Molecular Human Reproduction, Vol. 8, No. 6, 566-573,
June 2002
© 2002 European Society of Human Reproduction and Embryology
Implantation and pregnancy |
Localization of heparanase in normal and pathological human placenta
1 Department of Obstetrics and Gynecology, 2 Department of Oncology and 3 Department of Pathology, Hadassah Hebrew University Hospital, Jerusalem, Israel
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Abstract |
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Degradation of extracellular matrix (ECM) components is critical for invasion. Heparan sulphate proteoglycans are abundant in the ECM of the placenta and the decidua, hence their degradation may disassemble the matrix and facilitate placentation and trophoblast invasion. This study investigates the expression of heparanase in normal and pathological placentation using RT–PCR, in-situ hybridization and immunohistochemistry analysis to detect heparanase in specific cells of the placenta and at the fetal–maternal interface throughout pregnancy. Heparanase was observed in villous cytotrophoblasts (CT), syncytial trophoblasts (ST) and in intermediate trophoblast cell columns in normal first trimester, molar and ectopic pregnancies. The heparanase protein was preferentially expressed in the endothelium of fetal capillaries, and to a much lesser extent in larger fetal vessels. Extravillous trophoblasts (EVT) invading the decidua and the maternal vessels were also heparanase positive. In the second and third trimesters, villous CT remained heparanase positive whereas ST showed variable heparanase expression. EVT invading the placental implantation site were also positively stained. A similar pattern was observed in samples obtained from pre-eclamptic placentae and from placenta accreta. Our results indicate consistent expression of heparanase in normal and abnormal placenta, in small fetal vessels and in a variety of trophoblast subpopulations with different invasive potentials.
heparanase/hydatidiform mole/invasion/placenta/trophoblast
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Introduction |
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The extracellular matrix (ECM) is a heterogeneous mixture of proteins and polysaccharides that surrounds cells, providing physical support for cellular organization. Heparan sulphate proteoglycans (HSPG) are major components of the ECM, interacting with collagen, laminin, fibronectin and various growth factors such as basic fibroblast growth factor (bFGF), vascular endothelial growth factor and platelet-derived growth factor (Wight et al., 1992
; Vlodavsky et al., 1993; Iozzo, 1998; Bernfield et al., 1999). Studies of the involvement of ECM macromolecules in cell attachment, growth and differentiation have revealed a central role of HSPG in embryogenesis, placentation and trophoblast cell invasion (Farach et al., 1987; Carson et al., 1993; Dempsy et al., 2000; Selleck, 2000). Heparan sulphate-degrading endoglycosidase, commonly referred to as heparanase, was first detected in the human placenta (Klein and Von Figura, 1976) and later in cytotrophoblasts, skin fibroblasts, hepatocytes, endothelial cells, platelets, neutrophils and activated lymphocytes (Vlodavsky et al., 1992; Goshen et al., 1996; Elkin et al., 2001; Parish et al., 2001). Expression of heparanase correlates with the metastatic behaviour of cancer cells (Parish et al., 1987; Nakajima et al., 1988; Vlodavsky et al., 1994). Overexpression of the heparanase cDNA in low metastatic tumour cells confers a high metastatic potential in experimental animals (Vlodavsky et al., 1999). These findings suggested a critical role for heparanase during cell invasion associated with tumour metastasis and angiogenesis (Nakajima et al., 1988; Vlodavsky et al., 1999; Elkin et al., 2001; Parish et al., 2001).
Remodelling of the ECM takes place during implantation and trophoblastic invasion of the uterine wall (Cross et al., 1994). ECM-degrading proteinases, such as matrix metalloproteinase-9 and urokinase-type plasminogen activator regulate placental development (Librach et al., 1991; Zhang et al., 1996). Similar enzymatic mechanisms are shared by trophoblastic and malignant cells in the invasive process (Yagel et al., 1988; Murray and Lessey, 1999), but are employed in a highly concerted manner only in the trophoblast. The role of heparanase in the process of normal placentation is largely unknown. However, in light of its abundance in the placenta (Vlodavsky et al., 1999; Dempsey et al., 2000; Kizaki et al., 2001), it may play a role in trophoblastic invasion and ECM disintegration. Heparanase was isolated and purified from placental specimens (Klein and Von Figura, 1976; Goshen et al., 1996) and was further characterized to resemble the heparanase expressed by highly malignant tumour cells (Hulett et al., 1999; Vlodavsky et al., 1999). Using primary cytotrophoblast cultures, heparanase activity has been analysed by employing metabolically sulphate-labelled ECM as a natural substrate. Heparanase was highly active in lysates of cytotrophoblasts, and this activity resulted in the release of ECM-bound bFGF (Goshen et al., 1996). The cloning of human heparanase cDNA and its mRNA expression in various tissues including the placenta has been described (Hulett et al., 1999; Kussie et al., 1999; Toyoshima and Nakajima, 1999; Vlodavsky et al., 1999; Dempsey et al., 2000; Kizaki et al., 2001). Localization studies of the heparanase protein using monoclonal antibodies have identified the protein in cytotrophoblasts, syncytiotrophoblasts and in extravillous trophoblast cells of third trimester placenta (Dempsey et al., 2000). In continuation of these studies, we investigated the expression of heparanase in first, second and third trimester placenta, as well as in abnormal pregnancies such as hydatidiform mole, ectopic pregnancy, placenta accreta and pre-eclampsia.
Hydatidiform molar pregnancies are commonly characterized by uncontrolled trophoblastic invasion. Diploid, androgenic complete hydatidiform moles (CHM) are frequently more invasive then triploid partial hydatidiform moles (PHM). Penetration of the uterine wall and distant metastasis occur in 15% of CHM compared to only 1% of PHM. The cellular mechanisms that participate in molar trophoblastic invasion have not been fully explored (Bernischke and Kaufmann, 1995).
Benign ectopic pregnancies are another example of uncontrolled trophoblastic invasion. Tubal pregnancy occurs in one out of 70 human pregnancies. Implantation of trophoblastic tissue in the tubal wall takes place in an environment devoid of glandular decidua. For this reason, the ectopic placenta at the tube is also accreta.
Placenta accreta is a known severe obstetric complication that leads to failure of placental separation and post-partum haemorrhage. The uncontrolled penetration of the trophoblasts deep into the myometrium is attributed to absence of the normal decidua and of the Nitabuch membrane at the placental bed (Bernischke and Kaufmann, 1995).
Evidence that implicates the placenta as a source of pre-eclampsia centres on the abnormal trophoblast–uterine interaction manifested as a defect in the morphology of the placental bed (Zuspan et al., 1988). In pre-eclampsia, invasive trophoblasts are fewer in number and the invasion is relatively shallow. The maternal vessels do not undergo remodelling and render the placenta hypoxic (Gerretsen et al., 1981; Redman, 1991).
The present study was undertaken to analyse heparanase localization in vivo in a prospective design with stereological tissue sampling from normal and abnormal placenta. The main objective was a systematic evaluation of heparanase expression in villous and extravillous trophoblastic subpopulations within the basal plate, placental bed and maternal vessels.
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Materials and methods |
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Study design
Prospectively collected formalin-fixed, paraffin-embedded and cryostat sections of placental tissue were analysed by immunostaining with a monoclonal anti-human heparanase antibody and by in-situ hybridization. The localization of heparanase was evaluated in the different fetal and maternal cellular subpopulations. The histopathological analysis was performed by systematic analysis of different locations separately, i.e. the villous part of the placenta, the villi anchoring to the basal plate and the placental bed including the maternal vessels. Heparanase expression within sections was classified as positive or negative regardless of the staining intensity.
Tissue preparation
Tissue specimens from 20 first and second trimester normal intrauterine pregnancies (gestational age 6–20 weeks) and four complete and four partial moles (gestational age 6–14 weeks) were collected from elective pregnancy terminations by stereological random sampling. The intrauterine molar and normal placental tissue was first evacuated. Secondly, a deep scraping was done until muscle sound to achieve maternal tissue from the basal plate and placental bed encompassing decidua with interstitial trophoblastic invasion. Afterwards, 10–15 tissue blocks were randomly chosen and fixed in formalin overnight at random orientation. The tissue samples from the four complete and four partial moles had previously been analysed to document the molar chromosomes and parental origin. Tissue specimens from five unruptured ectopic pregnancies (gestational age 6–9 weeks) were surgically removed including the entire Fallopian tube and the pregnancy. After overnight fixation in formalin, consecutive cross-sections of the tube were performed. Ten placentas from third trimester normal pregnancies were obtained after normal or Caesarean delivery from patients with uncomplicated pregnancies and with no prepregnancy medical problems. Ten placentas from third trimester pregnancies with pre-eclampsia were obtained after normal or Caesarean delivery. All the work was performed in accordance with the protocol of the Human Subjects Committee approved by our institution. The primiparous patients suffering from pre-eclampsia were diagnosed as severe pre-eclampsia according to established criteria (American College of Obstetrics and Gynaecology, 1996): hypertension >160 mmHg systolic or >110 mmHg diastolic, proteinuria >5 g protein in 24 h urine collection and/or intrauterine growth factor of the fetus <10th percentile for gestational age. Tissue specimens from two patients diagnosed with placenta accreta by histopathological examination were obtained after hysterectomies.
RT–PCR
RNA was isolated with TRizol (Life Technologies) according to the manufacturer's instructions and was quantified by UV absorption. After reverse transcription of 500 ng total RNA by oligo(dT) priming, the resulting single-stranded cDNA was amplified using Taq DNA polymerase and buffer (Promega). Oligonucleotide primers HPU-355 (5'-TTCGATCCCAAGAAGGAATCAAC-3') and HPL-229 (5'-CTAGTGATGCCATGTAACTGAATC-3') were used. The PCR conditions were an initial denaturation of 4 min at 94°C and subsequent denaturation for 45 s at 94°C, annealing for 1 min at 60°C and extension for 1 min at 72°C, for 26 cycles. Aliquots of 10 µl of the amplification products were separated by 1.5% agarose gel electrophoresis and visualized by ethidium bromide staining. Only RNA samples that gave completely negative results in PCR without reverse transcription were further analysed.
In-situ hybridization
A 618bp fragment of human heparanase was subcloned, linearized and used as a template for in-vitro transcription of antisense or sense (control) riboprobes using T7 and T3 RNA polymerase (Promega, Madison, WI, USA), respectively as described (Friedmann et al., 2000). Riboprobes were labelled with digoxigenin labelling mix (NTP labelling mixture; Boehringer–Mannheim, Mannheim, Germany). In-situ hybridization was performed as described previously (Friedmann et al., 2000). Briefly, 5 µm sections were mounted on SuperFrost Plus slides (Manzel–Glaser, Braumschweig, Germany), dewaxed and rehydrated. Sections were first denatured with 0.2 N HCl for 10 min and then digested with proteinase K (20 µg/ml) at 37°C for 30 min. Digestion was stopped with two changes of H2O and slides were prehybridized and hybridized. Washes after hybridization, incubation with anti-digoxigenin antibodies and colorimetric detection were performed as described above (Friedmann et al., 2000).
Immunohistochemistry
Immunohistochemistry was performed as previously described (Friedmann et al., 2000). Briefly, 5 µm sections were deparaffinized and rehydrated. Tissue was then denatured for 3 min in a microwave oven in citrate buffer (0.01 mol/l, pH 6.0). Blocking steps included successive incubations in 0.2% glycine, 3% H2O2 in methanol and 5% normal horse serum. The first two steps were followed by two washes in phosphate-buffered saline (PBS). Sections were incubated with a monoclonal anti-human heparanase antibody (mAb 92.4 diluted 1:20), or with DMEM medium supplemented with 10% horse serum as control, followed by incubation with biotinlated secondary horse anti-mouse IgG + IgM antibody and for 30 min with avidin–biotin peroxidase conjugate (1:50 dilution) (Vectastain Elite Universal kit: Vector Laboratories, Burlingame, CA, USA). mAb 92.4 is directed against the N-terminus region of the 45 kDa enzyme. As such, this monoclonal antibody detects both the latent and the active forms of the enzyme. The preparation and specificity of this mAb were previously described and demonstrated (Vlodavsky et al., 1999). Colour was developed using either Sigma Fast 3,3-diaminobenzidine tablet sets (Sigma, St Louis, MO, USA) or Zymed AEC substrate kit (Zymed, South San Francisco, CA, USA) for 10 min followed by counterstain with Mayer's haematoxylin.
Western blot analysis
Freshly taken third trimester placental tissue was homogenized in lysis buffer and the supernatant fraction was applied onto CM Sepharose (Pharmacia Fine Chemicals AB, Uppsala, Sweden). Partially purified material was eluted from CM-Sepharose and separated on 10% sodium dodecyl sulphate–polyacrylamide gel electrophoresis, as described (Friedmann et al., 2000). Proteins were transferred to an Immobilon-P membrane (Millipore, Bedford, MA, USA), followed by successive incubations with block solution, anti-heparanase monoclonal antibodies in 1% bovine serum albumin, 10 mmol/l Tris–HCl, pH 7.5, 100 mmol/l NaCl, and 0.05% Tween-20, and horse-radish peroxidase-conjugated anti-mouse antibodies (Jackson Laboratories, Bar-Harbor, ME, USA), as previously described (Vlodavsky et al., 1999). Immunoreactive bands were detected by the enhanced chemiluminescence (ECL) reagent using luminol and p-cumaric acid (Sigma). The light emitted by the chemical reaction was detected by exposure to Hyperfilm ECL (Amersham Pharmacia Biotech, Uppsala, Sweden) for 30 to 120 s.
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Results |
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RT–PCR was applied to evaluate the expression of the heparanase gene by placental tissue (normal and molar) as well as human cytotrophoblastic cells. For this purpose, total RNA was reverse-transcribed and amplified using appropriate human heparanase primers and primers for the GAPDH housekeeping gene [Figure 1a
(A and B)]. The expected 585 bp cDNA was clearly demonstrated in all three cases. Reactions without reverse transcriptase, demonstrating the absence of genomic DNA contamination in RNA samples, are shown in Figure 1a (C).
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Localization of heparanase in villous first trimester placenta
The localization of heparanase in the fetal cellular subpopulations in intrauterine, ectopic and molar pregnancies is summarized in Table I
. Heparanase positive staining was seen in the cytotrophoblast–syncytiotrophoblast bilayer covering the chorionic villous core (Figure 2a,b). A similar pattern, albeit reduced expression in the syncytiotrophoblast compared with the cytotrophoblast layer, was detected by immunohistochemistry and by in-situ hybridization, indicating a general co-expression of the heparanase mRNA and protein (Figure 2). The intermediate trophoblast cells that form cell columns were also heparanase positive. A polarized pattern of staining could be appreciated in the cell column, where maximal staining was noticed at its margins (Figure 2b). Developing fetal vessels within first trimester villi were heparanase positive (Figure 2a). Heparanase staining was negative in Hofbauer cells of the chorionic villous stroma (Figure 2a,b). No staining was detected when normal mouse serum was applied instead of the anti-heparanase antibodies (Figure 2c). The specificity of the anti-heparanase antibodies used for immunostaining was confirmed by Western blot analysis of placental tissue, showing both the latent 65 kDa and active 50 kDa heparanase enzyme (Figure 1b
). In partial and complete hydatidiform molar placenta, the cytotrophoblasts and the multinucleated syncytiotrophoblast lining the hydropic villi were heparanase positive. The highly proliferating molar intermediate trophoblasts within the polypoid cell islands and columns were also heparanase positive (Figure 3a,b). Villous trophoblastic heparanase expression did not differ between normal, ectopic and partial or complete molar pregnancies.
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Localization of heparanase in villous normal placenta during pregnancy
The localization of heparanase in villous normal placenta during pregnancy is summarized in Table II
. In the second trimester, the multinucleated syncytial trophoblasts gradually outnumber the cytotrophoblasts lining the intervillous space. Both trophoblastic subpopulations remained heparanase positive (Figure 4a,b), although heparanase expression in the syncytial trophoblasts was less pronounced than in the cytotrophoblasts (Figure 4b). Likewise, heparanase staining remained unchanged in the intermediate trophoblast cells within cell islands and columns (Figure 4a). In the third trimester the placenta is characterized by abundance of terminal villi, located at the distal ends of the villous tree. They comprise a stroma rich in heparanase-positive fetal capillaries, lined by a bilayer of cytotrophoblasts and syncytiotrophoblasts. Reduced heparanase protein expression in the syncytiotrophoblast compared with the cytotrophoblast layer was detected by immunohistochemistry (Figure 4c,d). Heparanase mRNA expression was also observed in the villous trophoblasts of third trimester placenta (Figure 4e,f).
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An interesting pattern of staining was noted in endothelial cells comprising blood vessels of different size and maturation stage. It appeared that the heparanase protein is preferentially expressed in capillaries (Figures 2a and
4c,d), whereas the endothelium of larger, muscularis-enveloped, quiescent vessels showed little or no staining of heparanase (Figure 4d).
Localization of heparanase in the basal plate and placental bed during pregnancy
The localization of heparanase in the basal plate and placental bed during pregnancy is summarized in Table III. Within the first trimester basal plate samples, heparanase staining appeared positive in single cell extravillous interstitial trophoblasts invading the decidua and in extravillous trophoblasts during endovascular invasion (Figure 5a). Heparanase staining was positive in all endometrial glandular cells. Decidual stromal cells were heparanase negative (Figure 5a). In the superficial part of the basal plate of third trimester placenta, aggregating heparanase-positive extravillous trophoblasts were consistently observed within areas of maternal cells and fibrinoid deposits in the maternal–fetal junctional zone (Figure 5b). In cases of placenta accreta, in the absence of a decidual layer, heparanase-positive extravillous trophoblasts were observed invading the myometrium (Figure 5c).
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Localization of heparanase in the placenta and decidua in pre-eclampsia
Villous trophoblastic heparanase expression did not differ between normal and pre-eclamptic pregnancies. Samples of the placental implantation site in pre-eclampsia exhibited aggregates of heparanase-positive extravillous trophoblasts invading the decidua at the fetal–maternal junction.
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Discussion |
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The enzymatic activity of heparanase was first described in human placenta (Klein and Von Figura, 1976
). Since then, the placenta has been considered as a rich source of heparanase activity primarily originating from the trophoblast cell lineage (Goshen et al., 1996). Recently, a few studies investigating heparanase localization in the trophoblast subpopulations in human and bovine placentae have been published (Dempsey et al., 2000; Kizaki et al., 2001).
In the present study, heparanase was observed in villous cytotrophoblasts, syncytial trophoblasts and intermediate trophoblasts comprising cell columns and islands throughout the three trimesters of human gestation. Variable heparanase protein and mRNA expression was detected in the syncytial trophoblasts throughout pregnancy, suggesting transcriptional and enzymatic decay in those cells. Individual extravillous interstitial trophoblasts deeply located within the decidua and in the placental bed were heparanase positive throughout pregnancy. A similar pattern of expression was observed both at the mRNA and protein levels, indicating that the heparanase gene and protein are co-expressed. These results are in agreement with the findings of others. One study (Goshen et al., 1996) found the same heparanase activity in cytotrophoblast cells harvested from first and third trimester placenta. Another (Dempsy et al., 2000) reported heparanase expression by immunofluoresence staining using monoclonal antibodies in third trimester human placenta in both villous cytotrophoblasts and syncytiotrophoblasts and in extravillous trophoblasts. A third study (Kizaki et al., 2001) investigated the bovine placenta, comprising the fetal cotyledon and maternal caruncle, and detected heparanase mRNA expression in the cotyledon and in binucleate cell-rich fraction. The finding that heparanase protein was detected during all gestational stages may be surprising, given the fact that term placenta possesses less invasive characteristics than first trimester placenta. However, previous studies support the view that third trimester cytotrophoblasts maintain their invasive properties and even provide a model system for studying ECM attachment, proteolysis and invasion (Kliman and Feinberg, 1990; Shimonovitz et al., 1994).
The heparanase protein was preferentially expressed in fetal capillaries and small villous blood vessels, whereas the endothelium of adjacent mature, medium-sized vessels showed little or no detectable heparanase. Similarly, immunohistochemical staining of human tumours (colon, breast, pancreas) has revealed a high expression of the heparanase protein in the endothelium of sprouting capillaries, but not of mature quiescent vessels, suggesting up-regulation of the heparanase gene and protein in activated endothelial cells of angiogenic blood vessels (Elkin et al., 2001). These results suggest a significant role of endothelial heparanase in sprouting fetal vessels.
Given the detection of the heparanase protein in a variety of invasive as well as non-invasive trophoblast cell subpopulations, we may speculate that tight regulatory mechanisms control enzyme activity at the protein level. Heparanase activity could be regulated by microenvironmental conditions such as local pH, being optimal between pH 5.0 and 6.5, and decreasing at neutral pH (Gilat et al., 1995; Freeman and Parish, 1998). Additional mechanisms may exist to control heparanase activity, such as the presence of polysaccharides (Parish et al., 1987, 2001; Miao et al., 1999), or competing proteins that block the enzyme access to its substrate. Heparan sulphate-interacting protein (HIP), first identified in uterine epithelial cells, antagonizes heparan sulphate degradation by heparanase, presumably by competing for the same binding recognition site in the glycosaminoglycan chain (Liu et al., 1997; Marchetti et al., 1997). Activation of a latent heparanase into an active form is also under investigation. Conversion of the pro-enzyme into an active enzyme provides an attractive means by which heparanase-mediated cleavage of heparan sulphate is regulated at the protein level, under physiological and pathological conditions (Fairbanks et al., 1999). Expression of the cloned cDNA of the heparanase gene in mammalian cells yielded 65 and 50 kDa recombinant proteins, exhibiting heparanase activity (Vlodavsky et al., 1999). The 50 kDa enzyme represents an N-terminal processed enzyme that is at least 200-fold more active than the full-length 65 kDa form (Vlodavsky et al., 1999). N-terminus amino acid sequencing of the active enzyme indicates that the actual cleavage site is Glu157-Lys158 (Hulett et al., 1999). Processing has been readily demonstrated during incubation of the full-length recombinant enzyme with intact tumour cells (Vlodavsky et al., 1999). A proteolytic activation of a pro-enzyme is a common feature of enzymes (e.g. metalloproteinases, plasminogen activators) involved in degradation of ECM proteins and in cell invasion (Stetler-Stevenson, 1999; Vlodavsky et al., 2000). Differential immunostaining of the 65 kDa versus the 50 kDa heparanase enzyme is necessary to distinguish between expression of the latent and active forms of heparanase during the various gestational stages and in abnormal situations. Unfortunately, differential detection of the active 50 kDa enzyme could not be achieved by the presently available anti-heparanase antibodies.
Whether molar trophoblasts are more invasive than normal trophoblasts or if they merely represent de-differentiated phenotypes is still debated. The intermediate trophoblasts are the subcellular phenotype thought to be the most essential for invasion of the decidua, myometrium and maternal vessels (Shih and Kurman, 1997). The present study demonstrated heparanase expression in both normal, non-proliferating villous trophoblasts as well as in molar, highly proliferating villous and extravillous intermediate trophoblasts. A similar pattern of heparanase expression was observed in intrauterine and extrauterine pregnancies. The effect of the lack of decidua on the enzymatic mechanisms involved in invasion is yet to be investigated. A lack of a rich glandular decidua at the tube did not influence heparanase expression in villous and extravillous trophoblastic subpopulations. Likewise, in placenta accreta, the absence of decidual basal plate did not affect heparanase expression in invading extravillous trophoblasts. Hence, neither molar trophoblastic differentiation nor placental penetration site appear to affect the heparanase pattern of expression.
Mechanisms involved in proteolytic degradation of the ECM have been investigated with respect to the defective trophoblastic invasion in pre-eclampsia. Differential expression of gelatinase-B has been demonstrated in pre-eclampsia compared with normal placenta (Shimonovitz et al., 1994, 1998). In this study, heparanase detection in villous and extravillous trophoblasts in pre-eclampsia did not differ from that in normal pregnancy. Hence, we could not view heparanase expression in invasive trophoblasts as a major factor in the defective process of placentation in pre-eclampsia.
Our results indicate a broad array of heparanase expression from non-invasive villous trophoblasts to highly invasive extravillous trophoblasts. The consistent pattern of heparanase localization in several abnormal conditions, such as molar and ectopic pregnancies as well as placenta accreta and pre-eclampsia, is suggestive of a central role of heparanase in placental development and trophoblastic invasion, and calls for further investigation of the regulation of heparanase expression, processing and activity.
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This work was supported by grants from the Hadassah Medical Organization for research of women's health, Hadassah University Hospital, Jerusalem, and from the Israel Science Foundation.
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4 To whom correspondence should be addressed at: Department of Obstetrics and Gynecology, Hadassah University Hospital, Mount Scopus, P.O.Box 24035, il-91240, Jerusalem, Israel. E-mail: syagel{at}hadassah.org.il
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Submitted on July 20, 2001; resubmitted on November 28, 2001; accepted on February 18, 2002.
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