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/RXR
Heterodimers Control Human Trophoblast Invasion
INSERM, U-427, Faculté de Pharmacie (A.T., L.P., D.E.-B., T.F.), 75006 Paris, France; and Institut de Génétique et Biologie Moléculaire et Cellulaire, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique/INSERM (K.S., J.A., C.R.-E.), 67404 Illkirch, France
Address all correspondence and requests for reprints to: Dr. Thierry Fournier, INSERM, U-427, Faculté de Pharmacie, 75006 Paris, France. E-mail: t.fournier{at}pharmacie.univ-paris5.fr
Abstract
The ligand-dependent nuclear receptors PPAR
and RXR
/ß were
recently determined to be essential for murine placental development
and trophoblast differentiation. In the current study we examined the
expression and role of the PPAR/RXR heterodimers in human
invasive trophoblasts. We first report that in human first trimester
placenta, PPAR and RXR are highly expressed in cytotrophoblasts
at the feto-maternal interface, especially in the extravillous
cytotrophoblasts involved in uterus invasion. The coexpression of
PPAR and RXR genes in extravillous cytotrophoblast nuclei were
then confirmed by immunocytochemistry, immunoblot, and real-time
quantitative PCR using cultured purified primary extravillous
cytotrophoblasts. We next examined, using the extravillous
cytotrophoblast culture model, the biological role of PPAR/RXR
heterodimers in vitro, and we showed that both synthetic
(rosiglitazone) and natural [15-deoxy-
-(12,14)PGJ2]
PPAR agonists inhibit extravillous cytotrophoblast invasion in a
concentration-dependent manner and synergize with pan-RXR agonists.
Conversely, PPAR or pan-RXR antagonists promoted extravillous
cytotrophoblast invasion. Furthermore, the pan-RXR antagonist abolished
the inhibitory effect of the PPAR agonists. Together these data
underscore an important function of PPAR/RXR heterodimers in
the modulation of trophoblast invasion.
IMPLANTATION OF THE human conceptus
involves invasion of the uterine epithelium and the underlying stroma
by extraembryonic trophoblastic cells, which undergo a complex process
of proliferation, migration, and differentiation. As the fetal
placental cells, named trophoblasts, are in direct contact with
maternal blood, the human placenta has been classified as
hemomonochorial. One particularity of human placentation is therefore
the very high degree of trophoblast invasion during the first trimester
(1), unparalleled in other mammals. Indeed, as illustrated
in Fig. 1A
, the cytotrophoblasts located
at the tip of the villi contacting the uterine wall proliferate to form
multilayered columns of cells that rapidly invade the uterus. These
cells, named extravillous cytotrophoblasts (EVCT), invade the decidua
and the upper third of the myometrium. EVCT also invade the uterine
arterioles and replace the endothelial lining and most of the
musculoelastic tissue of the vessel wall. This arteriole remodeling
leads to low resistance vessels that provide an adequate supply of
maternal blood to the intervillous space necessary for fetal growth
(2). Defective invasion of the uterine spiral arteries is
directly involved in preeclampsia, a major and frequent complication of
human pregnancy with serious fetal and maternal consequences (for
review, see Ref. 3). The human trophoblastic invasion,
unlike tumor invasion, is precisely regulated. It is temporally
restricted to early pregnancy, and it is spatially confined to the
endometrium, the first third of the myometrium, and the associated
spiral arterioles (4, 5). Therefore, it offers a unique
model of a controlled and oriented cell invasion process, which remains
poorly understood.
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is a member of the nuclear receptor superfamily that
controls the expression of a large array of genes in a ligand-dependent
manner. DNA binding of PPAR to its response element, composed of a
direct repeat of the core hexanucleotide motif AGGTCA with one
intervening base, requires obligate heterodimerization with another
nuclear receptor, the RXR. PPAR controls a broad range of cellular
responses, such as differentiation, proliferation, cell death, and
inflammation (for review, see Ref. 6). Most importantly,
PPAR has been shown to be essential for the development of adipose
tissue (7, 8, 9), to play a critical role in glucose
homeostasis (10), and to inhibit the expression of a
number of proinflammatory genes (11, 12). PPAR is bound
and activated by natural ligands such as fatty acids (13),
oxidized low density lipoprotein compounds 11–13-hydroxy
octadecadienoic acid (14) and
15-deoxy--(12,14)PGJ2
(15D-PGJ2) (15, 16). In addition
to15D-PGJ2, synthetic ligands and agonists of
PPAR, such as the thiazolidinediones, have been developed and used
in the treatment of type 2 diabetes. Interestingly, PPAR/RXR
heterodimers can be activated by either selective RXR or PPAR
ligands; their combination results in an additive or synergistic effect
(17, 18).
Recent genetic studies performed in mice established that two nuclear
hormone receptors, RXRs, on the one hand, and PPAR, on the other
hand, are essential for placental development and vasculature. Indeed,
RXR-/-/RXRß-/-
conceptuses fail to develop a normal chorioallantoic placenta with a
functional labyrinthine zone, resulting in compromised maternal-fetal
exchanges and therefore in early embryonic death (19).
Likewise, PPAR-/- conceptuses exhibited
similar placental agenesis with defects in trophoblast differentiation
and vascular processes (7, 8). These studies suggested
that PPAR/RXR heterodimers might be essential for implantation and
the formation of a functional placenta in mice.
Whether PPAR/RXR heterodimers also play an essential role in the
early development of human placenta remains, however, largely unknown.
Due to the specificity of the human placenta, no easily accessible
animal models are available to study trophoblast invasion. Hence, we
used a recently developed in vitro model to investigate the
regulation of human trophoblast differentiation and invasion
(20). The present study demonstrates that both PPAR and
RXR are coexpressed in invasive EVCT and that activation of PPAR
and RXRs inhibits EVCT invasion, whereas their inhibition promotes
trophoblast invasion. These data underscore that PPAR/RXR
heterodimers play a key role in human placentation.
Materials and Methods
Detection of PPAR and RXR by immunohistochemistry
Placental tissues from first trimester legal induced abortions
were obtained from the Department of Obstetrics and Gynecology at the
Broussais and Saint-Vincent de Paul Hospitals. Paraffin tissue sections
(4 µm) were prepared as previously described (21).
Briefly, monoclonal antibodies against RXR (4RX3A2; 4.7 µg/ml
total IgG) (22), PPAR (2 µg/ml IgG1; E-8, Santa Cruz Biotechnology, Inc., Santa Cruz, CA), and cytokeratin 7
(4.15 µg/ml IgG1; OV-TL 12/30, DAKO Corp., Trappes,
France) were diluted in 1% BSA and incubated with the sections
overnight at 4 C. Controls were performed by omitting primary antibody
or by incubating the sections with nonspecific mouse IgG at the same
concentration as the primary antibody. Immunochemical staining was
performed using a universal streptavidin-alkaline phosphatase
immunostaining kit (Immunotech, Margency, France).
Staining was detected with the fast red chromogen after 10 min. Nuclei
were counterstained by incubation for 2 min with hematoxylin. Sections
were mounted in Gel TOL and were examined and photographed under a
microscope (BX60 microscope, Olympus Corp., New Hyde Park,
NY).
Isolation and purification of trophoblasts differentiating into EVCT
Chorionic villi from first trimester placental tissues were
dissected and incubated in Hanks’ solution containing 0.125% trypsin
(Difco Laboratories, Detroit, MI), 4.2 mmol/liter
MgSO4, 25 mmol/liter HEPES, and 50 U/ml
deoxyribonuclease type IV (Sigma, Saint-Quentin Fallavier,
France) for 35 min at 37 C without agitation. After tissue
sedimentation, the supernatant was taken and filtered (100-µm pores).
HBSS was added to the tissue and sedimented twice. Trypsin digestion
was stopped with 5% FCS. Cells were centrifuged at 300 x
g for 10 min. Cell suspensions were carefully layered over a
discontinuous Percoll gradient and centrifuged for 20 min at 1000
x g. The layer corresponding to 35–45% Percoll was washed
with DMEM, diluted to a concentration of 5 x
105 cells/2 ml, and then plated on
Matrigel-coated (5 mg/ml; Collaborative Biomedical Products, Le Pont de
Claix, France) 35-mm Falcon culture dishes. Cells were maintained in
DMEM (Life Technologies, Inc., Grand Island, NY)
supplemented with 10% FCS (Biological Industries, Beth Haemek,
Israel), 2 mmol/liter glutamine, 25 mmol/liter HEPES, 100 IU/ml
penicillin, and 100 µg/ml streptomycin and incubated in 5%
CO2 at 37 C. After a 3-h adhesion period, cells
were washed three times to eliminate debris and nonadherent cells, then
cultured in complete medium. These purified primary EVCT were
characterized using immunocytochemistry and real-time PCR as previously
described (20). EVCT were shown to express in
vitro the specific markers of human invasive trophoblasts
described in situ: cytokeratin 7 (23), human
leukocyte antigen G (24), human placental lactogen
(25), c-erbB2 (26), and
5-subunit of the fibronectin receptor
5ß1
(27).
Detection of PPAR and RXR by immunocytochemistry
Cells were cultured for 48 h, fixed for 20 min in 4%
paraformaldehyde and permeabilized for 30 min in 0.3% Triton
X-100. After preincubation with 7% sheep serum, monoclonal antibodies
against RXR (4RX3A2, diluted 1:500) and PPAR (E-8, diluted 1:100)
were applied overnight at 4 C. Bound antibodies were revealed after a
1-h incubation with a 1:200 dilution of a biotinylated antimouse
antibody (Amersham Pharmacia Biotech, Les Ulis, France),
followed by a 45-min incubation at room temperature in the dark with a
streptavidin-fluorescein complex (Amersham Pharmacia Biotech; 1:500). In all cases, cells were extensively washed
with PBS containing 0.1% Tween 20 between steps. Finally, slides were
coverslipped in a drop of fluorescent 4'6-diamidino-2-phenylindole
(Dapi) mounting medium (Vector Laboratories, Inc.,
Burlingame, CA) and analyzed under an epifluorescence microscope. To
ensure the specificity of the immunological reactions, negative
controls were performed by substituting the primary antibodies with a
nonimmune mouse serum.
Western blot analysis
Protein preparation and immunoblotting were performed exactly as
described previously (28, 29). Whole cell extracts were
prepared by four cycles of freezing and thawing in high salt buffer
[10 mmol/liter Tris-HCl (pH 8.0), 0.6 mol/liter KCl, and 1.5
mmol/liter EDTA] containing a protease inhibitor cocktail. After
centrifugation (30 min at 13,000 rpm), the resulting extract was
resolved by SDS-10% PAGE and electrotransferred onto nitrocellulose
membrane. The filters were then incubated with PPAR (E-8, diluted
1:100) and RXR (4RX3A4, 1:500) antibodies as previously described
(28, 29), followed by a peroxidase-conjugated antimouse
IgG secondary antibody, and developed using an enhanced
chemiluminescence kit (Amersham Pharmacia Biotech).
Quantification of specific transcripts by real-time RT-PCR
Total RNA was extracted from 48-h cultured EVCT using
QIAGEN RNeasy mini kit (Courtabeuf, France). cDNA
synthesis and PCR amplification were performed as described previously
(30). All PCR reactions were performed using an ABI PRISM
7700 Sequence Detection System (Perkin-Elmer Corp.,
PE Applied Biosystems, Foster City, CA) and the SYBR Green
PCR Core Reagents kit (Perkin-Elmer Corp., PE Applied Biosystems). We used the following primers: PPAR (+),
5'-AGT GGG GAT GTC TCA TAA TGC C-3'; and PPRAR (-), 5'-AGG TCA GCG
GAC TCT GGA TTC-3'; RXR (+), 5'-CCT TTC TCG GTC ATC AGC TC-3';
RXR (-), 5'-CTC GCA GCT GTA CAC TCC AT-3'; PPIA (+), 5'-GTC
AAC CCC ACC GTG TTC TT-3'; and peptidylprolyl isomerase A (PPIA) (-),
5'-CTG CTG TCT TTG GGA CCT TGT-3'. The gene PPIA coding for human PPIA
(cyclophilin A) was used as the endogenous RNA control, and each sample
was normalized on the basis of its PPIA content.
Invasion assays
To assess the invasive potential of cytotrophoblasts, cultured
EVCT were plated on Transwell inserts (6.5 mm; Costar,
Cambridge, MA) containing polycarbonate filters (8-µm pores) as
previously described (31). The upper side was coated with
10 µl 5 mg/ml Matrigel. EVCT (2.5 x 105
cells) were plated in 200 µl DMEM supplemented with 2% FCS, 2
mmol/liter glutamine, 25 mmol/liter HEPES, 100 IU/ml penicillin, and
100 µg/ml streptomycin. Six hundred microliters of the medium
supplemented with 20% FCS were added to the well. The cells were
treated with the synthetic retinoid RO25-7386 (a pan-RXR agonist)
dissolved in ethanol. Cells were also treated with rosiglitazone
(BRL 49653, a specific PPAR agonist) or
15D-PGJ2 (a PPAR ligand) dissolved in
dimethylsulfoxide. At the concentrations used, these compounds did not
affect cell viability (as tested by blue trypan exclusion), cell
morphology, or nuclei condensation and fragmentation (as tested by DAPI
staining). To abolish the activity of PPAR/RXR heterodimers we used
the pan-RXR-selective antagonist RO26-5405 and the partial PPAR
inhibitor bisphenol A diglycidyl ether (BADGE; Fluka, St. Quentin
Fallavier, France) (32). Control cultures were treated
with the same volume of solvent, ethanol, or dimethylsulfoxide (1%).
After 48 h of culture (5% CO2 at 37 C), the
Transwell inserts were washed three times with PBS, and cells were
fixed for 1 h in 4% paraformaldehyde at 4 C. Samples were rinsed
and fixed for 10 min at -20 C in methanol. Cells were incubated with
7% goat serum in PBS for 30 min to reduce nonspecific binding.
Cytokeratin 7 antibody (1:200; DAKO Corp., Trappes,
France) diluted in PBS containing 1% BSA was added for 2 h at
room temperature. Cells were washed in PBS-0.1% Tween and incubated
with fluorescein isothiocyanate-conjugated goat antimouse IgG
(Jackson ImmunoResearch Laboratories, Inc., West Grove,
PA) for 1 h and washed in PBS-0.1% Tween. Filters were dissected
with a scalpel, and the upper side of the filter was placed in contact
with a SuperFrost slide (Poly Labo, Strasbourg, France), mounted
in mounting medium (Vector Laboratories, Inc., Burlingame,
CA), and examined and photographed on an Olympus Corp.
BX60 epifluorescence microscope.
Scanning electron microscopy
Cells were fixed with 2.5% glutaraldehyde in 0.1 M cacodylate buffer for 1 h at room temperature. The cultures were then dehydrated with increasing concentrations of acetone and dried with a critical point drying apparatus (Balzers, Fürstentum, Liechtenstein) using acetone and liquid CO2. The dried specimens were coated with a 30-nm layer of gold in a vacuum evaporator.
Statistical analysis
Results are presented as the mean ± SD. Data were analyzed using nonparametric Kruskal-Wallis tests for multiple comparisons. Results were considered significant when Mann-Whitney tests had values of P < 0.05.
Results
PPAR and RXR are expressed in EVCT
In view of the recent data describing a role for PPAR in mouse
placentation, we first examined by immunohistochemistry, the expression
of this receptor in first trimester placenta. Fig. 1B
(panel a) shows
that PPAR is specifically expressed in the nuclei of
cytotrophoblasts from proximal and distal columns of the anchoring
villi. PPAR is also expressed in the invasive extravillous
cytotrophoblasts present in the decidua, but is, however, absent from
decidual cells (Fig. 1B, panel b). In contrast to PPAR, RXR is
expressed in both EVCT and decidual cells (Fig. 1B, panels c and d).
For these studies, cytokeratin 7 was used as a specific trophoblast
marker, and cytotrophoblasts were positive through the differentiating
pathway (Fig. 1A, right panel).
PPAR was also detected by immunocytochemistry in the nuclei of EVCT
isolated and purified from first trimester placentas (Fig. 2A, panel a) and colocalized with the
Dapi staining (Fig. 2A, panel b). Likewise, RXR protein was detected
in the nuclei of the EVCTs (Fig. 2A, panels e and f). EVCT PPAR and
RXR expressions were confirmed by immunoblotting (Fig. 2B, lanes 2
and 4). Surprisingly, PPAR levels were higher in EVCT (lane 2)
extracts than in differentiated murine 3T3-L1 adipocytes (lane 1),
which are known to express high amounts of PPAR. Finally, the
expression of PPAR and RXR mRNA was analyzed by real-time RT-PCR
in EVCT and fibroblasts isolated from first trimester human placentas.
In agreement with the immunohistochemistry and immunoblot results,
PPAR transcript levels were highly expressed in EVCT cultured for
48 h (PPAR/PPIA, 68.37 ± 21.94; mean ±
SD of three cultures from three separate placentas)
compared with human first trimester placental fibroblasts (4.30 ±
1.38). RXR gene expression was also confirmed by RT-PCR
(RXR/PPIA, 3.77 ± 0.80).
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and RXR agonists and is
increased by PPAR and RXR antagonists
An in vitro cell culture model of purified EVCT cells
has been developed in our laboratory to study early human placental
function (20). As EVCT are able to invade an
extracellular matrix in vitro, cellular invasion was
therefore analyzed using Matrigel-coated Transwells (Fig. 3A). In such a system, the EVTC present
in the upper well invade the Matrigel and emit pseudopods through the
membrane pores. These invading trophoblasts can be visualized and
quantified by immunostaining with cytokeratin 7 antibodies and
counterstaining with Dapi (Fig. 3B) or by scanning electron microscopy
(Fig. 3C). Figure 3D illustrates the modulation of trophoblast invasion
after different treatments (see figure legend).
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and PPAR being strongly expressed in cultured EVCT, we next
investigated whether their activation or inhibition might alter the
invasive properties of EVCT. Therefore, EVCT were cultivated in the
above in vitro system and treated with PPAR and pan-RXR
agonists either alone or in combination. Two PPAR agonists,
rosiglitazone (BRL 49653) and
15D-PGJ2, were tested at concentrations ranging
from 0.1–10 µmol/liter. These two PPAR agonists inhibited
trophoblastic invasion at 48 h, with a maximal inhibition of about
50% at 1 µmol/liter for BRL 49653 and 10 µmol/liter
for 15D-PGJ2 (Fig. 4A). In contrast, the pan-RXR agonist did
not significantly affect EVCT invasion (Fig. 4A). However, the
combination of this pan-RXR agonist with the PPAR agonist, both used
at a suboptimal concentration (0.1 µmol/liter) that on its own has no
effect, resulted in a clear inhibition of EVCT invasion (Fig. 4B),
indicating that these ligands can synergize. Thus, according to these
observations, activation of PPAR/RXR heterodimers appears to
inhibit EVCT invasion.
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and/or RXR had the opposite
effect on trophoblast invasion. Individually, the partial PPAR
antagonist BADGE (50 µmol/liter) (32) and the pan-RXR
antagonist (1 µmol/liter) increased trophoblast invasion by about
50%. When combined, the two antagonists increased trophoblast invasion
by the same order of magnitude (Fig. 5A).
It must be noted that the pan-RXR antagonist reversed the inhibitory
effect of the PPAR agonists (1 µmol/liter BRL 49653
or 10 µmol/liter 15D-PGJ2) on EVCT invasion
(Fig. 5B). It also reversed the inhibitory effect of the
PPAR/pan-RXR agonist combination (Fig. 5B).
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During the early stage of human implantation, trophoblast
differentiation occurs along two main pathways, villous and
extravillous. The syncytiotrophoblast, which results from the fusion of
villous cytotrophoblasts, is bathed in maternal blood and is the
endocrine unit of the human placenta. In contrast, extravillous
cytotrophoblasts migrate deep into the uterine mucosa as far as the
myometrium and invade the decidua and the uterine arterioles
(33). Recent studies have shown that activation of either
RXR (34, 35) or PPAR (36) stimulates
villous trophoblast differentiation and endocrine function. In the
present study performed in first trimester human placentas, we
demonstrate that PPAR coexpresses with RXR in the nuclei of
extravillous cytotrophoblasts from proximal and distal columns of the
anchoring villi. Therefore, it corroborates previous reports describing
the expression of PPAR in extravillous cytotrophoblasts from second
trimester (37) and in villous cytotrophoblasts from term
placentas (36). In fact, the interesting feature of our
study is the observation that PPAR and RXR are also coexpressed
in the invasive EVCT present in the decidua. Moreover, the finding
that, in contrast to RXR, PPAR is specifically expressed in EVCT
and is absent from the decidual cells underscored that this nuclear
receptor might play an important role in EVCT invasion.
As PPAR and RXR were also found to be strongly expressed in
purified human EVCT isolated from first trimester placenta and
maintained in primary culture, we applied the in vitro cell
culture model of EVCT that we recently developed (20) to
investigate the eventual role of PPAR/RXR heterodimers in EVCT
invasion in vitro. By using such a model, we found that both
synthetic (rosiglitazone) and natural (15D-PGJ2)
PPAR agonists inhibit trophoblast invasion. In contrast, these two
PPAR agonists were shown to have opposite effects on villous
trophoblast differentiation (36). In the present study it
is particularly noteworthy that at suboptimal concentrations
rosiglitazone acts synergistically with a pan-RXR agonist, as
previously described in other cell types (17, 18).
Reciprocally, PPAR and pan-RXR antagonists promote EVCT invasion and
reverse the agonist-induced inhibition. Such results are consistent
with the conclusion that the PPAR and RXR partners in
PPAR/RXR heterodimers cooperate to modulate EVCT invasion.
According to these results, it appears that activation of
PPAR/RXR heterodimers represses EVCT invasion. Therefore, the
amount of PPAR and RXR ligands synthesized by trophoblasts may play
a key role in the control of human placental invasion. Although the RXR
and PPAR ligands present in placenta have not been extensively
investigated, some studies performed in mammals, including humans,
strongly suggest that trophoblast and decidual cells synthesize
all-trans-retinoic acid and its 9-cis isomer, the
natural ligand for RXR (38, 39). The production of PPAR
ligands such as PGs is also likely, as human endometrium and decidua
express cyclooxygenase and produce PGs (40). The placental
tissue also produces considerable amounts of PGs (41, 42, 43)
and contains various lipids (44, 45). Thus, cells from
maternal and/or fetal origin may negatively control trophoblastic
invasion through the production of PPAR and/or RXR ligands and the
subsequent synergistic activation of PPAR/RXR heterodimers.
Consequently, one can hypothesize that abnormal increases in the
production of such ligands (i.e. PGs) can alter trophoblast
invasion and generate human pregnancy diseases such as
preeclampsia.
Finally, according to the present study PPAR/RXR heterodimers can
be added to the growing list of transcriptional regulators that control
human cytotrophoblast differentiation and invasion. Such transcription
factors, which include the basic helix-loop-helix transcriptions
factors such as Mash-2 (46) and Gcm1 (47),
the homeobox gene (48) and members of the Id family (Id-2)
(49) control an array of downstream effectors such as the
trophoblast major histocompatibility antigen HLA-G (50),
adhesion molecules (27), proteinases, and proteinases
inhibitors (51). Accordingly, PPAR has been
demonstrated to modulate the expression of proinflammatory genes such
as matrix metalloproteinases (12, 52, 53) and to control
cell motility and invasion in normal and tumor cells (46, 54). To determine whether PPAR/RXR heterodimers control
the expression of proteinases during trophoblast invasion requires
additional studies.
In conclusion, our results clearly indicate that activation of
PPAR/RXR heterodimers abrogates the invasive properties of EVCT,
whereas inhibition of these heterodimers promotes invasion. Therefore,
the present data demonstrate that PPAR/RXR heterodimers play a
key role in early human placentation through the control of trophoblast
invasion and extend the observations that PPAR- or RXR-deficient
mice have severe abnormalities in placental development.
Acknowledgments
We thank Dr. Leibowitz (Ligand, San Diego, CA) for the BRL 49653, and Dr. Kalus (Hoffman-LaRoche Inc., Basel, Switzerland) for the RO26-5405 and the RO25-7386. We also thank the Department of Obstetrics and Gynecology, Broussais and Saint-Vincent Hospitals (Paris, France), for donating placental tissues. We are grateful to V. Tricottet and R. Lai Kuen for scanning electron microscopy, C. Nessman for providing tissue sections, and Prof. M. Vidaud for real-time PCR.
Footnotes
This work was supported by Centre National de la Recherche Scientifique, INSERM, Hôpital Universitaire de Strasbourg, Association pour la Recherche sur le Cancer (Contract 9943), the Juvenile Diabetes Foundation (1-1999-819), the European Community RTD Program (QLG1-CT-1999-00674), and the Human Frontier Science Program (RG0041/1999-M).
Abbreviations: BADGE, Bisphenol A diglycidyl ether; Dapi,
4',6-diamidino-2-phenylindole; EVCT, extravillous cytotrophoblast;
15D-PGJ2, 15-deoxy--(12,14)PGJ2; PPIA,
peptidylprolylisomerase A.
Received May 7, 2001.
Accepted July 1, 2001.
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 E. B. E. Berry, J. A. Keelan, R. J. A. Helliwell, R. S. Gilmour, and M. D. Mitchell Nanomolar and Micromolar Effects of 15-Deoxy-{Delta}12,14-prostaglandin J2 on Amnion-Derived WISH Epithelial Cells: Differential Roles of Peroxisome Proliferator-Activated Receptors {gamma} and {delta} and Nuclear Factor {kappa}B Mol. Pharmacol., July 1, 2005; 68(1): 169 - 178. [Abstract] [Full Text] [PDF]
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 L. L. Waite, R. E. Louie, and R. N. Taylor Circulating Activators of Peroxisome Proliferator-Activated Receptors Are Reduced in Preeclamptic Pregnancy J. Clin. Endocrinol. Metab., February 1, 2005; 90(2): 620 - 626. [Abstract] [Full Text] [PDF]
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J. R. Miles, C. E. Farin, K. F. Rodriguez, J. E. Alexander, and P. W. Farin Angiogenesis and Morphometry of Bovine Placentas in Late Gestation from Embryos Produced In Vivo or In Vitro Biol Reprod, December 1, 2004; 71(6): 1919 - 1926. [Abstract] [Full Text] [PDF]
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L. Pavan, A. Hermouet, V. Tsatsaris, P. Therond, T. Sawamura, D. Evain-Brion, and T. Fournier Lipids from Oxidized Low-Density Lipoprotein Modulate Human Trophoblast Invasion: Involvement of Nuclear Liver X Receptors Endocrinology, October 1, 2004; 145(10): 4583 - 4591. [Abstract] [Full Text] [PDF]
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I. Bildirici, C.-R. Roh, W. T. Schaiff, B. M. Lewkowski, D. M. Nelson, and Y. Sadovsky The Lipid Droplet-Associated Protein Adipophilin Is Expressed in Human Trophoblasts and Is Regulated by Peroxisomal Proliferator-Activated Receptor-{gamma}/Retinoid X Receptor J. Clin. Endocrinol. Metab., December 1, 2003; 88(12): 6056 - 6062. [Abstract] [Full Text] [PDF]
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E. B. E. Berry, R. Eykholt, R. J. A. Helliwell, R. S. Gilmour, M. D. Mitchell, and K. W. Marvin Peroxisome Proliferator-Activated Receptor Isoform Expression Changes in Human Gestational Tissues with Labor at Term Mol. Pharmacol., December 1, 2003; 64(6): 1586 - 1590. [Abstract] [Full Text] [PDF]
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 L. Pavan, A. Tarrade, A. Hermouet, C. Delouis, M. Titeux, M. Vidaud, P. Therond, D. Evain-Brion, and T. Fournier Human invasive trophoblasts transformed with simian virus 40 provide a new tool to study the role of PPAR{gamma} in cell invasion process Carcinogenesis, August 1, 2003; 24(8): 1325 - 1336. [Abstract] [Full Text] [PDF]
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V. Tsatsaris, A. Tarrade, P. Merviel, J. M. Garel, N. Segond, A. Jullienne, and D. Evain-Brion Calcitonin Gene-Related Peptide (CGRP) and CGRP Receptor Expression at the Human Implantation Site J. Clin. Endocrinol. Metab., September 1, 2002; 87(9): 4383 - 4390. [Abstract] [Full Text] [PDF]
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 L. Blanchon, P. Sauvant, C. Bavik, D. Gallot, F. Charbonne, M.-C. Alexandre-Gouabau, D. Lemery, B. Jacquetin, B. Dastugue, S. Ward, et al. Human choriocarcinoma cell line JEG-3 produces and secretes active retinoids from retinol Mol. Hum. Reprod., May 1, 2002; 8(5): 485 - 493. [Abstract] [Full Text] [PDF]
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,
P < 0.05, BRL plus RXR agonist vs.
BRL or vs. RXR agonist.
) or
absence (
) of the pan-RXR antagonist (1 µmol/liter). Results
represent the mean ± SD from a representative
experiment performed in triplicate of at least three independent
cultures obtained from different placentas.