Causal effects of hypertensive disorders of pregnancy on structural changes in specific brain regions: a Mendelian randomization study.

This study utilized Mendelian randomization to explore the impact of hypertensive disorders of pregnancy and their subtypes on brain structures, using genome-wide association study data from the FinnGen consortium for hypertensive disorders of pregnancy exposure and brain structure data from the ENIGMA consortium as outcomes. The inverse-variance weighted method, along with Cochran's Q test, Mendelian randomization-Egger regression, Mendelian randomization-PRESSO global test, and the leave-one-out approach, were applied to infer causality and assess heterogeneity and pleiotropy. Findings indicate hypertensive disorders of pregnancy are associated with structural brain alterations, including reduced cortical thickness in areas like the insula, isthmus cingulate gyrus, superior temporal gyrus, temporal pole, and transverse temporal gyrus, and an increased surface area in the superior frontal gyrus. Specific associations were found for hypertensive disorders of pregnancy subtypes: chronic hypertension with superimposed preeclampsia increased cortical thickness in the supramarginal gyrus; preeclampsia/eclampsia led to thinner cortex in the lingual gyrus and larger hippocampal volume and superior parietal lobule surface area. Chronic hypertension was associated with reduced cortical thickness in the caudal and rostral anterior cingulate and increased surface area of the cuneus and thickness of the pars orbitalis cortex. Gestational hypertension showed no significant brain region changes. These insights clarify hypertensive disorders of pregnancies' neurological and cognitive effects by identifying affected brain regions.

NANOG regulate the JAK/STAT3 pathway to promote trophoblast cell migration and epithelial-mesenchymal transition (EMT) in hypertensive disorders of pregnancy (HDP) through protein interaction with CDK1.

PROBLEM: Hypertensive disorders of pregnancy (HDP) are a common pregnancy disease. NANOG and Cyclin-dependent kinase 1 (CDK1) are essential for regulating the function of cell proliferation and apoptosis. However, the mechanism of action in HDP is yet unclear. METHOD: The microarray dataset GSE6573 was downloaded from the GEO database. Emt-related gene set was downloaded from Epithelial-Mesenchymal Transition gene database 2.0 were screened differentially expressed genes by bioinformatics analysis. Pathway Commons and Scansite 4.0 databases were used to predict the interaction between proteins. Placental tissue samples were collected from HDP patients and patients with uneventful pregnancies. RT-qPCR, Western blot and immunohistochemistry were used to detect the expression of NANOG, CDK1, MMP-2, MMP-9, EMT markers and the JAK/STAT3 pathway proteins. Transfection NANOG overexpression/knockdown, and CDK1 knockdown into the human chorionic trophoblast cells (HTR-8/Svneo). CCK-8, Transwell and Wound-healing assay were used to evaluate cell proliferation, invasion and migration. CO-IP and GST pull-down assays were used to confirm the protein interaction. RESULTS: A total obtained seven EMT-related differentially expressed genes, wherein NANOG, NODAL and LIN28A had protein interaction. In the HDP patients' tissue found that NANOG and CDK1 had lower expression. NANOG overexpression promoted HTR-8/Svneo proliferation, migration and EMT, while NANOG knockdown had the opposite effect. Further a protein interaction between STAT3 and CDK1 with NANOG. NANOG overexpression downregulated the JAK/STAT3 pathway to promote HTR-8/Svneo proliferation, migration and EMT, which was reversed by CDK1 knockdown. CONCLUSIONS: NANOG downregulated the JAK/STAT3 pathway to promote trophoblast cell proliferation, migration and EMT through protein interaction with CDK1.

Pathologic maternal and neonatal outcomes associated with programmed embryo transfer.

PURPOSE: In this first of two companion papers, we critically review the evidence recently published in the primary literature, which addresses adverse maternal and neonatal pregnancy outcomes associated with programmed embryo transfer cycles. We next consider whether these pathological pregnancy outcomes might be attributable to traditional risk factors, unknown parental factors, embryo culture, culture duration, or cryopreservation. Finally, in the second companion article, we explore potential etiologies and suggest strategies for prevention. METHODS: Comprehensive review of primary literature. RESULTS: The preponderance of retrospective and prospective observational studies suggests that increased risk for hypertensive disorders of pregnancy (HDP) and preeclampsia in assisted reproduction involving autologous embryo transfer is associated with programmed cycles. For autologous frozen embryo transfer (FET) and singleton live births, the risk of developing HDP and preeclampsia, respectively, was less for true or modified natural and stimulated cycles relative to programmed cycles: OR 0.63 [95% CI (0.57-0.070)] and 0.44 [95% CI (0.40-0.50)]. Though data are limited, the classification of preeclampsia associated with programmed autologous FET was predominantly late-onset or term disease. Other adverse pregnancy outcomes associated with autologous FET, especially programmed cycles, included increased prevalence of large for gestational age infants and macrosomia, as well as higher birth weights. In one large registry study, FET was associated with fetal overgrowth of a symmetrical nature. Postterm birth and placenta accreta not associated with prior cesarean section, uterine surgery, or concurrent placenta previa were also associated with autologous FET, particularly programmed cycles. The heightened risk of these pathologic pregnancy outcomes in programmed autologous FET does not appear to be attributable to traditional risk factors, unknown parental factors, embryo culture, culture duration, or cryopreservation, although the latter may contribute a modest degree of increased risk for fetal overgrowth and perhaps HDP and preeclampsia in FET irrespective of the endometrial preparation. CONCLUSIONS: Programmed autologous FET is associated with an increased risk of several, seemingly diverse, pathologic pregnancy outcomes including HDP, preeclampsia, fetal overgrowth, postterm birth, and placenta accreta. Though the greater risk for preeclampsia specifically associated with programmed autologous FET appears to be well established, further research is needed to substantiate the limited data currently available suggesting that the classification of preeclampsia involved is predominately late-onset or term. If substantiated, then this knowledge could provide insight into placental pathogenesis, which has been proposed to differ between early- and late-onset or term preeclampsia (see companion paper for a discussion of potential mechanisms). If a higher prevalence of preeclampsia with severe features as suggested by some studies is corroborated in future investigations, then the danger to maternal and fetal/neonatal health is considerably greater with severe disease, thus increasing the urgency to find preventative measures. Presupposing significant overlap of these diverse pathologic pregnancy outcomes within subjects who conceive by programmed embryo transfer, there may be common etiologies.

Temporal patterns of pre- and post-natal target organ damage associated with hypertensive pregnancy: a systematic review.

AIMS: Hypertensive pregnancy is associated with increased risks of developing a range of vascular disorders in later life. Understanding when hypertensive target organ damage first emerges could guide optimal timing of preventive interventions. This review identifies evidence of hypertensive target organ damage across cardiac, vascular, cerebral, and renal systems at different time points from pregnancy to postpartum. METHODS AND RESULTS: Systematic review of Ovid/MEDLINE, EMBASE, and ClinicalTrials.gov up to and including February 2023 including review of reference lists. Identified articles underwent evaluation via a synthesis without meta-analysis using a vote-counting approach based on direction of effect, regardless of statistical significance. Risk of bias was assessed for each outcome domain, and only higher quality studies were used for final analysis. From 7644 articles, 76 studies, including data from 1 742 698 pregnancies, were identified of high quality that reported either blood pressure trajectories or target organ damage during or after a hypertensive pregnancy. Left ventricular hypertrophy, white matter lesions, proteinuria, and retinal microvasculature changes were first evident in women during a hypertensive pregnancy. Cardiac, cerebral, and retinal changes were also reported in studies performed during the early and late post-partum period despite reduction in blood pressure early postpartum. Cognitive dysfunction was first reported late postpartum. CONCLUSION: The majority of target organ damage reported during a hypertensive pregnancy remains evident throughout the early and late post-partum period despite variation in blood pressure. Early peri-partum strategies may be required to prevent or reverse target organ damage in women who have had a hypertensive pregnancy.

This review identifies evidence of damage to the heart, brain, and blood vessels during and after hypertensive disorders of pregnancy and compares the pattern of changes that occur to blood pressure variations. Changes in the heart, brain, and blood vessels are first found in women during a hypertensive pregnancy and are also reported early after pregnancy. The majority of target organ damage reported remains evident long after pregnancy despite variation in blood pressure levels.

Early Fetal Growth Restriction with or Without Hypertensive Disorders: a Clinical Overview.

Early onset fetal growth restriction (FGR) is one of the main adverse pregnancy conditions, often associated with poor neonatal outcomes. Frequently, early onset FGR is associated with early onset hypertensive disorders of pregnancy (HDP), and in particular preeclampsia (PE). However, to date, it is still an open question whether pregnancies complicated by early FGR plus HDP (FGR-HDP) and those complicated by early onset FGR without HDP (normotensive-FGR (n-FGR)) show different prenatal and postnatal outcomes and, consequently, should benefit from different management and long-term follow-up. Recent data support the hypothesis that the presence of PE may have an additional impact on maternal hemodynamic impairment and placental lesions, increasing the risk of poor neonatal outcomes in pregnancy affected by early onset FGR-HDP compared to pregnancy affected by early onset n-FGR. This review aims to elucidate this poor studied topic, comparing the clinical characteristics, perinatal outcomes, and potential long-term sequelae of early onset FGR-HDP and early onset n-FGR.

Automated detection of microscopic placental features indicative of maternal vascular malperfusion using machine learning.

INTRODUCTION: Hypertensive disorders of pregnancy (HDP) and fetal growth restriction (FGR) are common obstetrical complications, often with pathological features of maternal vascular malperfusion (MVM) in the placenta. Currently, clinical placental pathology methods involve a manual visual examination of histology sections, a practice that can be resource-intensive and demonstrates moderate-to-poor inter-pathologist agreement on diagnostic outcomes, dependant on the degree of pathologist sub-specialty training. METHODS: This study aims to apply machine learning (ML) feature extraction methods to classify digital images of placental histopathology specimens, collected from cases of HDP [pregnancy induced hypertension (PIH), preeclampsia (PE), PE + FGR], normotensive FGR, and healthy pregnancies, according to the presence or absence of MVM lesions. 159 digital images were captured from histological placental specimens, manually scored for MVM lesions (MVM- or MVM+) and used to develop a support vector machine (SVM) classifier model, using features extracted from pre-trained ResNet18. The model was trained with data augmentation and shuffling, with the performance assessed for patch-level and image-level classification through measurements of accuracy, precision, and recall using confusion matrices. RESULTS: The SVM model demonstrated accuracies of 70 % and 79 % for patch-level and image-level MVM classification, respectively, with poorest performance observed on images with borderline MVM presence, as determined through post hoc observation. DISCUSSION: The results are promising for the integration of ML methods into the placental histopathological examination process. Using this study as a proof-of-concept will lead our group and others to carry ML models further in placental histopathology.

Placental lesions attributed to shallow implantation, excess extravillous trophoblast and decidual hypoxia: Correlation with maternal vascular malperfusion and related obstetric conditions.

INTRODUCTION: Maternal vascular malperfusion (MVM) is one of four main patterns of placental injury defined by the Amsterdam consensus statement and is associated with adverse fetal and maternal outcomes. Laminar decidual necrosis (DLN), extravillous trophoblast islands (ETIs), placental septa (PS), and basal plate multinucleate implantation-type trophoblasts (MNTs) are lesions attributed to decidual hypoxia, excess trophoblast, and shallow implantation, but are not included in the current MVM diagnostic criteria. We aimed to investigate the relationship between these lesions and MVM. METHODS: A case-control model was used to evaluate for DLN, ETIs, PS, and MNTs. Placentas with MVM on pathologic examination (defined as ≥2 related lesions) constituted the case group, and maternal age- and GPA-status-matched placentas with less than 2 lesions constituted the control group. MVM-related obstetric morbidities were recorded, including hypertension, preeclampsia, and diabetes. These were correlated with the lesions of interest. RESULTS: 200 placentas were reviewed: 100 MVM cases and 100 controls. MNTs and PS showed significant enrichment in the MVM group (p < .05). Furthermore, larger foci of MNTs (>2 mm linear extent) were significantly associated with chronic or gestational hypertension (OR = 4.10; p < .05) and preeclampsia (OR = 8.14; p < .05). DLN extent correlated with placental infarction, but DLN and ETIs (including size and number) lacked association with MVM-related clinical conditions. DISCUSSION: As a marker of abnormally shallow placentation and related maternal morbidities, MNT merits inclusion within the MVM pathologic spectrum. Consistent reporting of MNTs >2 mm in size is recommended, as these lesions correlate with other MVM lesions and MVM-predisposing morbidities. Other lesions, particularly DLN and ETI, lacked such association questioning their diagnostic utility.

More Tools for Evaluating Decidual Artery Disease.

Introduction: Hypertensive disorders of pregnancy continue to pose the most important risks for adverse maternal and neonatal outcome. Among histological findings, decidual artery disease is one of the most common, one that has both good reproducibility among observers and whose abnormal vascular remodeling is the sole aspect of preeclampsia pathophysiology on which experts agree. Nevertheless, some aspects of arterial remodeling alterations are still under investigation. Methods: We selected 720 routine and consecutive placenta case studies, concordant with the Amsterdam consensus. From these studies, we collected maternal and neonatal clinical data and specific placental findings on spiral artery abnormalities. We took into account all criteria for decidual arteriopathy. Two hundred and fifteen (215) cases out of this population presented hypertensive disorders of pregnancy. Additional to expected arterial findings, we noted frequent persistent parietal trophoblast lining. Results: A large proportion of our population developed hypertensive disorders of pregnancy (30%). Among the histologic findings reported for preeclampsia, we paid particular attention to spiral artery abnormalities, and this interpretive analysis revealed high frequency of arterial remodeling abnormalities. We examined two additional aspects in our routine analysis: first, the novel one of parietal trophoblast persistence, and second, the established problem of associated acute inflammation, as a possible pitfall. Conclusion: In order to better understood, spiral maternal artery remodeling merits further study. The abnormalities in this process provide an objective tool in the study and diagnosis of important pregnancy complications; furthermore, abnormal remodeling is an expression of early pregnancy alteration, and subsequently related to preeclampsia etiology.

Decoding placental pathology: Usage of a comprehensive checklist and scoring system for reporting of placentas in the hypertensive disorders of pregnancy.

Introduction/Context: Hypertensive disorders of pregnancy (HDP) are major complications of pregnancy and seen in about 5% to 10% of all pregnancies. Among these, pre-eclampsia is a leading cause of perinatal and fetal morbidity and mortality. It is a multifactorial and multisystemic disorder that results in a variety of histomorphologic features, some of which may be missed if a diligent examination is not performed. Aims and Objectives: The present study aimed to propose a checklist and novel scoring system to ensure comprehensive placental examination. We also aimed to evaluate the correlation, if any, between histopathological and morphometric findings in HDP and with fetal growth. Materials and Methods: A total of 100 placentas of women diagnosed with hypertensive disorders of pregnancy were included in our cross-sectional, observational study. Morphometric features and histological features that are known to be seen in HDP were analyzed, and each of them was given a numerical score based on their severity. Statistical Analysis Used: Pearson correlation coefficient test was applied to correlate these findings, and ANOVA test was used to assess the correlation of these findings with fetal growth restriction (FGR). Results: More than 50% of the placentas studied recorded maximum scores for weight and volume. At least 25% of the placentas showed the presence of all histo-pathological features under study. The association of total morphometric and histological scores was not found to be statistically significant (P-value = 0.239). We found a significant difference between means of morphometric scores of cases with normal fetal growth and cases showing FGR (P-value = 0.008). Conclusion: Uneven distribution and presentation of the lesions in these cases may lead to the absence of correlation between morphometry and histopathology, as seen in our study. Morphometric derangements in the placenta correlate with FGR. Our proposed checklist and scoring system can be utilized to standardize reporting of placental specimens in the evaluation of placentas with HDP, in order to facilitate and standardize the placental reporting.

Correlation between N-terminal pro-atrial natriuretic peptide, corin, and target organ damage in hypertensive disorders of pregnancy.

The objective was to evaluate the correlation between N-terminal pro-atrial natriuretic peptide (NT-proANP), corin and the severity of target organ injury in hypertensive disorders of pregnancy. A total of 78 women with hypertensive disorders of pregnancy and 49 normotensive pregnancies were enrolled. The clinical characteristics, laboratory index and echocardiogram results were collected. NT-proANP, corin, sFlt-1 and PlGF levels were measured. A receiver's operating characteristics (ROC) curve was performed to evaluate the efficacy of predicting target organ injury in the HDP group. The NT-proANP, corin, and sFlt-1/PlGF ratio were increased in the HDP group (p < .05). The area under the curve (AUC) predicted by NT-proANP and corin were larger than sFlt-1/PlGF ratio (0.779, 0.867, and 0.766, respectively). The creatinine and urine protein were significantly increased, while the estimated glomerular filtration rate (eGFR) was dramatically decreased in the HDP group (p < .05 each). The left atrial diameter (LAD), left atrial volume index (LAVI), left ventricular posterior wall thickness (LVPWT), and left ventricular septal thickness (LVST) were larger in the HDP group (p < .001 each). The NT-proANP/corin levels were positively correlated with LAD, creatinine, and urine protein, and negatively correlated with eGFR in HDP group (p < .05 each). Multiple regressions demonstrated that NT-proANP was an independent risk factor of LAD and urine protein, and corin was an independent risk factor of creatinine and eGFR in HDP group. NT-proANP and corin may be reliable biomarkers for evaluating the severity of target organ damage in the hypertensive disorders of pregnant patients.

Paeoniflorin alleviates NG-nitro-L-arginine methyl ester (L-NAME)-induced gestational hypertension and upregulates silent information regulator 2 related enzyme 1 (SIRT1) to reduce H2O2-induced endothelial cell damage.

Pregnancy-induced hypertension (PIH) is a leading cause of maternal mortality. Paeoniflorin has been reported to alleviate hypertension, thus relieving the injury of target organ. This study aimed to investigate the role of paeoniflorin in PIH development by regulating SIRT1 in rats. The mean arterial pressure (MAP), urine protein and histopathological damage of placenta in gestational hypertension rats were, respectively, detected by noninvasive tail-artery pressure measuring instrument, BCA method and H&E staining. The viability of human umbilical vein endothelial cells (HUVECs) treated with paeoniflorin or/and H2O2 was observed by CCK-8 assay. SIRT1 protein expression in HUVECs treated with paeoniflorin or/and H2O2 was analyzed by Western blot. Tunel assay, wound healing assay and tube formation assay were used to detect the apoptosis, migration and tube formation of HUVECs administrated with paeoniflorin or/and H2O2 or/and EX527 (SIRT1 inhibitor). As a result, MAP, urine protein and histopathological damage of placenta were enhanced in PIH rats, which were then alleviated by paeoniflorin. Paeoniflorin decreased the levels of sFlt-1, PlGF and VEGF in serum and placental tissues of gestational hypertension rats as well as the inflammatory response and oxidative stress. In addition, paeoniflorin promoted the expressions of SIRT1 and NO/eNOS and inhibited the production of iNOS in gestational hypertension rats to improve vascular endothelial cell injury. However, SIRT1 inhibition could suppress the protective effects of paeoniflorin on endothelial dysfunction of H2O2-induced HUVECs. In conclusion, paeoniflorin could improve gestational hypertension development by upregulating SIRT1.

Changes in Circulating Kisspeptin Levels During Each Trimester in Women With Antenatal Complications.

CONTEXT: Antenatal complications such as hypertensive disorders of pregnancy (HDP), fetal growth restriction (FGR), gestational diabetes (GDM), and preterm birth (PTB) are associated with placental dysfunction. Kisspeptin has emerged as a putative marker of placental function, but limited data exist describing circulating kisspeptin levels across all 3 trimesters in women with antenatal complications. OBJECTIVE: We aimed to assess whether kisspeptin levels are altered in women with antenatal complications. METHODS: Women with antenatal complications (n = 105) and those with uncomplicated pregnancies (n = 265) underwent serial ultrasound scans and blood sampling at the Early Pregnancy Assessment Unit at Hammersmith Hospital, UK, at least once during each trimester (March 2014 to March 2017). The women with antenatal complications (HDP [n = 32], FGR [n = 17], GDM [n = 35], PTB [n = 11], and multiple complications [n=10]) provided 373 blood samples and the controls provided 930 samples. Differences in circulating kisspeptin levels were assessed. RESULTS: Third-trimester kisspeptin levels were higher than controls in HDP but lower in FGR. The odds of HDP adjusted for gestational age, maternal age, ethnicity, BMI, smoking, and parity were increased by 30% (95% CI, 16%-47%; P < 0.0001), and of FGR were reduced by 28% (95% CI, 4-46%; P = 0.025), for every 1 nmol/L increase in plasma kisspeptin. Multiple of gestation-specific median values of kisspeptin were higher in pregnancies affected by PTB (P = 0.014) and lower in those with GDM (P = 0.020), but not significantly on multivariable analysis. CONCLUSION: We delineate changes in circulating kisspeptin levels at different trimesters and evaluate the potential of kisspeptin as a biomarker for antenatal complications.

Liver pathology in pregnancy.

Liver dysfunction occurs in up to 3% of pregnancies and can be due to pregnancy-associated liver injury, exacerbation of pre-existing liver disease, or co-incident with pregnancy. The most common form of pregnancy-associated liver injury is intrahepatic cholestasis of pregnancy (ICP). This condition is typically benign and self-limited, but is associated with fetal morbidity and mortality with high levels of serum bile acids. Acute fatty liver of pregnancy (AFLP) and the hypertensive disorders of pregnancy (including pre-eclampsia, eclampsia, and hemolysis, elevated liver enzymes, and low platelets [HELLP] syndrome) are more commonly associated with maternal and fetal complications and may necessitate expedient delivery. Histologically, ICP shows nonspecific features of cholestasis, while AFLP and the hypertensive disorders have more characteristic histologic findings. While not a true liver disease, hyperemesis gravidarum can cause elevated liver enzymes. Pregnant patients are at increased risk of developing severe hepatitis E and herpesvirus infections, Budd-Chiari syndrome, and gallstones, and they may also experience worsening of known chronic liver disease. Mass lesions in pregnancy including hemangiomas, focal nodular hyperplasia, and hepatocellular adenomas and carcinomas can present unique challenges for diagnosis and management. This review will explore the pathophysiology, presentation, histologic features, and management of these conditions.

Proportionality of Clinical Outcome and Placental Changes to the Increasing Severity of Maternal Hypertension- An Observational Study.

OBJECTIVE: Preeclampsia and eclampsia remain the major causes of maternal and perinatal mortality and morbidity worldwide, causing 12-15% of direct maternal deaths. Although preeclampsia and related hypertensive disorders of pregnancy continue to affect 8% of all pregnancies, the incidence of preeclampsia has increased 40% in recent years. This study was carried out to analyse the different placental lesions and fetal outcome in different grades of maternal hypertension and to see if there is a linear relationship of the same. MATERIAL AND METHOD: A total of 539 placenta specimens received at the department of Pathology from October 2017 to March 2019 were collected after obtaining informed consent. Of the 539 placentas, 87 hypertensive cases were graded and grouped according to the severity as gestational hypertension, mild preeclampsia, severe preeclampsia, eclampsia, and chronic hypertension and compared with 88 normotensive cases. The gross and microscopic findings were tabulated and analysed using the Statistical Package for the Social Sciences (SPSS) software. RESULTS: Incidence of fetal death and growth restriction increased with increasing grade of maternal hypertension (p= 0.001). Abnormal shape of placenta (p= 0.034) and abnormal umbilical cord insertion (p= 0.028) were seen significantly more in the hypertensive group than in the normotensive group. Infarct and abnormal vasculo-syncytial membrane (p < 0.05) and abnormal villous maturation (p= 0. 039) were significantly increased in the hypertensive group than the normotensive group. CONCLUSION: The incidence of adverse fetal outcome and placental changes suggestive of feto-maternal malperfusions shows a proportional trend with the increasing grade of maternal hypertension.

Interleukin-1ß in Multifactorial Hypertension: Inflammation, Vascular Smooth Muscle Cell and Extracellular Matrix Remodeling, and Non-Coding RNA Regulation.

The biological activities of interleukins, a group of circulating cytokines, are linked to the immuno-pathways involved in many diseases. Mounting evidence suggests that interleukin-1ß (IL-1ß) plays a significant role in the pathogenesis of various types of hypertension. In this review, we summarized recent findings linking IL-1ß to systemic arterial hypertension, pulmonary hypertension, and gestational hypertension. We also outlined the new progress in elucidating the potential mechanisms of IL-1ß in hypertension, focusing on it's regulation in inflammation, vascular smooth muscle cell function, and extracellular remodeling. In addition, we reviewed recent studies that highlight novel findings examining the function of non-coding RNAs in regulating the activity of IL-1ß and its associated proteins in the setting of hypertension. The information collected in this review provides new insights into understanding the pathogenesis of hypertension and could lead to the discovery of new anti-hypertensive therapies to combat this highly prevalent disease.

Macula Densa NOS1ß Modulates Renal Hemodynamics and Blood Pressure during Pregnancy: Role in Gestational Hypertension.

BACKGROUND: Regulation of renal hemodynamics and BP via tubuloglomerular feedback (TGF) may be an important adaptive mechanism during pregnancy. Because the ß-splice variant of nitric oxide synthase 1 (NOS1ß) in the macula densa is a primary modulator of TGF, we evaluated its role in normal pregnancy and gestational hypertension in a mouse model. We hypothesized that pregnancy upregulates NOS1ß in the macula densa, thus blunting TGF, allowing the GFR to increase and BP to decrease. METHODS: We used sophisticated techniques, including microperfusion of juxtaglomerular apparatus in vitro, micropuncture of renal tubules in vivo, clearance kinetics of plasma FITC-sinistrin, and radiotelemetry BP monitoring, to determine the effects of normal pregnancy or reduced uterine perfusion pressure (RUPP) on macula densa NOS1ß/NO levels, TGF responsiveness, GFR, and BP in wild-type and macula densa-specific NOS1 knockout (MD-NOS1KO) mice. RESULTS: Macula densa NOS1ß was upregulated during pregnancy, resulting in blunted TGF, increased GFR, and decreased BP. These pregnancy-induced changes in TGF and GFR were largely diminished, with a significant rise in BP, in MD-NOS1KO mice. In addition, RUPP resulted in a downregulation in macula densa NOS1ß, enhanced TGF, decreased GFR, and hypertension. The superimposition of RUPP into MD-NOS1KO mice only caused a modest further alteration in TGF and its associated changes in GFR and BP. Finally, in African green monkeys, renal cortical NOS1ß expression increased in normotensive pregnancies, but decreased in spontaneous gestational hypertensive pregnancies. CONCLUSIONS: Macula densa NOS1ß plays a critical role in the control of renal hemodynamics and BP during pregnancy.

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.

Placenta pathology in recipient versus donor oocyte derivation for in vitro fertilization in a setting of hypertensive disorders of pregnancy and IUGR.

INTRODUCTION: Assisted reproductive technology including in vitro fertilization (IVF) and oocyte donation (OD) may increase risk for placenta-mediated diseases. Comprehensive analysis of histopathological placental lesions according to source of oocytes used in the IVF procedure - recipient derived (RD-IVF) vs oocyte donation (OD-IVF), has not been conducted in a population with a hypertensive disorder of pregnancy (HDP) and/or intrauterine growth restriction (IUGR). METHODS: A retrospective cohort study of archived placenta specimens from RD-IVF and OD-IVF pregnancies affected by HDP and/or IUGR was conducted with blinded histopathological placental examination. Three categories of lesions were differentiated and defined as main outcomes: maternal vascular malperfusion (MVM), chronic inflammation, and fetal vascular malperfusion (FVM). To determine the relationship between conception method and placental lesions, multivariable regressions were performed with maternal age, gestational age, HDP, birth and placental weight percentiles as model covariates. RESULTS: 115 placentas were included 83 (72.2%) RD-IVF, 32 (27.8%) OD-IVF. Adjusted OR (aOR) for conception method was 5.05 (95%CI 0.58-43.90, p=0.142) for MVM, 1.87 (95%CI 0.68-5.15, p=0.228) for chronic inflammatory and 0.61 (95%CI 0.15-2.37, p=0.471) for FVM lesions. Multiple gestation demonstrated borderline association with MVM (aOR=0.24, 95%CI 0.04-1.51, p=0.129) and total pathology score (aRR=0.79, 95%CI 0.62-1.01, p=0.058). Subgroup analysis suggested greater odds of villitis of unknown etiology (VUE) for OD-IVF (aOR=2.98, 95%CI 1.12-7.93, p=0.029). DISCUSSION: Source of oocyte derivation demonstrated no evidence of association with main outcomes in cases of HDP and/or IUGR. Subgroup analysis demonstrated increased rates of inflammatory lesions for OD-IVF. Multiple gestation may be associated with decreased MVM and total lesions.

A case of hypertensive disorders of pregnancy that developed at 9 weeks of gestation.

Preeclampsia and superimposed preeclampsia usually develop after 20 weeks of gestation. We report a case of a 35-year-old Japanese woman who developed hypertensive disorders of pregnancy (HDP) before 20 weeks of gestation. She presented with hypertension and proteinuria at 9 and 11 weeks of gestation, respectively, and developed nephrotic syndrome at 17 weeks of gestation. She did not have definite hypertension or urinary abnormalities before pregnancy. The patient was serologically positive for the antinuclear antibody. However, the complement levels were normal and anti-phospholipid antibody was not detected. A renal biopsy performed at 18 weeks of gestation showed diffuse endotheliosis and tip lesions of secondary focal segmental glomerulosclerosis but no hypertensive changes of the arterioles. Although electron microscopic examination showed electron-dense deposits in the subendothelial lesions, they were considered nonspecific plasma exudation by mass spectrometry. An abortion was performed at 20 weeks gestation because the patient's congestive symptoms due to nephrotic syndrome had worsened and marked fetal growth restriction was observed. After delivery, the patient's symptoms resolved immediately without any additional treatment; however, continuous antihypertensive medication was required. Finally, the patient was diagnosed with HDP based on the renal biopsy findings and her clinical course after delivery. Compared to previous reports, this case describes the earliest onset of HDP. Thus, HDP should be considered as a differential diagnosis in pregnant women with hypertension or proteinuria presenting with symptoms before 20 weeks of gestation.

Serum from patients with hypertension promotes endothelial dysfunction to induce trophoblast invasion through the miR­27b­3p/ATPase plasma membrane Ca2+ transporting 1 axis.

Pregnancy­induced hypertension is often accompanied by preeclampsia. The present study investigated whether microRNA (miR)­27b­3p affected the occurrence of preeclampsia by regulating the function of endothelial cells. Expressions levels of miR­27b­3p and ATPase plasma membrane Ca2+ transporting 1 (ATP2B1) were determined using reverse­transcription quantitative PCR. miR­27b­3p targeting ATP2B1 was predicted using bioinformatics and further confirmed by dual­luciferase reporter assays. Cell Counting Kit­8, Transwell and Matrigel tube formation assays were performed to detect the effects of miR­27b­3p on proliferation, migration and tube formation of human umbilical vein endothelial cells (HUVECs), respectively. Moreover, HTR8/SVneos cells were co­cultured with HUVECs to detect the invasion of trophoblast cells, and the expression levels of vascular endothelial growth factor (VEGF), matrix metalloproteinase (MMP)­2 and MMP­9 of HUVECs and HTR8/SVneos were detected by western blotting. Expression levels of miR­27b­3p were upregulated in the serum of patients with hypertension and preeclampsia, which could target and regulate the expression of ATP2B1. The expression levels of miR­27b­3p were increased and those of ATP2B1 were reduced in HUVECs from hypertensive serums. Moreover, miR­27b­3p mimics reduced the expression level of ATP2B1, and miR­27b­3p inhibitor reversed the effect of hypertensive serum on ATP2B1 expression. Furthermore, patients with hypertension showed increased endothelial dysfunction, reduced trophoblastic invasion and the expressions of VEGF, MMP­2 and MMP­9, and miR­27b­3p mimics and silencing of ATP2B1 produced similar results to HUVECs. The miR­27b­3p inhibitor reversed the effect of hypertensive serum, and silencing of ATP2B1 inhibited the improvement of miR­27b­3p inhibitor to HUVECs and HTR­8/SVneo cells in proliferation, migration and tube formation. The current findings suggested that miR­27b­3p promoted proliferation, migration and tube formation of HUVECs and enhanced invasion of trophoblast cells, via regulation of ATP2B1. Thus, miR­27b­3p could be considered as a molecular risk factor in the pathogenesis and development of preeclampsia.