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Departments of Obstetrics and Gynecology, and Physiology, Virginia Commonwealth University, Richmond, Virginia 23298-0034, USA; and
* Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-6602, USA
1Correspondence: Virginia Commonwealth University, Department of Obstetrics and Gynecology, Sanger Hall, Rm. 11–039, 1101 E. Marshall St., Richmond, VA 23298-0034, USA. E-mail: swwalsh{at}hsc.vcu.edu
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Key Words: placenta • malondialdehyde • oxidative stress • isoprostanes
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Isoprostanes are recently discovered prostaglandin-like products
formed in vivo by free radical-catalyzed nonenzymatic
peroxidation of arachidonic acid (1)
. Isoprostanes are
considered to be accurate markers of oxidative stress and endogenous
lipid peroxidation (2
3
4
5)
. They are formed in
situ, esterified in phospholipids, and then released in free form,
presumably by phospholipases (6)
. Isoprostanes are carried
in the circulation bound to lipoproteins.
The isoprostanes have been proposed as markers of oxidative damage, but
they also exert biological actions. Isoprostanes are potent
vasoconstrictors in the kidney, lung, heart, brain and placenta
(1
, 7
8
9
10)
. Isoprostanes also stimulate IP3 and
mitogenesis in vascular smooth muscle cells and induce the release of
endothelin from endothelial cells (11
, 12)
. Some
investigators report increased maternal circulating levels of
endothelin in preeclampsia, which is thought to result from endothelial
cell dysfunction (13
, 14)
. The biological actions of
isoprostanes suggest that they could contribute to abnormalities of
preeclampsia such as hypertension, endothelial cell dysfunction, renal
vasoconstriction, placental vasoconstriction, and cerebral vasospasm of
eclampsia.
Circulating and urinary levels of the F2-isoprostanes are high in
patients with pathologies involving oxidative stress (15
, 16)
. Inhibition of the antioxidant enzyme copper-zinc superoxide
dismutase (Cu-Zn SOD) results in increased plasma levels of isoprostane
(17)
. In this regard, our previous finding that Cu-Zn SOD
activity is decreased in placentas of preeclamptic women
(18)
suggests that placental isoprostane production would
be increased in preeclampsia. The recent finding that maternal serum
levels of free isoprostane are significantly higher in preeclampsia
than in normal pregnancy (19)
might be explained by
increased secretion of placentally derived isoprostanes.
In the following study, we determined whether 1) the
human placenta produces isoprostanes; 2) placental
production and tissue levels of isoprostanes are higher in preeclampsia
than normal pregnancy; 3) the human placenta secretes
isoprostanes; and 4) oxidative stress stimulates placental
production and secretion of isoprostanes. As an indicator of
isoprostanes, we measured 8-Iso prostaglandin
F2
(8-Iso-PGF2), which
is now referred to as 15-F2t-IsoP according to
the nomenclature system approved by the Eicosanoid Nomenclature
Committee (20)
. We hypothesized that preeclamptic
placentas would be characterized by significantly elevated levels of
isoprostanes.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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110/70 mmHg, no
proteinuria, and no other complications. Preeclamptic patients had
maternal blood pressures of 140/90 mmHg or higher, with proteinuria
(>300 mg/24 h) on two separate readings at least 6 h apart.
Preeclamptic patients also had pathological edema. There was no
difference in the age of the preeclamptic patients vs. the normal
patients (24.8±1.6 years vs. 22.3±1.3 years, respectively,
P>0.1). The preeclamptic patients weighed significantly
more than the normal patients (227.6±15.2 lb vs. 162.1±6.5 lb,
P<0.001), and delivered earlier (36.1±1.0 wk vs. 39.4±0.3
wk of gestation, P<0.01). Babies born to the preeclamptic
women weighed less than babies born to normal pregnant women (2716±256
g vs. 3225±123 g, P<0.05) and placental weights were less,
although the difference in placental weight did not reach statistical
significance (596±63 g vs. 684±49 g, P>0.1). There were
six cesarean sections in the preeclamptic group and five in the normal
group.
Extraction and hydrolysis of isoprostane from phospholipids in
placental tissue
Placentas were obtained immediately after delivery from 13 women
with preeclampsia and 12 women with normal pregnancy. Placental tissue
pieces were initially separated by sterile dissection from different
cotyledons, excluding chorionic and basal plates, rinsed with saline,
and snap frozen in liquid nitrogen. The tissue pieces were stored in a
freezer at -80°C. At the time of assay, 1 g of tissue was
homogenized in 1.0 ml phosphate-buffered saline (PBS). Samples were
extracted with 2.0 ml ethanol containing 0.005% butylated
hydroxytoluene (BHT) to prevent oxidation during processing and with
5000 cpm of 3H-PGF2 to
determine recovery of 15-F2t-IsoP. Samples were
centrifuged and the supernatants were split into two aliquots of 1.5 ml
each. To one of the aliquots, 8.5 ml ultrapure
H2O was added and the samples were acidified to
below pH 4.0 to determine free 15-F2t-IsoP. To
the other aliquot, 1.5 ml of 15% potassium hydroxide (KOH) was added
to determine total 15-F2t-IsoP by base
hydrolysis. These samples were incubated at 40°C for 1 h under
nitrogen. Seven milliliters of ultrapure H2O was
then added and the samples were acidified to below pH 4.0. All samples
were purified by Sep-Pak C-18 cartridges before analysis by enzyme
immunoassay (EIA).
Whole placental villi incubation
Placental tissues from seven preeclamptic women and seven normal
pregnant women were incubated as described previously and validated
(21
, 22)
. Briefly, placental tissue was gently separated
by sterile dissection from different cotyledons, excluding chorionic
and basal plates, minced with scalpel blades, and washed repeatedly
with 0.9% sodium chloride to remove blood from the intervillous space.
Whole villous tissue (350 mg/well) was incubated in 6-well 35 mm
polystyrene tissue culture dishes in 7 ml of serum-free Dulbecco’s
modified Eagle’s medium (DMEM; Life Technologies, Inc. BLR, Grand
Island, N.Y.) for 48 h at 37°C in an incubator gassed with air
and 5% CO2 (CH/P Tri Gas Processor incubator,
Forma Scientific, Inc., Marietta, Ohio). Placental tissues were
incubated in duplicate for each treatment. Medium samples were
collected after 48 h and stored at -20°C. The placental tissue
from each well was collected and frozen at -80°C for protein
analysis.
Protein assay
Tissue protein concentrations were measured by the Coomassie
blue dye binding method. Coomassie Plus protein assay reagent was
purchased from Pierce Chemical Company (Rockford, Ill.). Bovine serum
albumin was diluted in PBS for the standard curve.
Isolated human placental cotyledon perfusion
This methodology was used as described previously and validated
(23
, 24)
. Placentas were obtained from six normal pregnant
women. A chorionic plate artery leading to a single placental cotyledon
and a chorionic plate vein draining the cotyledon were catheterized and
perfusion was begun immediately. Krebs-Ringer bicarbonate (KRB) buffer
gassed with 95% O2, 5% CO2 and
warmed to 37°C was used for perfusion. The composition of the KRB
buffer was 125 mmol/l NaCl, 4.5 mmol/l KCl, 0.2 mmol/l
Na2HPO4, 0.7 mmol/l
NaH2PO4, 2.5 mmol/l
CaCl2, 1.0 mmol/l MgSO4,
4.4 mmol/l glucose (80 mg%), 29.8 mEq/l NaHCO3.
The placenta was placed in a water-jacketed perfusion chamber warmed to
37°C by a Haake constant temperature circulating water bath (Haake
model D1L, Fisher Scientific Co., Pittsburgh, Pa.). To continuously
monitor the perfusion pressure, the fetal arterial catheter was
connected to a pressure transducer connected to a Transbridge TBM 4
transducer amplifier connected to a MP100WS data acquisition
workstation (World Precision Instruments, Inc., Sarasota, Fla.). A
Macintosh computer was used with AcqKnowledge waveform data analysis
software (World Precision Instruments). The fetal side of the cotyledon
was perfused at a rate of 2–4 ml/min to adjust the starting fetal side
perfusion pressure to ~30 mmHg. The intervillous space on the
maternal side of the cotyledon was perfused at a rate of 6–7 ml/min by
placing a butterfly needle attached to a catheter underneath the basal
plate. Two Masterflex multichannel pumps were used for perfusion
(Cole-Parmer Instrument Co., Chicago, Ill.). Treatment perfusion
solutions were perfused for 20 min periods. Maternal and fetal effluent
samples were collected during the last 5 min of each perfusion period
and the effluent flow rates were recorded. Five milliliters of each
sample were evaporated under vacuum centrifugation (SpeedVac
Concentrator, Savant Instruments, Holbrook, N.Y.) and then
reconstituted with ultrapure water to 0.5 ml. Samples were stored at
-20°C. Oxygen consumption and carbon dioxide production were
calculated to verify viability of the placental cotyledon. After each
experiment, Crystal Violet dye was injected into the fetal arterial
catheter in order to verify the cotyledon that was perfused. Placental
secretion rates were calculated by multiplying the concentrations in
either the fetal or maternal effluent by their respective effluent
perfusion flow rates. Placental vascular resistance was calculated by
dividing the chorionic plate arteriovenous pressure difference by the
fetal effluent flow rate.
Isoprostane EIA
Isoprostane was measured by a commercially available EIA kit
(Cayman Chemical, Ann Arbor, Mich.). The antibody was highly specific
for 15-F2t-IsoP (8-Iso
PGF2). The range of the standard curve was from
3.9 to 500 pg/ml. Samples were assayed at 50 µl after a 1:10 or 1:20
dilution. The samples were read at 420 nm in a 96-well Spectra
Microplate Autoreader (Tecan, Research Triangle park, N.C.). Serial
sample dilutions were parallel to the standard curve. Within- and
between-assay variations were < 10%. Analysis of
15-F2t-IsoP by EIA was confirmed by gas
chromatography-mass spectrophotometry (GC-MS). The correlation
coefficient for medium samples analyzed by EIA vs. GC-MS was
r = 0.969.
Malondialdehyde (MDA) assay
Lipid peroxides were estimated by an improved analysis of
malondialdehyde for human body fluids (25)
. A sample size
of 200 µl was used. Tetramethoxypropane was used to generate MDA for
the standard curve. BHT was added to prevent oxidation during the
heating step with thiobarbituric acid. The n-butanol extracts of
standards and samples were pipetted into 96-well microplates and the
difference in absorption at 530 nm and 570 nm was measured in a
spectrophotometer (Spectra Microplate Autoreader, Tecan). Serially
diluted samples were parallel to the standard curve and within- and
between-assay variations were < 10%.
Statistical analysis
Normally distributed data were analyzed by the unpaired
t test or analysis of variance (random complete block), and
non-normally distributed data by the Mann-Whitney Rank Sum test or the
Kruskal-Wallis test. A statistical computer software program was used
(StatView, SAS Institute Inc., Cary, N.C.). A probability level of
P < 0.05 was considered significant. Data are presented as
the mean ± SE.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, P<0.01). Levels for esterified
15-F2t-IsoP averaged 602 ± 107 pg/g for
preeclamptic tissue and 411 ± 80 pg/g for normal tissue
(P<0.2). Tissue levels of total
15-F2t-IsoP averaged 1038 ± 142 pg/g for
preeclamptic pregnancy and 669 ± 84 pg/g for normal pregnancy
(Fig. 1
, P<0.05). Tissue levels of
15-F2t-IsoP were not affected by the mode of
delivery (P>0.9).
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Release of 15-F2t-IsoP from placental explants in
culture was predominantly free 15-F2t-IsoP
(93%), with a smaller amount representing
15-F2t-IsoP still esterified in phospholipids
(7%). Placental production of free 15-F2t-IsoP
was significantly higher for women with preeclampsia than for normally
pregnant women. Figure 2
shows representative time courses of the concentrations of free
15-F2t-IsoP in the medium of placental explants
from a woman with normal pregnancy and a woman with preeclampsia.
Concentrations of 15-F2t-IsoP increased
progressively during the 48 h incubation period. After 48 h
of incubation, the average concentrations of free
15-F2t-IsoP for placental explants averaged
15.8 ± 2.7 ng/mg protein for the preeclamptic group
(n=7), but only 6.5 ± 0.6 ng/mg protein for the normal
group (n=7) (P<0.01).
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To determine whether oxidative stress would stimulate the production of
15-F2t-IsoP, tissue explants from a normal
placenta were incubated for 48 h with or without xanthine (X, 0.5
mM) plus xanthine oxidase (XO, 0.005 units/ml). Xanthine oxidase
generates the superoxide anion during enzymatic conversion of xanthine
to uric acid. The X + XO treatment increased free
15-F2t-IsoP production by explants from the
normal patient to a rate that was equivalent to that of explants from
preeclamptic patients (Fig. 3
). After 24 h of incubation, the concentration for control explants
was 6.3 ng/mg protein and 14.1 ng/mg protein for the X + XO-stimulated
explants. After 48 h, the levels were 10.6 ng/mg for control and
19.7 ng/mg for X + XO.
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The placental production rate of lipid peroxides, as estimated by MDA,
was significantly higher for placental explants from preeclamptic women
than for placental explants from normal pregnant women. Concentrations
of MDA increased progressively for both preeclamptic and normal groups
during 48 h of incubation similar to concentrations of
15-F2t-IsoP (Fig. 4
). After 48 h, the concentrations of MDA averaged 6.0 ± 1.2
µmol/mg protein for explants from preeclamptic women (n=7)
and 2.2 ± 0.4 µmol/mg protein for explants from normal pregnant
women (n=7) (P<0.01). The concentrations of MDA
in the medium were highly correlated with the concentrations of
15-F2t-IsoP (r=0.978).
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Free 15-F2t-IsoP was secreted by isolated
placental cotyledons of normal placentas into the maternal and fetal
effluents, but the secretion rate into the maternal effluent was
significantly higher than the rate into the fetal effluent (Fig. 5
). The secretion rate toward the maternal side of the placental
cotyledon was 1.03 ± 0.49 ng/min as compared to the secretion
rate toward the fetal side of 0.13 ± 0.02 ng/min
(P<0.01, n=6). To determine whether
15-F2t-IsoP secretion could be stimulated acutely
and could be correlated with placental perfusion pressure and vascular
resistance, isolated cotyledons of normal placentas were perfused with
control buffer or t-butyl hydroperoxide (100 µmol/l) for 20 min
periods (n=6). Compared to the initial control perfusion
(C-1), perfusion with t-butyl hydroperoxide (Px) significantly
increased the secretion rate of free 15-F2t-IsoP
on the maternal side of the placental cotyledon by sixfold (1.03±0.49
vs. 6.48±2.87 ng/min, P<0.05), and on the fetal side by
almost twofold (0.133±0.023 vs. 0.213±0.041 ng/min,
P<0.05) (Fig. 6
). Secretion rates returned to control levels when t-butyl hydroperoxide
was discontinued. Perfusion with t-butyl hydroperoxide also
significantly increased perfusion pressure of the placental cotyledon.
Compared to the initial control, perfusion pressure increased from
30.4 ± 1.6 to 46.8 ± 3.2 mmHg (P<0.01).
Increases in the maternal and fetal secretion rates of
15-F2t-IsoP were significantly and positively
correlated with the increase in perfusion pressure, r =
0.544 and r = 0.547, respectively (P<0.05).
Vascular resistance was also significantly increased by perfusion with
t-butyl hydroperoxide (12.7±1.0 for C-1 vs. 24.5±4.0 mmHg±min/ml for
Px, P<0.01). The increases in perfusion pressure and
vascular resistance returned to control levels after discontinuation of
t-butyl hydroperoxide.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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.
Placental tissue explants produced isoprostane progressively during a
48 h incubation period. Concentrations of
15-F2t-IsoP in the medium at 48 h of
incubation were 2.4-fold higher for preeclamptic tissue explants than
for normal tissue explants. Placentas of preeclamptic women are
characterized by an increase in oxidative stress (22
, 27)
.
It was therefore of interest to determine whether normal placental
tissue exposed to oxidative stress would be stimulated to produce
isoprostane. We found that placental explants from a normal placenta
exposed to the superoxide anion generated by xanthine plus xanthine
oxidase produced 15-F2t-IsoP at a rate equivalent
to that of placental explants from preeclamptic women. This suggests
that the increase in isoprostane in preeclampsia occurs because of
oxidative stress.
To further study the relationship between oxidative stress and isoprostane in the human placenta, we also measured MDA, a breakdown product of oxidized lipids and a commonly used indicator of lipid peroxidation. Concentrations of MDA in the medium increased in a progressive manner during 48 h of incubation in a pattern similar to that observed for 15-F2t-IsoP. After 48 h, the medium concentrations of MDA were 2.7-fold higher for the placental explants from preeclamptic women than for the placental explants from normal pregnant women. Concentrations of MDA in the medium were highly correlated with 15-F2t-IsoP. The correlation coefficient ‘r’ was 0.978, demonstrating an extremely close association between placental lipid peroxidation and the production of isoprostane.
We used the isolated perfused placental cotyledon model to determine
whether the human placenta secretes isoprostane.
15-F2t-IsoP was secreted into both the maternal
and fetal effluents of the placental cotyledon, but the secretion rate
toward the maternal side of the cotyledon was eightfold greater than
the secretion rate toward the fetal side. Barden et al.
(19)
have reported that the concentrations of free
isoprostane are significantly higher in the maternal circulation in
women with preeclampsia than normally pregnant women. Our data suggest
that the increase in circulating levels of free isoprostane in women
with preeclampsia could originate from placental secretion.
To determine whether placental secretion of isoprostane was rapidly
responsive to changes in oxidative stress, we perfused placental
cotyledons for 20 min periods with control buffer, then with t-butyl
hydroperoxide to induce oxidative stress, and then with control buffer
again. We previously demonstrated that perfusion of the isolated
placental cotyledon, with t-butyl hydroperoxide leads to a rapid
increase in oxidative stress as evidenced by placental secretion of
lipid peroxides (28)
. Perfusion with t-butyl hydroperoxide
led to a rapid increase in the maternal and fetal secretion rates of
15-F2t-IsoP, with most of the isoprostane being
secreted toward the maternal side. Perfusion with t-butyl hydroperoxide
also caused an increase in the perfusion pressure of the cotyledon that
was correlated with the secretion of 15-F2t-IsoP.
Recently, 15-F2t-IsoP was demonstrated to cause
vasoconstriction in the isolated perfused placental cotyledon
(10)
. These data suggest that increased placental
production of isoprostane could be a cause of increased placental
vasoconstriction in preeclampsia.
In summary, we found that 1) the human placenta contains, produces and secretes 15-F2t-IsoP; 2) the production rate of free 15-F2t-IsoP by placental explants and tissue levels of both free and total 15-F2t-IsoP are significantly higher for placentas obtained from women with preeclampsia than from women with normal pregnancies; 3) the isolated placental cotyledon secretes 15-F2t-IsoP, but the secretion rate toward the maternal side is eightfold greater than toward the fetal side; 4) oxidative stress induced by xanthine plus xanthine oxidase or t-butyl hydroperoxide stimulates production and secretion of 15-F2t-IsoP, which is correlated with placental vasoconstriction. We also found that production by placental explants of malondialdehyde, a breakdown product of lipid peroxides, is significantly higher for placentas from preeclamptic women than for placentas from normal pregnant women, and that MDA is highly correlated with 15-F2t-IsoP. These data suggest that elevated placental levels of isoprostane could contribute to placental vasoconstriction in preeclampsia and that placental secretion of isoprostane into the maternal circulation could contribute to vasoconstriction in maternal vascular beds.
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ACKNOWLEDGMENTS |
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Received for publication August 31, 1999.
Revision received December 2, 1999.
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