Pathogenesis Of Pregnancy-induced Hypertension Research Articles

CircYTHDF1/miR-19b-3p/YTHDF1 axis contributes to pregnancy-induced hypertension development by enhancing vascular endothelial cell injury

ABSTRACT Objective The biological role of circ_0004858 (circYTHDF1) in pregnancy-induced hypertension (PIH) and the underlying mechanisms were unknown, and which were explored in this study. Methods ELISA was employed to detect the level of inflammatory cytokines and biochemical parameters; flow cytometry was employed to detect cell apoptosis; western blot and qRT-PCR were employed to examine expression level. Results The level of IL-1β, TNF-α, IL-6, TGF-β1, ET-1, and Ang-II were significantly elevated in the peripheral blood of PIH patients. The co-culture of HUVEC and CD4+ T cells isolated from the peripheral blood of PIH patients significantly elevated the apoptosis and expression level of NRF2/HO-1 but reduced the protein level of ferroptosis-related markers (GPX4, FSP, and CoQ10B) in HUVEC. Also, the expression of circYTHDF1 and YTHDF1 were markedly up-regulated in HUVEC co-cultured with CD4+ T cells isolated from PIH patients, but miR-19b-3p expression was markedly down-regulated, and the similar results were observed in Ang-II-treated HUVEC. Based on the predicted binding sites, the luciferase reporter assay confirmed the interaction between miR-19b-3p and circYTHDF1 or YTHDF1. The results of qRT-PCR and western blot further demonstrated that circYTHDF1 competitively bound to miR-19b-3p to up-regulate YTHDF1 in HUVEC. Functionally, deleting circYTHDF1markedly reduced ferroptosis and apoptosis in Ang-II-treated HUVEC, but both which were reversed by miR-19b-3p inhibitor, suggesting the involvement of circYTHDF1/miR-19b-3p/YTHDF1 axis in vascular endothelial cell injury in PIH. Conclusions This study may provide a novel insight into the pathogenesis of PIH as well as a new treatment strategy.

Estimation of Serum Aldosterone and Electrolytes in Pregnancy Induced Hypertension

Pregnancy Induced Hypertension(PIH) is one of the most frequent complications of pregnancy , however little is known about its etiology. The renin angiotensin aldosterone system(RAAS) has been implicated in the pathogenesis of PIH. The study of serum electrolytes is gaining ground in the pathophysiology of hypertension. The study sample consist of 50 normal non pregnant women, 50 normotensive pregnant women, and 50 preeclamptic pregnant women in their third trimester in Mosul city. The aim of this study was designed to evaluate the role of serum aldosterone and the serum electrolytes in pathogenesis of PIH. The results of this study showed that there was a highly significant reduction (P<0.000) in serum sodium, calcium, and aldosterone levels in preeclamptic pregnant women in comparison with normotensive pregnant women & the control group. While there is a highly significant elevation (P<0.000) in the serum level of potassium in preeclamptic women in comparison with normotensive pregnant women & the control group. The serum chloride level showed a highly significant reduction (P<0.006) in preeclamptic women in comparison with the normotensive pregnant women. The serum aldosterone has a positive and negative correlation with serum sodium and potassium respectively in preeclamptic pregnant women

First-Trimester Serum Cytokine Profile in Pregnancies Conceived After Assisted Reproductive Technology (ART) With Subsequent Pregnancy-Induced Hypertension.

Pregnancy-induced hypertension (PIH) is one of the most common pregnancy complications that seriously affects the mother and fetus. The incidence of PIH is higher in pregnancies conceived after assisted reproductive technology (ART) than in spontaneous pregnancies; thus, exploring potential serum biomarkers before PIH onset is of great significance for effective early prediction and prevention of PIH in the ART population. Cytokines are involved in the inflammatory response and immune regulation, which play an essential role in the pathogenesis of PIH. A description of the cytokine profile in the first trimester of pregnancy could help identify new diagnostic tools and develop targeted therapies for PIH in the ART population. The concentrations of classical predictive markers for PIH and another 48 cytokines were measured in the first-trimester pregnancy serum samples from 33 PIH patients and 33 matched normotensive controls (NC), both of whom conceived after ART treatment. The measured values were compared and analyzed between NC and PIH, followed by comprehensive bioinformatic analysis and logistic regression analysis. There was no significant difference in classical predictive markers, including Activin A, PlGF, sFLT1 (VEGFR), and sFLT1/PlGF, between the PIH and NC groups (P > 0.05), while 29 cytokines were significantly lower in the PIH group than in the NC group (P < 0.05). Logistic regression analysis revealed that 17 cytokines (IL-2Rα, M-CSF, IL-6, IL-2, β-NGF, IL-7, IL-12 (p70), SCF, IL-10, IL-9, MIG, GM-CSF, LIF, IL-1α, MCP-3, IL-4, and HGF) in the first-trimester pregnancy serum were significantly negatively correlated with the subsequent onset of PIH. With the top 3 cytokines (IL-7, MIG, and SCF) of receiver operating characteristic (ROC) analysis, we constructed an efficient multifactor combined detection and prediction model for PIH in ART pregnancy. Classical early predictors for hypertensive disorder complicating pregnancy cannot distinguish PIH from their normal peers in ART pregnancy. In comparison, the description of the cytokine profile in the first trimester of pregnancy enables us to distinguish high-risk ART pregnancy for PIH, permitting enough time for PIH prevention therapy. The cytokine profile we described also provides immunological insight into the further mechanistic exploration of PIH.

Loss of E-Cadherin Staining Continuity in the Trophoblastic Basal Membrane Correlates with Increased Resistance in Uterine Arteries and Proteinuria in Patients with Pregnancy-Induced Hypertension.

Pregnancy-induced hypertension (PIH), especially when complicated with pre-eclampsia (PE), could be a life-threatening complication of pregnancy. Pre-eclampsia is one of the leading causes of perinatal morbidity and mortality in women. Pre-eclampsia is mainly characterized by hypertension and kidney damage with proteinuria. Abnormal placentation and altered structure of the placental barrier are believed to participate in the pathogenesis of pregnancy-induced hypertension, leading to PE. In the current study, we aimed to analyze the immunohistochemical expression pattern of E-cadherin and p120, two markers of epithelial–mesenchymal transition, in placental samples derived from a group of 55 patients with pregnancy-induced hypertension, including pre-eclampsia and 37 healthy pregnant controls. The results were correlated with the presence of an obtained early uterine artery flow notching during diastole on Doppler ultrasound. We observed a higher frequency of discontinuous E-cadherin staining in the basement membrane of syncytiotrophoblast in patients with PIH/PE compared to controls (p < 0.001, Fisher’s exact test). Moreover, the loss of continuity of E-cadherin expression correlated with the presence of a bilateral early diastolic notch on Doppler ultrasound (p < 0.001, Fisher’s exact test) and the presence of proteinuria (p = 0.013, Fisher’s exact test). These findings suggest that E-cadherin contributes to the integrity of the placental barrier, and its loss could be an immunohistochemical marker of PE.

Association of Urinary Strontium Levels with Pregnancy-induced Hypertension.

Pregnancy-induced hypertension (PIH), including gestational hypertension and preeclampsia, accounts for the majority of maternal and perinatal morbidity and mortality. Strontium (Sr) has been recently associated with preeclampsia in a small group of women; however, the role of Sr in PIH is not fully understood and warrants further investigation. In this study, we examined the association between urinary Sr levels and PIH, and assessed the effect of maternal age on the association. Urinary Sr concentrations were measured in 5423 pregnant women before delivery by inductively coupled plasma mass spectrometry (ICP-MS). Logistic regression analysis adjusting for potential confounders was applied to explore the association between Sr and PIH, and to evaluate the Sr-PIH relationship stratified by maternal age. Among the participants, 200 (3.83%) women were diagnosed with PIH. Compared with non-PIH women, women who developed PIH had lower urinary Sr concentrations (131.26 vs. 174.98 μg/L creatinine, P<0.01). With the natural log-transformed urinary creatinine-standardized Sr concentrations increasing, the risk of PIH decreased significantly [adjusted OR=0.60 (95%CI: 0.51, 0.72)]. Furthermore, the significant association of Sr with PIH was found among women under 35 years (P<0.01). Our finding suggested that Sr may play a potential protective role in the pathogenesis of PIH, especially among young pregnant women under 35 years old.

Zonulin as marker of pregnancy induced hypertension: a case control study

BackgroundZonulin has been implicated in many metabolic disorders including hypertension and obesity. However, there is insufficient information about the involvement of zonulin in pregnancy induced hypertension (PIH) which comprises preeclampsia (PE) and gestational hypertension (GH). This study was therefore aimed at finding the level of this biochemical marker of regulation of tight junctions among women with PIH.MethodsA total of 88 women with PIH and 60 age and body mass index (BMI) matched healthy pregnant women controls were enrolled. Blood pressure at 11–13 weeks and after 20 weeks of gestation, body mass index (BMI) in addition to serum Zonulin levels and lipid profile were compared between the groups. Student’s t-test was used for comparisons of the mean between the two groups. Correlation analyses were performed using Pearson’s correlation and binary logistic regression was used to evaluate the factors associated with PIH.ResultsZonulin level was significantly higher in the participants with PIH as compared to the normal pregnant controls 56.81 ± 7.72 ng/ml vs 40.4 ± 8.60 ng/ml p < 0.0001 and had strong positive correlation with PIH (OR = 1.805; CI1.139–1.275; p < 0.0001). However, the association between first trimester lipids and PIH was weak.ConclusionThe results showed a strong positive correlation between zonulin and PIH, thus changes in intestinal permeability occur in early stages of pregnancy and may be involved in the pathogenesis of PIH.

ALTERATION OF VARIOUS LIPIDS IN PREGNANCIES COMPLICATED BY HYPERTENSIVE DISORDERS

Background: Preeclampsia is a common medical problem associated with pregnancy with substantial risk to the mother and fetus. Abnormal lipid metabolism seems important in the pathogenesis of pregnancy-induced hypertension. Objective: The objective was to study the alteration of various lipids in pregnancies complicated by hypertensive disorders. Materials and Methods: This prospective study was conducted among 150 pregnant women in the department of obstetrics and gynecology, from September 2009 to May 2011. The subjects were divided into two groups of normotensive women and women with complicated pregnancy by hypertensive disorder with 75 patients each. Serum lipid profile including total cholesterol, triglyceride (TG), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) was determined and compared between the two groups. The data were analyzed using the Chi-square test and analysis of variance test. p<0.05 was considered statistically significant. Results: The mean TG level in the normotensive women was 121.5±25.0, while in the preeclamptic women were 311.4±79.5 (p<0.001). The mean cholesterol level was 181.7±27.8 in the normotensive and 259.4±40.6 in the hypertensive arm (p<0.001). Mean LDL was 122.6±24.6 in the normotensive group whereas 255.3±41.9 in the hypertensive pregnant women (p<0.001). HDL was 49.4±5.6 in the normotensive and 49.7±5.5 in the hypertensive arm (p=0.69). Conclusion: The endothelial dysfunction in preeclampsia could be due to an altered lipid profile. This association of hyperlipidemia may be significant in understanding the pathogenesis of preeclampsia and may help in developing strategies for early diagnosis and prevention of preeclampsia.

Role of nitric oxide in the pathophysiology of pregnancy-induced hypertension

Background: Pregnancy-induced hypertension (PIH) is a major cause of morbidity and mortality during pregnancy. Previous research suggests that endothelial dysfunction is important in the pathogenesis of PIH and may lead to alterations in nitric oxide (NO) synthesis. As endothelial cell damage is considered pivotal in the pathogenesis of pre-eclampsia, this study was initiated to determine whether NO production is decreased in patients with PIH. Objective: The objectives of this study were to determine the role of NO levels on the increased vascular resistance in the pathophysiology of PIH. Materials and methods: A case–control study was conducted. A total of 60 women in the second trimester of pregnancy with PIH and 60 healthy, normotensive women in second trimester matched with respect to maternal age, gestational age, and body mass index were selected. The resting blood pressure of the subjects was recorded on 2 consecutive days, and the average of the two values was recorded. Fasting blood samples of the subjects was obtained for the estimation of NO levels. Results: The mean serum NO levels of both the groups were compared. A decrease was observed in the mean serum NO levels (μM) in subjects with PIH (18.5 ± 5.8) compared with the controls (36.9 ± 3.9). The difference was statistically significant at P < 0.05. Conclusion: The present study shows a significantly less level of serum NO in women in their second trimester of pregnancy with PIH compared to the controls. This finding may be one of the major clues in unravelling the role of endothelial dysfunction in the pathophysiology of PIH and hence aid in its management.

Renin-Angiotensin-Aldosterone System in the Pathogenesis of Pregnancy-Induced Hypertension.

Hypertension occurs in 7-10% of pregnant women. Despite the continuous development of medicine, it is still an important risk factor for perinatal mortality of both mothers and fetuses. Pregnant women with hypertension are at greater risk of complications such as: placental abruption, cerebral and cardiac incidents, multiorgan failure, and disseminated intravascular coagulation. The aim of this review was to discuss multilevel disorders of the renin-angiotensin-aldosterone system in the etiopathogenesis of pregnancy-induced hypertension.

PD-1/PD-L1 regulates Treg differentiation in pregnancy-induced hypertension.

Pregnancy-induced hypertension (PIH) causes significant maternal and fetal morbidity and mortality. A decreased number of regulatory T (Treg) cells is associated with the pathogenesis of PIH. The programmed cell death-1 (PD-1)/PD-ligand 1 (PD-L1) pathway is critical to normal pregnancy (NP) by promoting Treg cell development. However, the relationship between PD-1/PD-L1 and Treg differentiation in PIH has not been fully elucidated. In this study, venous blood was obtained from 20 NP and 58 PIH patients. Peripheral blood mononuclear cells (PBMCs) were isolated from venous blood. The levels of Treg-related cytokines (TGF-β, IL-10, and IL-35) in serum and PBMCs were measured by ELISA. The percentage of Treg cells in PBMCs was assessed by flow cytometry. The mRNA levels of Treg-specific transcription factor Foxp3 in PBMCs, and PD-1 and PD-L1 in Treg cells were detected by qRT-PCR. The protein levels of PD-1 and PD-L1 in Treg cells were evaluated by western blot. The serum levels of TGF-β, IL-10, IL-35, and Foxp3 mRNA expression and CD4+CD25+ Treg cell percentage in PBMCs were decreased in PIH. Furthermore, a significant increase of PD-1 in Treg cells was found in PIH compared with NP. In addition, PD-L1 Fc, an activator of PD-1/PD-L1 pathway, increased Treg cell percentage, enhanced Foxp3 mRNA expression, and elevated levels of TGF-β, IL-10, and IL-35 in PBMCs. However, anti-PD-L1 mAb exerted a reverse effect. These findings revealed that PD-L1 Fc had a favorable effect on Treg cell differentiation, indicating a potential therapeutic value of PD-1/PD-L1 pathway for PIH treatment.

Reduction of Uterine Perfusion Pressure Induced Redistribution of Endothelin Receptor Type-B Between the Intima and Media Contributes to the Pathogenesis of Pregnancy-Induced Hypertension

Studies have shown that a change in endothelin receptor expression in the artery is related to pregnancy-induced hypertension (PIH). However, the mechanism underlying this change remains unclear. To test whether the distribution of endothelin receptor type-A (ETAR) and type-B (ETBR) plays an important role in PIH, a reduction of uterine perfusion pressure (RUPP) rat model was used to mimic some of the features of PIH; the resulting variable endothelin receptor expression was investigated in the media and intima of the aorta. Single vascular smooth muscle cells (VSMCs) were isolated from RUPP and normal pregnant (NP) rats to study the effect of ETAR and ETBR in smooth muscle cells. Compared with NP rats, RUPP rats had a significant redistribution of ETBR expression in the intima and media, while there was no significant difference in ETAR expression between the two groups. ETBR upregulation in VSMCs enhanced cellular contraction and contributed to PIH. The TNF-α plasma levels in RUPP rats were two-fold higher than those of NP rats, which upregulated the expression of ETBR in VSMCS through the NF-κB pathways in RUPP rats. Redistribution of ETBR between the media and intima played an important role in the pathogenesis of PIH.

Comparison of lipid profile and malondialdehyde with severity of blood pressure in pregnancy-induced hypertension

Background: Abnormal lipid profile and increased lipid peroxidation have a basic role in pathogenesis of pregnancy-induced hypertension (PIH). The association of dyslipidemia and lipid peroxidation product malondialdehyde (MDA) with severity of PIH has emerged as important diagnostic tool in predicting its progression. Objective: To establish the correlation of serum lipid profile and lipid peroxidation product MDA with severity of PIH considering systolic and diastolic blood pressure (BP). Materials and Methods: Study subjects included 70 women with diagnosed PIH and divided into two groups taking cutoff point of systolic BP 160 mm Hg and diastolic BP 110 mm Hg, respectively. Level of lipoproteins and MDA in patients with PIH was compared in both groups of systolic and diastolic BP. Statistical analysis was done by applying independent Student’s t-test, coefficient of correlation r was determined, and p-value

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Objectives An association between the renin-angiotensin system and the pathogenesis of pregnancy-induced hypertension has been reported. The prorenin receptor was discovered in 2002, and Wanatabe et al. reported that women with plasma soluble prorenin receptor concentrations above the 75th percentile at delivery had a significantly increased risk of preeclampsia. We evaluated plasma prorenin concentrations during pregnancy, and we assessed the incidence of pregnancy-induced hypertension. Methods We measured plasma prorenin concentrations in 430 pregnant women (565 samples). Regression analysis was performed to determine the associations between the plasma prorenin level and maternal/neonatal complications. Results The plasma prorenin concentration and gestational age had a positive correlation in non-pregnancy-induced hypertension in women with singleton pregnancies (Spearman rank-correlation coefficient, −0.215; p p p = 0.0107). Conclusions The plasma prorenin levels during pregnancy may be adversely correlated with the prorenin receptor, and low prorenin levels during late pregnancy were significantly associated with pregnancy-induced hypertension. Disclosures Y. Mikami: None. T. Narita: None. Y. Takai: None. K. Baba: None. H. Seki: None. K. Matsuoka: None.

The Progression of Serum Prorenin Concentration during Pregnancy

Objective: An association between the renin-angiotensin system and the pathogenesis of pregnancy-induced hypertension has been reported. The prorenin receptor was discovered in 2002, and Wanatabe et al. reported that women with plasma soluble prorenin receptor concentrations above the 75th percentile at delivery had a significantly increased risk of preeclampsia. We evaluated serum prorenin concentrations during pregnancy, and we assessed the incidence of pregnancy-induced hypertension. Methods: We measured serum prorenin concentrations in 430 pregnant women (565 samples). Regression analysis was performed to determine the associations between the serum prorenin level and maternal/neonatal complications. Results: The serum prorenin concentration and gestational age had a positive correlation in non-pregnancyinduced hypertension in women with singleton pregnancies (Spearman rank-correlation coefficient, -0.215: p<0.0001). The serum prorenin concentration in women with multiple pregnancies was significantly higher than that in women with singleton pregnancies (multiple linear regression analysis, p<0.0001). Low prorenin levels in the third trimester (≤20.1 percentile) were significantly associated with pregnancy-induced hypertension (adjusted odds ratio, 18.16: 95% confidential interval, 1.95-412.41: p=0.0107). Conclusion: The serum prorenin levels during pregnancy may be adversely correlated with the prorenin receptor, and low prorenin levels during late pregnancy were significantly associated with pregnancy-induced hypertension.

Selected polymorphisms of Renin-Angiotensin System in the pathology of hypertensive disorders of pregnancy

Pregnancy induced hypertension and pre-eclampsia, defined as hypertension and proteinuria after 20 weeks of pregnancy with no history of such symptoms, are a great challenge in the field of perinatology They are a serious threat to the mother and the child. Regardless of numerous studies on the subject, the pathogenesis of pregnancy-induced hypertension and pre-eclampsia is still unknown, although a crucial role of genetic factors combined with environmental factors has been confirmed. New theory based on genetic analysis of Renin-Angiotensin System and its impact on blood pressure in pregnant women, has been subject to much debate recently Numerous genes have been studied but angiotensinogen remains to be the best known. Little is known about angiotensin receptor type 1 and 2. This paper presents the knowledge about selected genes of RAS and their impact on pregnancy

Magnesium sulfate therapy of preeclampsia: an old tool with new mechanism of action and prospect in management and prophylaxis

A disturbed balance between angiogenic and antiangiogenic growth factors is a highly accepted mechanism in the pathogenesis of pregnancy-induced hypertension and proteinuria, which is clinically known as preeclampsia (PE). We investigated the effect of magnesium sulfate (MgSO4) therapy on vascular endothelial growth factor (VEGF), placental growth factor (PlGF), nitric oxide (NO) metabolites, soluble fm-like tyrosine kinase-1 (sFlt-1) and endoglin levels in PE rats and the effect of this treatment on the feto-maternal outcome. The PE group showed hypertension, proteinuria and decreased number and weight of live pups relative to the control group. This result was associated with increased sFlt-1, VEGF receptor-2 (VEGFR-2), VEGFR-3 and endoglin levels but decreased NO metabolites. MgSO4 therapy ameliorated systolic hypertension and proteinuria and decreased sFlt-1, VEGFR-2, VEGFR-3 and endoglin levels but increased NO metabolites in the treated group. Physiological and biochemical changes and improved pup weight and viability were observed in the treated group. The vasodilator action of MgSO4 and increased NO production are expected to increase placental blood flow and help fetal nutrition and development. Relief of placental ischemia decreases the production of antiangiogenic growth factors and restores the bioavailability of angiogenic factors (PlGF and VEGF). These changes resulted in better fetal outcome and an improved clinical picture of PE. These findings are promising and encourage further study of the mechanism of action of MgSO(4) to support its widespread use in the prevention and management of the etiopathological changes underlying the vast majority of the manifestations and complications of PE.

4G/5G Variant of Plasminogen Activator Inhibitor-1 Gene and Severe Pregnancy-Induced Hypertension: Subgroup Analyses of Variants of Angiotensinogen and Endothelial Nitric Oxide Synthase

BackgroundPregnancy-induced hypertension (PIH) is a common cause of perinatal mortality. It is believed to result from the interaction of several factors, including those related to the blood coagulation system. We performed genotyping and subgroup analyses to determine if the 4G/5G genotypes of the plasminogen activator inhibitor-1 gene (PAI-1) play a role in the pathogenesis of PIH, and to evaluate possible interactions of the PAI-1 polymorphisms with those of the angiotensinogen gene (AGT) and the endothelial nitric oxide synthase gene (NOS3).MethodsAn association study of PAI-1 polymorphism, and subgroup analyses of common variants of AGT and NOS3, among 128 patients with PIH and 376 healthy pregnant controls.ResultsNo significant differences were found between the cases and controls in the frequencies of allele 4G or the 4G/4G genotype. In subgroup analyses, after adjustment for multiple comparison, a significant association with the AGT TT genotype was found among women with the PAI-1 4G/4G genotype, and an association with the NOS3 GA+AA genotype was found among women with the 5G/5G or 4G/5G genotypes.ConclusionsOur findings suggest that there are at least 2 pathways in the pathogenesis of severe PIH. However, with respect to early prediction and prevention of severe PIH, although the PAI-1 4G/4G genotype alone was not a risk factor for severe PIH, the fact that PAI-1 genotypes are associated with varying risks for severe PIH suggests that PAI-1 genotyping of pregnant women, in combination with other tests, may be useful in the development of individualized measures that may prevent severe PIH.

Tissue kallikrein and kininogen levels in fetoplacental tissues from normotensive pregnant women and women with pregnancy-induced hypertension

Objectives An imbalance of vasoconstrictor and vasodilator substances in the placenta has been postulated in the pathogenesis of pregnancy-induced hypertension (PIH). There is however little information available on the kallikrein-kinin system (KKS) in women with PIH. The aim of this study therefore was to determine tissue kallikrein and kininogen levels and their distribution patterns in fetoplacental tissues from both normotensive pregnant (NTP) women and women with PIH. Study design The study group consisted of 24 women, 12 of whom had normal pregnancies, while 12 had PIH. Portions of amnion, chorion laeve, placental plate chorion, fetal placenta and maternal placenta were dissected from each freshly delivered placenta. Tissue kallikrein (total, active and inactive) and kininogen levels were estimated using a synthetic chromogenic substrate, S-2266 and an enzyme immunoassay, respectively. The data were analysed using Mann–Whitney U and Kruskal–Wallis tests. Results No significant differences were found for total, active and inactive tissue kallikrein levels in all fetoplacental tissues between both groups. However, kininogen levels were found to be significantly lower in chorion laeve, placental plate chorion, fetal placenta and maternal placenta from women with PIH when compared to those in similar tissues from NTP women. Conclusion These findings suggest the presence of an abnormality in the kallikrein-kinin system in the placentas of women with PIH, which requires further study.

Expression of endothelial nitric oxide synthase traffic inducer in the pladenta of pregnancy induced hypertension

The expression of endothelial nitric oxide synthase traffic inducer (NOSTRIN) in the placenta of the patients with pregnancy induced hypertension (PIH) was detected and its role in the pathogenesis of PIH was studied. The pathological changes in placental vessels were observed by HE staining. NO2-/NO3-, the stable metabolic end products of NO, was measured with nitrate reductase. The eNOS activity in placental tissues was assayed by spectrophotometry. Western blot analysis was applied to detect NOSTRIN expression. The incidence of thickening and fibronoid necrosis of placental vessels was significantly higher in women with PIH than in the normal group (P < 0.01). The levels of placental NO2-/NO3- in PIH patients (27.53 +/- 7.48 micromol/mg) were significantly lower than in normal group (54.27 +/- 9.53 micromol/mg, P < 0.01). The activity of eNOS was significantly decreased in PIH group (12.826 +/- 3.61 U/mg) as compared with that in normal group (21.72 +/- 3.83 U/mg, P < 0.01). Western blot analysis revealed that both groups expressed 58 kD NOSTRIN, but the protein level was significantly higher in women with PIH than in the normal group (P < 0.01). A significant negative correlation existed between the expression of NOSTRIN protein and the activity of eNOS in placental tissue of women with PIH (r = -0.57, P < 0.01). It was concluded that the level of NOSTRIN expression in placenta of women with PIH was increased, which may play an important role in the pathogenesis of PIH.

Nicotine suppresses pro-inflammatory responses by human placental cells

CELLS OONAGH DOWLING, BURTON ROCHELSON, CHRISTINE N. METZ, Institute for Medical Research at North Shore-LIJ, Center for Patient Oriented Research, Manhasset, New York, North Shore University Hospital, Division of Maternal-Fetal Medicine, Manhasset, New York OBJECTIVE: Pregnancy-Induced Hypertension (PIH) a leading causes of perinatal morbidity and mortality. Although the pathogenesis of PIH is poorly understood, numerous reports support the hypothesis that aberrant proinflammatory cytokine production and endothelial dysfunction within the placenta mediate PIH development. While smoking during pregnancy is associated with many adverse effects, several studies show that smoking protects against the development of PIH. Based on recent studies revealing the anti-inflammatory properties of nicotine, we have examined the effect of nicotine on inflammatory cytokine production by human placenta cells in vitro. STUDY DESIGN: Anonymous human placentas (free of gross abnormalities) were processed within 3 hr of delivery to isolate placenta cells. Placenta cells (2! 10 cells/ml in 96 well plates) were treated with nicotine 10 M to 10 M for 30 min prior to LPS stimulation (1-100 ng/ml). After an overnight incubation, cell culture supernatants were collected and assayed for TNF production by ELISA. Statistical significance was determined by ANOVA followed by Tukey post hoc analysis to make pairwise comparisons. RESULTS: LPS (1-1000 ng/ml) stimulation induced a dose-dependent production of the pro-inflammatory mediator, TNF, by human placenta cells. Nicotine (10 M to 10 M) significantly reduced TNF production by placenta cells, with the greatest reduction (up to 45%) observed at 10 M nicotine. CONCLUSION: Our observations reveal that nicotine inhibits pro-inflammatory cytokine production by placenta cells in vitro. This finding is consistent with studies demonstrating the anti-inflammatory effects of nicotine in numerous pathological conditions, including ulcerative colitis, experimental sepsis, and experimental ileus. Our results suggest a mechanism by which smoking may protect against the development of PIH.