Molecular Human Reproduction, Vol. 9, No. 4, 199-203,
April 2003
© 2003 European Society of Human Reproduction and Embryology
Article |
Inhibin, activin, follistatin, activin receptors and ß-glycan gene expression in the placental tissue of patients with pre-eclampsia
Submitted on November 28, 2002; accepted on January 8, 2003
1 Department of Obstetrics and Gynaecology, Royal Free UCL Medical School, 86–96 Chenies Mews, London WC1E 6HX, 2 Department of Haematology, University College London, 88, Chenies Mews, London, 3 Nuffield Department of Obstetrics and Gynaecology, John Radcliffe Hospital, Oxford OX3 9DU, UK
4 To whom correspondence should be addressed at: Department of Obstetrics and Gynaecology, RFUCL Medical School, 86–96 Chenies Mews, London WC1E 6HX, UK. e-mail: s.muttukrishna{at}ucl.ac.uk
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ABSTRACT |
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The objective of this study was to quantify the relative expression of inhibin
, inhibin/activin ßA, ßB, ßC, follistatin, activin receptors and ß-glycan genes in placental tissue of term pre-eclamptic patients and controls to investigate if these genes are up-regulated in the placenta in pre-eclampsia. Seven women with pre-eclampsia symptoms were matched with 10 normal pregnant controls for gestational age, maternal age, and parity. Total RNA was isolated from each sample. Complementary DNA samples produced by reverse transcription were used in the real time PCR to quantify the expression of inhibin subunit, inhibin/activin ßA, ßB, ßC subunits, follistatin, ACTRIA, ACTRIB, ACTRIIA, ACTRIIB, ß-glycan and GAPDH genes. The ratio between the target and GAPDH expression was calculated to provide relative gene expression. Inhibin :GAPDH and inhibin/activin ßA:GAPDH ratios were significantly higher in placental tissue from women with pre-eclampsia (P = 0.04 and P = 0.01 respectively) compared with matched control placental gene expression. Placental samples from both groups expressed ßB, ßC, follistatin, activin receptors and ß-glycan genes. However, there was no significant difference in the relative expression of these genes between the groups. Increases in the placental expression of inhibin and inhibin/activin ßA subunit genes could contribute to the rise in circulating levels of inhibin A and activin A in pre-eclampsia. The mechanism(s) involved in increased gene expression in pre-eclampsia is as yet unclear. Key words: activin/activin receptors/ß-glycan/follistatin/inhibin
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Introduction |
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Inhibins (
–ß dimers) and activins (ß–ß dimmers) are glycoprotein hormones belonging to the transforming growth factor ß super family. Follistatin is a high-affinity activin binding protein. There are two types of activin receptors, ACTRI (A and B) and ACTRII (A and B). ACTRIIA and ACTRIIB are membrane receptors to which activin binds and promotes the recruitment and phosphorylation of type I receptor serine kinase which then regulates gene expression by activating Smad proteins (Carcamo et al., 1994; Attisano et al., 1996). Binding of activin to the Type II receptor stabilizes the receptor complex and activates signal transduction. Inhibin can also bind to Type II activin receptors but it does not activate the receptor complex. Recently, type III TGF-ß receptor ß-glycan was shown to function as an inhibin co-receptor with ACTRII (Lewis et al., 2000). ß-glycan binds inhibin with high affinity and enhances binding in cells co-expressing ACTRII and ß-glycan. ß-glycan also confers inhibin sensitivity to cell lines that otherwise respond poorly to this hormone (Lewis et al., 2000).
We and several others have previously shown that the levels of activin A (ßA–ßA dimers) and inhibin A (–ßA dimers) are significantly elevated in the circulation of women who have developed pre-eclampsia (PE) (Petraglia et al., 1995; Muttukrishna et al., 1997a; Fraser et al., 1998), and in women who subsequently develop pre-eclampsia compared with gestational age-matched control pregnant women (Cuckle et al., 1998; Aquilina et al., 1999; Silver et al., 1999; Muttukrishna et al., 2000). Although circulating levels of follistatin were reported to be unaltered in patients with pre-eclampsia (D’Antona et al., 2000), recently it was reported to be raised modestly in patients with pre-eclampsia compared with controls (Keelan et al., 2002). Several studies have shown that inhibin A and activin A levels are higher in pre-eclamptic patients; the mechanism involved in the rise of these proteins is as yet unclear. Placenta is a source of inhibin/activin subunits, dimeric proteins, follistatin and activin receptors (Petraglia, 1997; Fowler et al., 1998; Peng et al., 1999; Debieve et al., 2000; Manuelpillai et al., 2001). Pro-inflammatory cytokines are potent stimulators of activin A from intrauterine tissues (Keelan et al., 1998). Term placental cells secrete increased levels of inhibin A and activin A in the presence of inflammatory cytokines, which are increased in pre-eclampsia (Mohan et al., 2001). Activin A is produced by peripheral mononuclear cells (Tannetta et al., 2001) and endothelial cells (Schneider-Kolsky et al., 2002).
Pre-eclampsia is a major cause of maternal and fetal morbidity and mortality. It develops in late pregnancy and the cause is as yet unknown. The only treatment for pre-eclampsia is the delivery of the placenta, after which the symptoms regress rapidly suggesting that it is a placental disease. It is associated with poor placentation with incomplete physiological adaptation of the spiral arteries, which prevents them from dilating to accommodate the increased utero-placental blood flow of late gestation (Redman, 1991). It is believed that the maternal syndrome of pre-eclampsia (hypertension, proteinuria, oedema) results from a generalized inflammatory response, which causes maternal endothelial dysfunction (Redman et al., 1999). This response is triggered by circulating factor(s), possibly released from the placenta by apoptosis of the syncytiotrophoblast.
The placenta expresses inhibin/activin mRNA and activin receptor mRNA (Petraglia et al., 1991; Peng et al., 1999) throughout pregnancy. A recent study reported an increase in inhibin and inhibin/activin ßA subunit protein in placenta from women with pre-eclampsia (Jackson et al., 2000). Whilst Manuelpillai et al. (2001) reported no change in the ßA subunit protein distribution in pre-eclamptic placenta, dimeric activin A contents were increased in placental homogenates of pre-eclamptic patients. They also reported activin receptor protein levels in pre-eclamptic placenta.
We hypothesized that raised maternal circulating levels of inhibin A and activin A in pre-eclampsia are due to increased production and up-regulation of the and ßA subunit gene expression in the placenta. The objectives of this study were: (i) to quantify the gene expression of inhibin and ßA subunit in term pre-eclamptic patients and matched controls; and (ii) to study the gene expression of ßB, ßC subunits, follistatin, and activin receptors and ß-glycan to provide more insights into the probable action of these proteins in the placenta in pre-eclampsia.
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Materials and methods |
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Placental tissue
Ethical approval was obtained from the local ethics committee for this study. All patients gave informed consent. Ten of these placentas were from control pregnancies at term (
37 weeks of gestation) and seven from women with pre-eclampsia at term (37 weeks of gestation). Pre-eclampsia was defined as new, sustained diastolic blood pressure >90 mmHg and new, sustained proteinuria with 500 mg protein/24 h urinary sample in the absence of urinary tract infection. Pre-eclamptic patients in this study fitted these criteria. These patients were not on any medication. The maternal age was 30.7 ± 4.9 (SD) in the control and 30.8 ± 2.7 years in the pre-eclamptic group. There was no difference in fetal weight (no SGA babies). Placentas were obtained from 17 women who had normal spontaneous vaginal deliveries. Labour was uneventful in all cases. Tissue samples were cut randomly from different parts of the placentas within half-hour of delivery, extensively rinsed in sterile saline and snap-frozen in liquid nitrogen and stored at –80°C at the John Radcliffe Hospital in Oxford, UK.
RNA extraction
Trizol reagent (Life Technologies Inc, USA) was used to isolate total RNA according to the manufacturer’s protocol. Briefly, 100–200 mg of placental tissue was homogenized in 500 µl of Trizol. Chloroform (200 µl) was added and the solution was incubated at room temperature for 5 min. It was then centrifuged at 1089 g for 15 min at 4°C. The upper aqueous phase was incubated with 500 µl isopropanol at room temperature for 5 min and centrifuged at 1089 g for 10 min. The RNA pellet was washed in 75% ethanol and centrifuged again at 1089 g for 5 min. The resulting pellet was dried and resuspended in 80% ethanol made up in diethylpyrocarbonate (DEPC)-treated water (Sigma–Aldrich, UK) and stored at –80°C. The concentration of RNA was analysed on a spectrophotometer (Jenway Ltd, UK). The ratio between the absorbance at 260 and 280 nm was >1.6.
cDNA synthesis
Total RNA (2 µg) was reverse-transcribed into cDNA for each RNA sample extracted from placental tissue using TaqMan reverse transcription kit (Applied Biosystems Ltd, UK) according to the manufacturer’s protocol.
Each cDNA sample obtained was checked by TaqMan (Applied Biosystems Ltd, UK) PCR reaction, using glyceraldehyde phosphate dehydrogenase (GAPDH) primers. PCR was carried out using the following cycle: 50°C for 2 min, 95°C for 10 min, followed by 40 cycles of 95°C for 15 s and 60°C for 1 min. PCR products were run on a 2% agarose gel.
Real time PCR
Real time PCR was used for relative gene expression using an ABI Prism 7700 Sequence Detection System thermal cycler (Applied Biosystems, USA).
Primers and probes were designed using Primer Express 1.5 Software and synthesized commercially (Applied Biosystems Ltd, UK). The sequences for each gene are shown in Table I. All PCR products were 85–150 base pairs (bp) in size. The optimal concentrations of all primers and probes were evaluated according to the optimization protocol provided by Applied Biosystems.
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A stock placental cDNA pool was prepared as a standard stock and used for all real time assays. PCR reaction mixes for each standard and samples were prepared in separate tubes, using TaqMan Universal PCR master mix, primers, probe and cDNA. All samples were assayed in triplicate and an aliquot of 25 µl reaction mix was transferred to each well of a MicroAmp optical 96-well reaction plate (Applied Biosystems, USA). The thermocycler parameters were: 50°C for 2 min, 95°C for 10 min, followed by 40 cycles of 95°C for 15 s and 60°C for 1 min.
A GAPDH pre-designed assay from Applied Biosystems was used to detect the expression of the housekeeping gene GAPDH in each sample using the same standard preparation. Target gene expression was normalized with GAPDH gene expression in each sample and the ratio between the target and GAPDH was expressed in all samples.
Statistical analysis
All values are expressed as mean ± SEM. Data were normally distributed. Log-transformed data were used for Student’s t-test (GraphPad Prism, USA). P < 0.05 was considered significant.
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Results |
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Using real-time PCR, relative expression of activin/inhibin subunits, follistatin, activin receptor and ß-glycan genes were calculated by normalizing with GAPDH gene expression in RNA extracted from both control and pre-eclamptic placentas. Mean GAPDH expression in placental tissue from pre-eclamptic patients and controls were not significantly different (data not shown).
Inhibin/activin subunits and follistatin gene expression
The mean ratio of inhibin subunit:GAPDH gene expression in pre-eclamptic placentas (2.06 ± 0.59) was 
3-fold higher (P = 0.04) than in the controls (0.67 ± 0.20; Figure 1a). The mean ratio of inhibin/activin ßA subunit:GAPDH in pre-eclamptic placental tissue (11.16 ± 4.37) was 4-fold higher (P = 0.01) than the control placental tissue (2.73 ± 1.20; Figure 1b). The ratio between inhibin/activin ßB:GAPDH and ßC subunit:GAPDH in pre-eclamptic placental tissue tended to be lower than the controls (0.73 ± 0.27, 2.88 ± 2.38 respectively) although it did not reach statistical significance (2.6 ± 1.42, 4.7 ± 1.64 respectively; Figure 1c and d). The mean ratio of follistatin:GAPDH gene expression in pre-eclamptic placentas (6.68 ± 5.59) was not altered compared with the controls (8 ± 3.04; Figure 1e).
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Expression of activin receptors and ß-glycan genes
The mean ratio of ACTRIA:GAPDH and ACTRIB:GAPDH in the pre-eclamptic placentas (2.78 ± 0.98, 5.23 ± 1.86 respectively) was not significantly altered from the controls (3.03 ± 1.9, 4.18 ± 1.76 respectively; Figure 2a and b). Although ACTRIIA:GAPDH and ACTRIIB:GAPDH expression in the pre-eclamptic placental tissue (1.68 + 0.53, 6.68 + 2.86 respectively) tended to be lower from the control tissue (3.93 ± 1.85, 15.57 ± 6.74 respectively; Figure 2c and d), this effect was not statistically significant.
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ß-glycan:GAPDH ratio was not significantly altered in pre-eclamptic placental tissue (0.69 ± 0.31) compared with controls (0.84 ± 0.69, Figure 2e).
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Discussion |
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This study shows that inhibin
and inhibin/activin ßA subunit genes are up-regulated in term pre-eclamptic placenta. Using real-time PCR, we have shown for the first time, the expression of inhibin subunit, ßA, ßB and ßC subunits, follistatin, ß-glycan and activin receptor genes (ActR IA, ActR IB, ActR IIA and ActR IIB), in placental tissue from both uncomplicated term pregnancies and term pregnancies with pre-eclampsia. These results support our previous observations in maternal serum (Muttukrishna et al., 2000) and placental homogenate (Bersinger et al., 2002) of elevated levels of inhibin A and activin A in pre-eclampsia. Expression of some of these genes in reproductive tissues has been examined in previous studies either by using RT–PCR in ovarian and placental samples (Peng et al., 1999), or by using real-time PCR in endometrial samples collected at all stages of the menstrual cycle and early pregnancy (Jones et al., 2002).
A recent study by Silver et al. (2002) has reported an 2-fold significant rise with pre-eclampsia in :GAPDH ratio and ßA:GAPDH ratio using semi-quantitative RT–PCR and densitometry measurements of the bands. Our results using real-time PCR, a sensitive and precise quantitative method, are consistent with the above study.
It has been known for a few years that inhibin A levels are increased in pregnant women with pre-eclampsia (Muttukrishna et al., 1997b, 2000). Since there is no evidence of another likely source of inhibin A during pregnancy, this placental subunit gene up-regulation may play an important, if not the most important, role in increasing the levels of inhibin A in women with pre-eclampsia.
The magnitude of rise in the expression of ßA subunit gene in pre-eclamptic placental samples compared with those obtained from uncomplicated pregnancies found in the present study is similar to the increase in activin A measured in the maternal circulation in pre-eclamptic women (Petraglia et al., 1995; Muttukrishna et al., 1997b, 2000).
Follistatin levels in pre-eclamptic patients were reported to be unaltered by D’Antona et al. (2000) and raised by Keelan et al. (2002). In this study we found that follistatin gene expression was not altered significantly in term pre-eclamptic patients.
The exact origin of the increased levels of activin A and inhibin A during normal and pre-eclamptic pregnancies has been subject to great controversy. It is generally accepted that the placenta is the major source of circulating activin A in normal pregnancy (Muttukrishna et al., 1997a) and it has been assumed that the source of activin A and inhibin A in pre-eclampsia is predominantly from placental tissue, reflecting abnormal placentation and trophoblast function (Aquilina et al., 1999; Silver et al., 1999). Moreover, the observation by Jackson et al. (2000) of increased inhibin subunit (50%) and ßA subunit (100%) protein expression in term pre-eclamptic placental tissue is supported by our present observation.
There is some evidence that activins are released early in the cascade of circulatory cytokines during systemic inflammatory episodes (Phillips et al., 2001). The source(s) of activins in such conditions is not yet established, but prime candidates include monocytes and macrophages (Yu and Dolter, 1997; Phillips et al., 2001). Since pre-eclampsia is characterized by a systemic and intense inflammatory response, it is possible that activin A production by monocytes may contribute to elevated circulating levels (Yu and Dolter, 1997). There is emerging evidence in the literature that the vascular endothelium is a potent source of activin A (Phillips, 2001), and because both endothelial cells and monocytes undergo activation in pre-eclampsia, a significant contribution from these sources cannot be discounted (Yu and Dolter, 1997; Phillips, 2001).
Several studies have led to the conclusion that gene expression is altered in pre-eclampsia, and hypoxia may play a role in cases of placental gene up-regulation (Rajakumar et al., 2001; Tsoi et al., 2001; Sagawa et al., 2002). It has been said that oxygen tension regulates the expression of several genes that are critical to the proliferation and differentiation of cytotrophoblasts, which is proposed to contribute to the pathogenesis of pre-eclampsia (Mise et al., 1998). Placental hypoxia in the second half of gestation, as a consequence of reduced utero-placental blood flow, may result in aberrant expression of genes that contribute to the pathophysiology of pre-eclampsia. Some of these up-regulated genes might encode certain cytokines and vasoactive molecules (Graham et al., 2000). The reason for up-regulation of the inhibin/activin subunit RNA is unclear. It could be due to increased reactive oxygen species (ROC), due to oxidative stress in pre-eclampsia and/or an alteration in the promoter region of the and ßA gene which has caused an increase in the synthesis of RNA. However, there is controversial evidence for the regulation of activin A under hypoxia. Jenkin et al. (2001) has reported that feto-placental hypoxaemia is an acute trigger for increased activin secretion, most probably from the feto-placental unit in late pregnancy in sheep. By contrast, recent in-vitro studies have reported human placental explants cultured under hypoxic conditions (2 or 6%) secrete lower levels of activin A compared with explants cultured at normal oxygen tension (20%) (Blumenstein et al., 2002; Manuelpillai et al., 2003). The discrepancy between the in-vivo and in-vitro studies could be due to species variation and/or in-vitro culture conditions. Clearly further studies have to be carried out to unravel the mechanisms involved in up-regulating inhibin and ßA subunit RNA in term pre-eclamptic placental tissue.
The expression of the subunits, receptors and binding proteins in the same tissue suggests tightly controlled local action for the proteins. Although specific actions of these proteins in the placenta are yet unclear, there is evidence for activin A to promote invasion in early pregnancy (Caniggia et al., 1997). However, in other tissues these proteins are known to have specific effects. Follistatin is a promoter of angiogenesis and is up-regulated during endothelial cell proliferation (Kozian et al., 1997) and activin A is an inhibitor of angiogenesis (McCarthy and Bicknell, 1993). The evidence for follistatin in serum is controversial, with D’Antona et al. (2000) reporting unaltered levels and Keelan et al. (2002) reporting raised levels of follistatin in the circulation of pre-eclamptic patients. The evidence so far regarding pre-eclampsia suggests that activin A subunits and protein are up-regulated in the disease with little or no changes in the binding protein (follistatin) expression. Therefore, we could speculate that there is an increased level of ‘free activin A’ in the tissue that could be biologically active. However, inhibin A is also known to antagonize activin A binding to its receptors. Hence, an increased level of inhibin A in pre-eclamptic placenta could provide a regulatory mechanism for activin action in the same tissue.
In conclusion, the present study on activin/inhibin subunits, follistatin and activin receptor gene expression provides further pathophysiological evidence of abnormal gene expression in pre-eclamptic compared with uncomplicated pregnancies. These findings strengthen the hypothesis that differential gene expression may be one of the aetiologies of increased production of these proteins in pregnancies complicated with pre-eclampsia. There is a need for further studies with a larger number of patients; to determine the factors that may alter this abnormal expression for understanding the pathophysiology of this disease.
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Acknowledgement |
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S.Muttukrishna acknowledges the financial support from the Wellcome Trust.
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