto a variety of lipoprotein particles, including HDL and phospholipids vesicles, presumably also onto nascent HDL particles previously formed via ABCA1 activity.40 The molecular mechanisms of potential interactions of the respective acceptor particles with these transporters or with specific plasma membrane domains are still not clarified.41,42 The present study is the first to demonstrate a prominent role of ABCG1 in HDL-mediated cholesterol release from ECs. This conclusion is based on (1) basal expression of ABCG1 mRNA and protein, (2) induction of ABCG1 expression levels along with an increase of cholesterol efflux to HDL, and (3) decreasing effect of ABCG1 silencing on cholesterol efflux to HDL. Interestingly, although expressed in HUVECs (see supplemental Figure I, B, and II, B) and HAECs,39 ABCG1 does not seem to contribute to cholesterol efflux from these cells. Similarly, we did not find evidence for its role in cholesterol release from pBCECs.36 The apparent different functions of ABCG1 in various types of ECs might be related to its different cellular localization or posttranscriptional activation and should be addressed in future studies.
The in vivo environment of HPECs is different from other ECs in the human adult and must be considered in any interpretation of our in vitro findings. At term of gestation, total and LDL cholesterol levels in cord blood are approximately one-third, whereas HDL cholesterol level is approximately half that of adult levels, resulting in a lower LDL to HDL ratio in fetal blood. ApoE is prominent in cord blood and more than 80% of it is associated with HDL.13 It can be hypothesized that the unique lipoprotein composition of cord blood facilitates cholesterol transfer from the maternal to the fetal circulation. Lower levels or even loss of the key apolipoproteins in this process can have detrimental effects on fetal development.43 We found that lipid-free apoE and apoA-I are comparably efficient in accepting cholesterol from HPECs, whereas, interestingly, apoE-enriched HDL3 bound cholesterol more efficiently than HDL3. This may reflect an increased capacity of ABCG1 to efflux cholesterol to apoE-containing HDL versus apoE-free HDL. The source of cord blood apolipoproteins is not clear at present. Although the fetal liver is a likely candidate, HPECs, unlike pBCECs,36 do not express and secrete endogenous apoA-I or apoE (C Wadsack, C Schweinzer, U Panzenboeck, unpublished data, 2008).44 It remains to be established whether apolipoproteins pass across HPECs by transcytosis similar to aortic ECs.45
In conclusion, ABCA1 and ABCG1 have a major role in mediating net cholesterol efflux from HPECs to apoA-I, apoE, and HDL (Figure 8). This facilitates maternal–fetal cholesterol transfer at the end of gestation and implies LXR activators/antagonists as potential drugs that could provide a future strategy to influence this process. In vivo the functional cooperation of ABCA1 and ABCG1 may allow a sequential loading of cholesterol first onto HDL apolipoproteins derived from fetal liver and, subsequently, onto nascent HDL.
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Acknowledgments |
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We thank Susanne Kopp, Johann Semmler, and Anton Ibovnik for technical assistance.
Sources of Funding
This work was supported by Austrian Science Foundation grants P17474-B09 (to U.P.) and P21004-B02 (to G.M.), the Jubilee Fund, Austrian National Bank grants 10053 and 11165 (to G.D. and C.W., respectively), and the Molecular Medicine PhD Program of the Medical University Graz (U.P. and C.S.). The study was conducted as part of the key research action on Reproduction and Pregnancy at the Medical University Graz.
Disclosures
None.
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Footnotes |
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*Both authors contributed equally to this work.
Both authors contributed equally to this work.
Original received August 12, 2008; revision received January 8, 2009; accepted January 12, 2009.
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