Modulation of matrix metalloproteases by ciliary neurotrophic factor in human placental development.

Ciliary neurotrophic factor (CNTF) is a pleiotropic cytokine that signals through a receptor complex containing a specific subunit, CNTF receptor α (CNTFRα). The two molecules are constitutively expressed in key structures for human placental growth and differentiation. The possible role of CNTF in enhancing cell proliferation and/or invasion during placental development and remodelling was investigated using HTR-8/SVneo and BeWo cells, taken respectively as cytotrophoblast and syncytiotrophoblast models. In both cell lines, treatment with human recombinant (hr) CNTF activated JAK2/STAT3 signalling and inhibited the ERK pathway. Interestingly, in HTR-8/SVneo cells, 50 ng hrCNTF induced significant downregulation of matrix metalloprotease (MMP)-1 and significant upregulation of MMP-9. Moreover, pharmacological inhibition of JAK2/STAT3 signalling by AG490 and curcumin resulted in MMP-9 downregulation; it activated the ERK signalling pathway and upregulated MMP-1 expression. Collectively, these data suggest a role for CNTF signalling in extravillous cytotrophoblast invasion through the modulation of specific MMPs.

CD93 a potential player in cytotrophoblast and endothelial cell migration.

CD93, also known as complement component C1q receptor, is expressed on the surface of different cellular types such as monocytes, neutrophils, platelets, microglia, and endothelial cells, and it plays a pivotal role in cell proliferation, cell migration, and formation of capillary-like structures. These processes are strictly regulated, and many fetal and maternal players are involved during placental development. At present, there are no studies in literature regarding CD93 in placental development, so we investigated CD93 expression in first and third trimester and PE placentas by immunohistochemistry and western blotting analysis. In addition, we performed in vitro experiments under oxidative stress conditions to demonstrate how oxidative stress acts on CD93 protein expression. Our data showed that CD93 was expressed in villous cytotrophoblast cells, in some fetal vessels of first and third trimester and PE placentas and in the extravillous cytotrophoblast of cell columns in the first trimester placentas. Moreover, we detected a significant decrease of CD93 expression in third trimester and PE placentas compared to first trimester placentas, while no differences were detected between third and PE placentas. No differences of CD93 expression were detected in oxidative stress conditions. We suggest that CD93 can guide extravillous cytotrophoblast migration through ß1-integrin in uterine spiral arteries during placentation in the first trimester of pregnancy and that the decrease of CD93 expression in third trimester and PE placentas could be linked to the poor extravillous cytotrophoblast cells migration. So, it might be interesting to understand the role of CD93 in the first phases of PE onset.

Pre-eclampsia onset and SPARC: A possible involvement in placenta development.

Pre-eclampsia (PE) is a multisystem disorder commonly diagnosed in the latter half of pregnancy and it is a leading cause of intrauterine fetal growth retardation (IUGR). The aim of this study was to investigate the localization and the role of SPARC, secreted protein acidic, and rich in cysteine, in PE and PE-IUGR placentas in comparison with normal placentas. SPARC was mainly expressed in the villous and extravillous cytotrophoblastic cells in first trimester, whereas in PE, PE-IUGR and at term placentas, SPARC immunostaining was visible in both cytotrophoblastic cells and syncytiotrophoblast. SPARC expression significantly decreased in normal placenta from first to third trimester and a further significant reduction was demonstrated in PE and PE-IUGR. The latter downregulation of SPARC depends on hypoxic condition as shown by in vitro models. In conclusion, SPARC can play a pivotal role in PE and PE-IUGR onset and it should be considered as a key molecule for future investigations in such pathologies.

Omega-3 fatty acids modulate the lipid profile, membrane architecture, and gene expression of leiomyoma cells.

Uterine leiomyomas (fibroids or myomas) are the most common benign tumors of premenopausal women and new medical treatments are needed. This study aimed to determine the effects of omega-3 fatty acids on the lipid profile, membrane architecture and gene expression patterns of extracellular matrix components (collagen1A1, fibronectin, versican, or activin A), mechanical signaling (integrin ß1, FAK, and AKAP13), sterol regulatory molecules (ABCG1, ABCA1, CAV1, and SREBF2), and mitochondrial enzyme (CYP11A1) in myometrial and leiomyoma cells. Myometrial tissues had a higher amount of arachidonic acid than leiomyoma tissues while leiomyoma tissues had a higher level of linoleic acid than myometrial tissues. Treatment of primary myometrial and leiomyoma cells with eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA) reduced the monounsaturated fatty acid (MUFA) content and increased the polyunsaturated fatty acid (PUFA) content in both cell types. Myometrial and leiomyoma cell membranes were in the liquid-crystalline phase, but EPA- and DHA-treated cells had decreased membrane fluidity. While we found no changes in the mRNA expression of ECM components, EPA and DHA treatment reduced levels of ABCG1, ABCA1, and AKAP13 in both cell types. EPA and DHA also reduced FAK and CYP11A1 expression in myometrial cells. The ability of omega-3 fatty acids to remodel membrane architecture and downregulate the expression of genes involved in mechanical signaling and lipid accumulation in leiomyoma cells offers to further investigate this compound as preventive and/or therapeutic option.

Expression of extracellular matrix and adhesion proteins in pelvic organ prolapse.

Pelvic organ prolapse (POP) is a common disorder in women. It is characterized by the descent of the vaginal wall with consequent drop of pelvic organs. Pregnancy, labour and childbirth seem to be important events leading to the development of POP, since they are associated with prolonged stretch and mechanical stress of muscles, ligaments and connective tissue supporting pelvic organs. In pubocervical fascia, we explored the expression level of extracellular matrix and adhesion molecules. Tissue samples were obtained from twenty patients with POP who underwent cystocele repair, and from twenty control subjects during hysterectomy surgery. The PCR array analysis was performed and data were confirmed by Real-Time PCR and Western Blot.  Real-Time PCR results showed a significant upregulation for extracellular matrix protein 1 (ECM1) and integrin beta 3 (ITGB3) and a significant downregulation for FBLN5 in POP group. The decreased mRNA expression of FBLN5 in pathological samples was paralleled by a quantitative decrease in the corresponding protein, as Western Blot test highlighted. Our data provide an understanding of molecular mechanisms involved in POP-related pathophysiological processes and might represent an important tool to develop novel therapeutic agents for the treatment of this condition.

Cesarean Section Revealing an Unsuspected Renal Angiomyolipoma in a Woman with Severe Hypertension During Pregnancy: A Case Report.

Background: Renal angiomyolipomas are uncommon during pregnancy, but it is important to consider them in the differential diagnosis, for the increased risk of complications such as bleeding, renal artery compression, and renovascular hypertension. Case: A 42-year-old woman was admitted at 34 weeks of gestation for severe abdominal pain in the right flank associated with severe hypertension. During the postadmission immediate cesarean section for fetal compromise, abdominal exploration revealed a massive retroperitoneal hematoma (around 30 cm) up to the cecal region until the lower edge of the liver. The diagnosis was the rupture of a renal angiomyolipoma causing renovascular hypertension. Conclusion: Renovascular hypertension should be considered in patients who present with accelerated hypertension, particularly if the hypertension is resistant to medical therapy and not associated with laboratory features of preeclampsia/eclampsia.

The effect of astaxanthin on the aging rat brain: gender-related differences in modulating inflammation.

BACKGROUND: Astaxanthin (Ax) is a ketocarotenoid of the xanthophyll family with activities such as antioxidation, preservation of the integrity of cell membranes and protection of the redox state and functional integrity of mitochondria. The aim of this study was to investigate potential gender-related differences in the effect of Ax on the aging rat brain. RESULTS: In females, interleukin 1 beta (IL1ß) was significantly lower in treated rats in both cerebral areas, and in the cerebellum, treated animals also had significantly higher IL10. In males, no differences were found in the cerebellum, but in the hippocampus, IL1ß and IL10 were significantly higher in treated rats. CONCLUSION: These are the first results to show gender-related differences in the effect of Ax on the aging brain, emphasizing the necessity to carefully analyze female and male peculiarities when the anti-aging potentialities of this ketocarotenoid are evaluated. The observations lead to the hypothesis that Ax exerts different anti-inflammatory effects in female and male brains.

Management of fibroids in perimenopausal women.

PURPOSE OF REVIEW: This article reviews fibroids management in the perimenopausal period, and addresses future directions in care. RECENT FINDINGS: Aromatase inhibitors, selective estrogen receptor modulators and antiprogestogens for medical management and minimally surgical techniques are promising treatments. SUMMARY: The disease and the symptoms may persist in the peri and postmenopausal periods. The assumption that they will resolve with the onset of the menopause is too simplistic and not always valid. The number of perimenopausal women who wish to retain their uterus for reasons other than childbearing is increasing. The accurate diagnosis of these conditions may result in minor surgical or medical treatments being directed at the specific pathology and may avoid the need for major surgery.

Noninvasive fetal electrocardiography: an overview of the signal electrophysiological meaning, recording procedures, and processing techniques.

BACKGROUND: Noninvasive fetal electrocardiography (fECG), obtained positioning electrodes on the maternal abdomen, is important in safeguarding the life and the health of the unborn child. This study aims to provide a review of the state of the art of fECG, and includes a description of the parameters useful for fetus clinical evaluation; of the fECG recording procedures; and of the techniques to extract the fECG signal from the abdominal recordings. METHODS: The fetus clinical status is inferred by analyzing growth parameters, supraventricular arrhythmias, ST-segment variability, and fetal-movement parameters from the fECG signal. This can be extracted from an abdominal recording obtained using one of the following two electrode-types configurations: pure-abdominal and mixed. Differently from the former, the latter also provides pure maternal ECG tracings. From a mathematical point of view, the abdominal recording is a summation of three signal components: the fECG signal (i.e., the signal of interest to be extracted), the abdominal maternal ECG (amECG), and the noise. Automatic extraction of fECG includes noise removal by abdominal signal prefiltration (0.5-45 Hz bandpass filter) and amECG cancellation. CONCLUSIONS: Differences among methods rely on different techniques used to extract fECG. If pure abdominal electrode configurations are used, fECG is extracted directly from the abdominal recording using independent component analysis or template subtraction. Eventually, if mixed electrode configurations are used, the fECG can be extracted using the adaptive filtering fed with the maternal ECG recorded by the electrodes located in the woman thorax or shoulder.

Diabetes during Pregnancy: A Transgenerational Challenge.

For many years, gestational diabetes mellitus (GDM) has been defined as "a glucose intolerance of variable magnitude that begins or is first diagnosed in pregnancy" and that, in most cases, resolves after delivery [...].

The involvement of inflammatory cytokines in the pathogenesis of recurrent miscarriage.

OBJECTIVE: To investigate the inflammatory cytokine expression pattern in trophoblastic tissue from women with unexplained recurrent miscarriage (RM). STUDY DESIGN: Trophoblasts were obtained during uterine evacuation from 11 women with RM and from 20 healthy pregnant women undergoing elective termination of pregnancy, who served as controls. The array was performed using GEArray Q Series Human Inflammatory Cytokines & Receptors Gene Array HS-015 membranes. Data were confirmed by quantitative real-time PCR. The Mann-Whitney U test was performed for statistical analysis. RESULTS: Microarray analysis identified three genes that were differentially expressed between RM patients and controls. We observed significant downregulation of Transforming Growth Factor beta 3 (TGF-ß3) and Interleukin 25 (IL-25) (5-fold reduction and 2.5-fold reduction, respectively) and significant upregulation of CD-25, also known as Interleukin 2 receptor alpha (IL-2RA) (7-fold increase) in women with RM compared with controls. The median ΔC(t) of TGF-ß3 was 8.2 (interquartile range, 7.67-8.9) in RM patients vs. 5.85 (interquartile range, 5.3-6.09) in controls; the median ΔC(t) of IL-25 was 5.18 (interquartile range, 4.46-5.76) in RM patients vs. 3.85 (interquartile range, 3.6-4.51) in controls, and the median ΔC(t) of CD-25 was 9.62 (interquartile range, 7.81-12.42) in RM patients vs. 12.44 (interquartile range, 11.02-13.86) in controls. DISCUSSION: Our results suggest that the immunological and inflammatory regulation mechanisms of the placental environment play a key role in recurrent miscarriage. The observed trophoblast cytokine expression pattern at the maternal-fetal interface confirms the immunotrophic theory, as demonstrated by a switch from a T-helper-1 (Th1) profile to a T-helper-2 (Th2) profile in women who experience recurrent miscarriages.

Nitric oxide and peroxynitrite platelet levels in gestational hypertension and preeclampsia.

The aim of the study was to investigate platelet nitric oxide (NO) pathways in women with Gestational Hypertension (GH), Preeclampsia (PE) and Controls. Platelet NO(x) and peroxynitrite (ONOO(-)) levels, inducible (iNOS) and endothelial nitric oxide synthase (eNOS) and Nitrotyrosine expression (N-Tyr) in 30 women with GH, 30 with PE and 30 healthy pregnant controls, age, parity and gestational age-matched, were assessed. Platelet NO(x) and ONOO(-) levels were significantly higher in GH and PE vs. Controls, with higher levels in GH vs. PE. At the same way, iNOS and N-Tyr were significantly higher in GH and PE vs. Controls, with higher levels in GH vs. PE. Since GH expressed higher amount of NO metabolites and higher activation of iNOS compared to PE, we can hypothesize that the severity of hypertensive pathology is almost not related to only NO metabolism, this research confirmed that GH and PE are associated with marked changes in NO pathways; it is not easy to understand if they could be interpreted as causes or consequence of these pathologic states.

Nifedipine versus labetalol in the treatment of hypertensive disorders of pregnancy.

PURPOSE: To assess the maternal and fetal outcomes of pregnancies affected by hypertensive disorders treated with nifedipine versus labetalol. METHODS: A retrospective study in hypertensive patients treated during pregnancy with nifedipine or labetalol was conducted. After the charts review the patients were divided in the four groups: gestational hypertension (113 patients); mild preeclampsia (77 patients); severe preeclampsia (31 patients); HELLP syndrome (21 patients). The pregnancy and neonatal records were analyzed by paired and unpaired t test. RESULTS: We found that there was an higher rate of intrauterine growth restriction infants among women treated with labetalol compared with those treated with nifedipine (38.8 vs. 15.5 %; p < 0.05), but only in the subgroup of women affected by Gestational Hypertension and Mild Preeclampsia. In this group was also higher the rate of fetal worsening assessed by fetal heart rate tracing (33.3 vs. 14.2 %; p < 0.05). No neonatal malformations and no differences in the rate of adverse side effects were observed. CONCLUSIONS: Antihypertensive therapy in pregnancy with Labetalol may have the potential to impair fetal behavior in low degrees hypertensive diseases of pregnancy. Optimal care must balance the potentially conflicting risks and benefits to mother and fetus.

Maternal Inherited Thrombophilia in Monochorionic Twin Pregnancy with Twin-Twin Transfusion Syndrome.

BACKGROUND: To study the frequency of inherited thrombophilia in monochorionic twin pregnancies with twin-twin transfusion syndrome (TTTS). METHODS: At the Department of Obstetrics of the Polytechnic University of Marche (Ancona, Italy) a population of monochorionic diamniotic pregnant women was selected retrospectively. After termination of the pregnancy, genotyping for Factor I, Factor V Leiden, Factor II and Methylenetetrahydrofolate Reductase (MTHFR), as well as activities of the plasma proteins C and S, was performed. RESULTS: Regarding the 32 patients with TTTS, from a cohort of 104 monochorionic pregnancies recruited, at least one thrombophilic defect was more frequent (OR: 3.24), and the allele polymorphism frequency was higher for Factor I (OR: 4.4) and for Factor V Leiden (OR: 11.66). CONCLUSIONS: Maternal inherited thrombophilia, possibly also inherited from monochorial fetuses, may result in impaired development of the placental vascular architecture. This inheritance hypothesis may explain why only a fraction of monochorionic diamniotic twins develop TTTS.

Placental expression of endothelial and inducible nitric oxide synthase and nitric oxide levels in patients with HELLP syndrome.

OBJECTIVE: To determine placental gene expression of endothelial and inducible nitric oxide synthases and measure nitric oxide levels in patients with hemolysis, elevated liver enzyme levels, and low platelet count syndrome. STUDY DESIGN: Preterm placentas were obtained from 15 patients with hemolysis, elevated liver enzyme levels, and low platelet count syndrome and 30 controls matched for age, parity, and gestational age. mRNA levels were evaluated by real-time polymerase chain reaction, whereas nitric oxide and peroxynitrite production was measured by a commercially available kit. RESULTS: Placental gene expression of inducible nitric oxide and endothelial nitric oxide synthases were significantly lower in the hemolysis, elevated liver enzyme levels, and low platelet count syndrome group than in controls, whereas nitric oxide and peroxynitrite production were significantly higher in hemolysis, elevated liver enzyme levels, and low platelet count syndrome compared with controls. CONCLUSION: The reduced endothelial nitric oxide and inducible nitric oxide synthases gene expression in women with hemolysis, elevated liver enzyme levels, and low platelet count syndrome may indicate extreme placental dysfunction that is unable to compensate the endothelial derangement and the related hypertension. The higher nitric oxide formation found in hemolysis, elevated liver enzyme levels, and low platelet count syndrome placentas could be explained as a counteraction to the impaired fetoplacental perfusion, typical of the syndrome.

HTRA family proteins in pregnancy outcome.

HTRA (High temperature requirement protease A) family proteins includes HTRA1 (L56 or PRSS11), HTRA2/Omi, HTRA3 (PRSP) and HTRA4. These are oligomeric serine proteases highly conserved from bacteria to humans and are involved in a variety of biological functions including the maintenance of normal cell physiology and pathogenicity such as cell growth, apoptosis, neurodegenerative disorders, inflammation diseases and cancer. These proteins are normally expressed in placental villi during all pregnancy but their expression is found to be altered in pathological pregnancies suggesting a possible role of those proteins in the development of human placenta. Moreover, some HTRA family proteins have also been found in maternal blood and were impaired in pathological pregnancy suggesting a possible role of some of these proteins as early markers of pregnancy outcome. The aim of this review is to summarize the data currently available on the role of HTRA family proteins in pregnancy focalizing their role in pregnancy complications such as Preeclampsia (PE), IntraUterine Growth Restriction (IUGR) and Spontaneus PreTerm Birth (SPTB).

Pre-eclampsia predictive ability of maternal miR-125b: a clinical and experimental study.

Pre-eclampsia (PE) is a systemic maternal syndrome affecting 2-8% of pregnancies worldwide and involving poor placental perfusion and impaired blood supply to the foetus. It manifests after the 20th week of pregnancy as new-onset hypertension and substantial proteinuria and is responsible for severe maternal and newborn morbidity and mortality. Identifying biomarkers that predict PE onset prior to its establishment would critically help treatment and attenuate outcome severity. MicroRNAs are ubiquitous gene expression modulators found in blood and tissues. Trophoblast cell surface antigen (Trop)-2 promotes cell growth and is involved in several cancers. We assessed the PE predictive ability of maternal miR-125b in the first trimester of pregnancy by measuring its plasma levels in women with normal pregnancies and with pregnancies complicated by PE on the 12th week of gestation. To gain insight into PE pathogenesis we investigated whether Trop-2 is targeted by miR-125b in placental tissue. Data analysis demonstrated a significant association between plasma miR-125b levels and PE, which together with maternal body mass index before pregnancy provided a predictive model with an area under the curve of 0.85 (95% confidence interval, 0.70-1.00). We also found that Trop-2 is a target of miR-125b in placental cells; its localization in the basal part of the syncytiotrophoblast plasma membrane suggests a role for it in the early onset of PE. Altogether, maternal miR-125b proved a promising early biomarker of PE, suggesting that it may be involved in placental development through its action on Trop-2 well before the clinical manifestations of PE.

Placental thrombomodulin expression in recurrent miscarriage.

BACKGROUND: Early pregnancy loss can be associated with trophoblast insufficiency and coagulation defects. Thrombomodulin is an endothelial-associated anticoagulant protein involved in the control of hemostasis and inflammation at the vascular beds and it's also a cofactor of the protein C anticoagulant pathway. DISCUSSION: We evaluate the Thrombomodulin expression in placental tissue from spontaneous recurrent miscarriage and voluntary abortion as controls. Thrombomodulin mRNA was determined using real-time quantitative polymerase chain reaction. Reduced expression levels of thrombomodulin were found in recurrent miscarriage group compared to controls (1.82-fold of reduction), that corresponds to a reduction of 45% (from control group Delta CT) of thrombomodulin expression in spontaneous miscarriage group respect the control groups. SUMMARY: We cannot state at present the exact meaning of a reduced expression of Thrombomodulin in placental tissue. Further studies are needed to elucidate the biological pathway of this important factor in the physiopathology of the trophoblast and in reproductive biology.