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§
From the Departments of Obstetrics, Gynecology, and Reproductive
Sciences,*
Stomatology,
Pharmaceutical Chemistry,
and
Anatomy,§
University of California San
Francisco, San Francisco, California
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Both the etiology and the only known cure for this condition involve the placenta. One of the most important risk factors is an increase in placental mass. As a result, women carrying multiple fetuses are prone to development of this syndrome.3 Preeclampsia also can occur in hydatidiform mole, a condition in which genetically abnormal placental tissue (eg, trophoblast) proliferates in the absence of a fetus.4 In all cases the only known cure is removal of the placental tissue. If this is done before term, however, it can cause iatrogenic prematurity, further contributing to the morbidity and mortality associated with preeclampsia.
The placenta's role in preeclampsia has been enigmatic. Microscopic analyses of placental specimens from affected patients show that the cellular composition of floating chorionic villi—the subpopulation that floats in maternal blood and mediates gas and nutrient exchange—is relatively unaffected. In contrast, anchoring chorionic villi—the subpopulation that anchors the placenta to the uterine wall—show distinct anomalies.5-8 Normally, the invasive cytotrophoblasts that emanate from these anchoring villi are found in abundance throughout the interstices of the endometrium and the first third of the myometrium. In addition, they deeply invade the uterine spiral arterioles and open the superficial portions of the associated veins, a process that initiates flow of maternal blood to the placenta. In preeclampsia, the interstitial component of invasion is variably compromised, with abnormally shallow invasion most often associated with the appearance of signs in early gestation (Zhou and Fisher, unpublished results). But endovascular invasion is consistently rudimentary. As a result, the flow of oxygenated blood to the fetal-placental unit is reduced.
Our laboratory has been studying the differentiation pathway that
normally leads to cytotrophoblast invasion and the defects in this
process that are associated with preeclampsia. Knowledge of the cells'
ability to intricately switch their adhesion molecule expression during
the invasion process has been instrumental to the progress we have
made. Thus far we know that, as part of the differentiation pathway
that normally leads to endovascular invasion, cytotrophoblasts
down-regulate the expression of adhesion molecules that are indicative
of their epithelial origin (eg, E-cadherin, integrin 
6ß4) and
up-regulate the expression of those that are important for endothelial
cell function (eg, VE-cadherin, integrin Vß3,
1ß1).9
In preeclampsia most aspects of this
transition fail to occur, and undifferentiated, epithelial-like
cytotrophoblast stem cells are found within the uterus.10
Recently we discovered that culturing normal cytotrophoblasts in a
hypoxic atmosphere has the unusual effect of causing them to enter the
cell cycle; this occurs at the expense of some aspects of the
differentiation process, including the ability to up-regulate integrin
1ß1 expression and their own invasiveness.11,12
This
finding suggests one possible mechanism by which a reduction in
maternal blood flow to the placenta could contribute to the altered
placental phenotype associated with preeclampsia. Here we investigated
the consequences of the aberrations we observed by testing the
hypothesis that in preeclampsia, the presence of abnormally
differentiated fetal cytotrophoblasts among the resident maternal cells
of the uterus triggers apoptosis of one or both populations.
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Materials and Methods |
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Placental bed biopsy specimens were collected by direct visualization of the placental attachment site. Chorionic villi with attached decidua were dissected from three to five randomly chosen placental sites immediately after elective terminations or delivery. Nine control samples were obtained from women who were between 26 and 40 weeks of gestation. Of these, two samples were obtained from women who were delivered at 26 weeks, one because of cervical incompetence and the other because of inoperable conjoined twins. Seven specimens were obtained from control nulliparous women who underwent Cesarean sections at 33 (one), 34 (one), 35 (one), or 38 weeks of gestation (one) or delivered spontaneously at 39 (two) or 40 weeks (one). None of the control subjects had evidence of preeclampsia, gestational hypertension, chorioamnionitis, or chronic hypertension or a medical history that suggested they were at risk for developing preeclampsia.
Nine samples were obtained from preeclamptic patients at 26–39 weeks
of gestation. Preeclampsia was diagnosed according to the following
criteria, recommended by Chesley13
: nulliparity; no
history of hypertension before pregnancy; increase in diastolic
pressure of 15 mm Hg or systolic pressure of 30 mm Hg compared with
blood pressure obtained before 20 weeks of gestation; proteinuria
0.3 g/24 hours (or 1+ on urine dipstick) in a catheterized specimen;
hyperuricemia >5.5 mg/dl (or one SD greater than the normal mean
value before term); and return to normal blood pressure and resolution
of proteinuria by 12 weeks postpartum. Severe preeclampsia was
diagnosed according to the following criteria, recommended by the
American College of Obstetrics and Gynecology: systolic blood pressure
160 mm Hg and/or diastolic pressure 110 mm Hg; proteinuria of 5 g
in a 24-hour period or 3+ on urine dipstick; and presence of cerebral
or visual disturbances. Seven patients were diagnosed with severe
preeclampsia and were delivered by Cesarean section (one each at 27,
28, and 31 weeks; two at 26 and 32 weeks); two with preeclampsia had
vaginal deliveries (38 and 39 weeks).
Detection of Apoptotic Cells
Samples were processed immediately after they were obtained. The tissues were fixed in 3% paraformaldehyde for 30 minutes, infiltrated with 5–15% sucrose, embedded in optimal cutting temperature compound, and frozen in liquid nitrogen as previously described.14 Five to seven sections from three separate tissue blocks were used for detection of apoptosis and immunostaining.
Apoptotic cells were identified by the TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling) method, a commercial kit that fluorescein-labels DNA strand breaks (Boehringer-Mannheim, Indianapolis, IN). To identify trophoblasts among other fetal and maternal cells, TUNEL-stained frozen sections were double stained with a rat monoclonal antibody that specifically reacts with cytokeratin. The antibody was produced in this laboratory by using purified human cytotrophoblasts as the immunogen.15 Antibody binding was detected by using a rhodamine-conjugated secondary antibody as previously described.14 To identify immune and decidual cells, we used primary antibodies that specifically react with either CD45 (DAKO, Carpinteria, CA) or prolactin (Zymed, South San Francisco, CA), respectively, and the species-appropriate secondary antibodies.
The sections were then viewed with a Zeiss Axiophot epifluorescence microscope equipped with filters to selectively view the rhodamine and fluorescein images with no cross-contamination. The number of apoptotic nuclei, observed at a magnification of x400 with an oil immersion lens, was expressed as a percentage of the total number of cytokeratin-positive cells examined from each slide (300–1000). Statistical significance of the data was determined by using Student's paired t-test.
Cytotrophoblast nuclear morphology was also assessed by staining with Hoechst 33342 (Molecular Probes, Eugene, OR). After tissue sections were labeled with anti-cytokeratin, they were rinsed in buffer and placed in the dye (10 µg/ml phosphate-buffered saline) for 2 minutes. After rinsing, immunoreactivity was assessed as described above. Hoechst staining was photographed under ultraviolet illumination.
Detection of Mitotic Cells
Sections immediately adjacent to those used for the detection of apoptotic cells were double stained (1 hour at room temperature) with a mixture of antibody against a specific cell cycle marker and rat anti-cytokeratin. The former included mouse anti-Ki67 (1:200, v/v; Novocastra Laboratories, Newcastle on Tyne, UK), mouse anti-cyclin A (H432) (2 µg/ml; Santa Cruz Biotechnology, Santa Cruz, CA), mouse anti-cyclin B (D-11) (2 µg/ml; Santa Cruz Biotechnology), and rabbit anti-phosphohistone H3 (2 µg/ml; Upstate Biotechnology, Lake Placid, NY). Antibody binding was detected by using the appropriate secondary antibody, and samples were examined as described above.
Detection of Bcl-2–Expressing Cells
Sections immediately adjacent to those used for the detection of apoptotic cells were double stained (2 hours at room temperature) with a mixture of mouse anti–Bcl-2 (5 µg/ml; Oncogene Research Products, Cambridge, MA) and rat anti-cytokeratin. Antibody binding was detected and samples were examined as described above.
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Results |
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In floating villi from either sample population, there was no
evidence of apoptotic nuclei in trophoblast cells; a few stromal cells
(
1%) in the villus cores were randomly labeled (data not shown).
Likewise, in control samples the cytotrophoblast population that arose
from anchoring villi and invaded the uterine wall showed very little
apoptosis. Figure 1
is typical of the
results we obtained. A 26-week sample from the control group contained
an anchoring villus with abundant cytokeratin-positive cytotrophoblasts
below the site of uterine attachment (Figure 1A)
. None of these fetal
cells reacted with TUNEL (Figure 1B)
. Typically, a few
cytokeratin-negative cells per field were labeled. This is in accord
with the work of other investigators who have detected relatively few
apoptotic cells in the human placenta from the first trimester
onward.16
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.
As we and others have previously described,5,8,10
invasion
was limited to the superficial portion of the uterus. TUNEL labeling
showed evidence of widespread apoptosis among the cytotrophoblasts in
this sample (Figure 1D)
and in another specimen from a patient
diagnosed with this syndrome at 31 weeks of gestation (Figure 1F)
. In
these two samples and in one other specimen obtained at 28 weeks (data
not shown), we also observed widespread apoptosis of cells that did not
express cytokeratin. We subsequently investigated the identity of these
cells by staining adjacent sections with antibodies that recognized
either immune (anti-CD45) or decidual cells (anti-prolactin). The
cytokeratin-negative cells that labeled in Figure 1D
expressed CD45
and therefore were primarily derived from the bone marrow, as were
the cells in the 28-week specimen (data not shown). In contrast, the
cytokeratin-negative cells that labeled in Figure 1F
expressed neither
CD45 nor prolactin. Thus we could not determine whether they were
derived from yet another cell lineage or were apoptotic cells that had
degraded the marker proteins we used for identification. In the
remaining samples from preeclamptic patients, only apoptotic
cytotrophoblasts in the uterine wall were observed.
Despite the intense nuclear staining of invasive cytotrophoblasts in
severe preeclampsia, many of the TUNEL-labeled cytotrophoblast nuclei
had relatively normal sizes and shapes, suggesting that they were in
the initial stages of apoptosis (inset, Figure 1D
). Somewhat fewer
labeled cells had condensed, fragmented nuclei (Figure 1F)
. Hoechst
staining demonstrated a similar spectrum of nuclear morphologies
(Figure 2)
. Whereas the nuclei of some
cytokeratin-positive cells had a normal appearance (Figure 2B)
, many
others showed evidence of either chromatin condensation (Figure 2, D and F)
or fragmentation (Figure 2, H and J)
. Previous reports suggest
that apoptotic cells are recognized, ingested, and degraded beyond
histological recognition in 1–2 hours.17,18
Thus, our
data likely suggest that preeclampsia is associated with the sudden
onset of widespread apoptosis of invasive cytotrophoblasts, and
sometimes maternal cells, within the uterine wall.
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summarizes the number of
apoptotic (TUNEL-labeled) invasive cytotrophoblasts that were detected
in tissue samples obtained from control (n = 9)
and preeclamptic (n = 9) patients at 26–40
weeks of gestation. Little or no apoptosis was observed in the control
samples until term, when most of the invasive cytotrophoblasts with
labeled nuclei were localized in the deeper portions of the decidua
(data not shown). In contrast, substantial apoptosis (mean 30.1% ± SD
17.9% of cytotrophoblasts) was observed in eight of nine samples when
the pregnancy was complicated by preeclampsia (P
0.001). There was no correlation with gestational age; the two
highest values, 53% and 54%, were obtained by analysis of samples
obtained at 27 and 38 weeks of gestation, respectively.
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Because other investigators have reported enhanced cytotrophoblast proliferation in preeclampsia,19 we also examined this issue. We localized Ki67 (a nuclear antigen associated with proliferation/S phase), cyclin A (G1-S marker), cyclin B (G2-M marker), and phosphohistone H3 (mitosis marker) in all of our control and preeclampsia samples (data not shown). We saw no difference in the number of mitotic cytotrophoblasts in the two groups, which in all cases was very low. Nevertheless, the possibility exists that enhanced proliferation precedes apoptosis and that different endpoints are detected in samples obtained at different stages during the disease process.
Invasive Cytotrophoblasts Fail to Express Bcl-2 in Preeclampsia
Next, we used sections cut from these same tissue samples to
determine whether preeclampsia is associated with a change in
expression of Bcl-2, an oncoprotein that can suppress programmed cell
death in both normoxic and hypoxic conditions.20,21
In
preliminary experiments we proved antibody specificity (data not
shown); immunoblot analysis of placental villus lysates showed that the
anti–Bcl-2 monoclonal antibody we used reacted with a single band of
the expected molecular weight (Mr
24,000–26,000). We then used this antibody to stain sections of
floating villi found in the placenta proper. As has been shown by other
investigators,22
in control samples intense
immunoreactivity was detected in association with both the
cytotrophoblast layer that is attached to the trophoblast basement
membrane and the overlying fused syncytiotrophoblasts (Figure 4B)
. This pattern did not change when the
placental sample was obtained from a pregnancy complicated by
preeclampsia (Figure 4D)
. We next examined Bcl-2 expression by invasive
cytotrophoblasts that were found within the uterine wall, ie, the
population in which a significant number of cells in preeclamptic
samples were undergoing programmed cell death. In control pregnancies,
groups of cytotrophoblasts stained intensely; a few
cytokeratin-positive cells (20%) did not react with the anti-Bcl-2
antibody (Figure 5B)
. In contrast, no
staining above background was detected in cytotrophoblasts that
invaded the uteri of patients with preeclampsia (eg, Figure 5D
).
Likewise, cytotrophoblasts in the sample from the preeclampsia
patient that showed low levels of apoptosis failed to express Bcl-2.
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Discussion |
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Because many apoptotic cells appear to enter the cell cycle,26-28 the unusual effects of low oxygen on cytotrophoblast mitotic activity could also be relevant to our finding that these cells undergo apoptosis in preeclampsia. Before the cytotrophoblasts reach a supply of maternal blood, they proliferate in the hypoxic environment, near the uterine lumen, of the placenta proper. Within the uterine wall they stop dividing and differentiate along gradients of increasing oxygen tension, which we postulate helps to direct them toward maternal arterioles. Recently we modeled in vitro the situation that happens in preeclampsia. When the cells were confronted with an extracellular matrix in an hypoxic environment, they continued to proliferate while they differentiated, albeit abnormally.12 We hypothesize that prolonging this situation, the likely scenario in preeclampsia, could eventually lead the cells to exit the cycle in G1, directing them toward apoptosis rather than passage into S and mitosis. It would be of great interest to know when, during pregnancy, this cascade of events is initiated. In an attempt to answer this question we collected 100 chorionic villous samples, but none contained the population of invasive cytotrophoblasts that undergo apoptosis in preeclampsia.
Finally, our findings could help explain several well-recognized clinical aspects of this syndrome. For example, preeclampsia is associated with fibrin deposition at the maternal-fetal interface.29 Recent data suggest that phosphatidyl serine, a neoantigen on the surface of apoptotic cells, has potent procoagulant activity.30 Thus it seems likely that cytotrophoblasts undergoing programmed cell death could elicit fibrin deposition, as well as platelet activation, another common feature of preeclampsia.31 It remains to be determined whether this phenomenon is also relevant to the fact that women with anti-phospholipid antibodies have an increased risk of developing preeclampsia.32 Likewise, we do not know whether the effects we observed are limited to the chorion frondosum or spread to the chorion laeve. Currently, we are collecting the appropriate tissue samples to answer this question.
Another unique aspect of the clinical presentation of preeclampsia is its sudden appearance, particularly in patients with the most severe signs. Our findings suggest that the fetal cytotrophoblasts in direct contact with resident uterine cells are undergoing programmed cell death without a compensatory increase in mitosis. As a result, the maternal-fetal interface is likely to rapidly disintegrate. This is in contrast to other pregnancy complications, such as intrauterine growth retardation, which is associated with a comparatively small increase in programmed cell death among placental cells (0.14% versus 0.24%).33 We suggest that apoptosis on the magnitude we observed could have catastrophic consequences for pregnancy, such as the signs observed in preeclampsia.
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Acknowledgements |
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Footnotes |
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Supported by National Institutes of Health grant HD30367.
Drs. DiFederico and Genbacev contributed equally to this work.
Accepted for publication March 13, 1999.
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