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.

Causal relationships exist between polycystic ovary syndrome and adverse pregnancy and perinatal outcomes: a Mendelian randomization study.

Introduction: Previous observational studies have shown that polycystic ovary syndrome (PCOS) was associated with adverse pregnancy and perinatal outcomes. However, it remains controversial whether PCOS is an essential risk factor for these adverse pregnancy and perinatal outcomes. We aimed to use instrumental variables in a two-sample Mendelian randomization (MR) study to determine causality between PCOS and adverse pregnancy and perinatal outcomes. Materials and methods: Summary statistics were extracted from a recent genome-wide association study (GWAS) meta-analysis conducted in PCOS, which included 10,074 cases and 103,164 controls of European ancestry. Data on Adverse pregnancy and perinatal outcomes were summarized from the FinnGen database of European ancestry, which included more than 180,000 samples. The inverse variance weighted (IVW) method of MR was applied for the main outcome. To assess heterogeneity and pleiotropy, we conducted sensitivity analyses, including leave-one-out analysis, weighted median, MR-PRESSO (Mendelian Randomization Pleiotropy RESidual Sum and Outlier), and MR-Egger regression. Results: Two-sample MR analysis with the IVW method suggested that PCOS exerted causal effects on the risk of hypertensive disorders of pregnancy [odds ratio (OR) 1.170, 95% confidence interval (CI) 1.051-1.302, p = 0.004], in particular gestational hypertension (OR 1.083, 95% CI 1.007-1.164, p = 0.031), but not other pregnancy and perinatal diseases (all p > 0.05). Sensitivity analyses demonstrated pleiotropy only in pre-eclampsia or eclampsia (p = 0.0004), but not in other pregnancy and perinatal diseases (all p > 0.05). The results remained consistent after excluding two outliers (all p > 0.05). Conclusions: We confirmed a causal relationship between PCOS and hypertensive disorders of pregnancy, in particular gestational hypertension, but no association with any other adverse pregnancy or perinatal outcome. Therefore, we suggest that women with PCOS who are pregnant should have their blood pressure closely monitored.

DNA methylation landscape in pregnancy-induced hypertension: progress and challenges.

Gestational hypertension (PIH), especially pre-eclampsia (PE), is a common complication of pregnancy. This condition poses significant risks to the health of both the mother and the fetus. Emerging evidence suggests that epigenetic modifications, particularly DNA methylation, may play a role in initiating the earliest pathophysiology of PIH. This article describes the relationship between DNA methylation and placental trophoblast function, genes associated with the placental microenvironment, the placental vascular system, and maternal blood and vascular function, abnormalities of umbilical cord blood and vascular function in the onset and progression of PIH, as well as changes in DNA methylation in the progeny of PIH, in terms of maternal, fetal, and offspring. We also explore the latest research on DNA methylation-based early detection, diagnosis and potential therapeutic strategies for PIH. This will enable the field of DNA methylation research to continue to enhance our understanding of the epigenetic regulation of PIH genes and identify potential therapeutic targets.

Pregnancy induced hypertension and umbilical cord blood DNA methylation in newborns: an epigenome-wide DNA methylation study.

OBJECTIVIES: Pregnancy induced hypertension (PIH) syndrome is a disease that unique to pregnant women and is associated with elevated risk of offspring cardiovascular diseases (CVDs) and neurodevelopmental disorders in their kids. Previous research on cord blood utilizing the Human Methylation BeadChip or EPIC array revealed that PIH is associated with specific DNA methylation site. Here, we investigate the whole genome DNA methylation landscape of cord blood from newborns of PIH mother. METHODS: Whole-genome bisulfite sequencing (WGBS) was used to examine the changes in whole genome DNA methylation in the umbilical cord blood of three healthy (NC) and four PIH individuals. Using methylKit, we discovered Hypo- and hyper- differentially methylated probes (DMPs) or methylated regions (DMRs) in the PIH patients' cord blood DNA. Pathway enrichments were assessed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment assays. DMPs or DMRs relevant to the immunological, neurological, and circulatory systems were also employed for enrichment assay, Metascape analysis and PPI network analysis. RESULTS: 520 hyper- and 224 hypo-DMPs, and 374 hyper- and 186 hypo-DMRs between NC and PIH group, respectively. Both DMPs and DMRs have enhanced pathways for cardiovascular, neurological system, and immune system development. Further investigation of DMPs or DMRs related to immunological, neurological, and circulatory system development revealed that TBK1 served as a hub gene for all three developmental pathways. CONCLUSION: PIH-associated DMPs or DMRs in umbilical cord blood DNA may play a role in immunological, neurological, and circulatory system development. Abnormal DNA methylation in the immune system may also contribute to the development of CVDs and neurodevelopment disorders.

Uterine leiomyoma causes an increase in systolic blood pressure: a two-sample Mendelian randomization study.

Objectives: Hypertension and hypertensive disorders of pregnancy (HDP) are common diseases in women at different stages, which affect women's physical and mental health, and the impact of the latter on the offspring cannot not be ignored. Observational studies have investigated the correlation between uterine leiomyoma (UL) and the above conditions, but the relationship remains unclear. In this study, we employed two-sample Mendelian randomization (MR) analysis to assess the association between UL and hypertension, HDP, as well as blood pressure. Methods: We collected genetic association data of UL (35,474 cases), hypertension (129,909 cases), HDP (gestational hypertension with 8,502 cases, pre-eclampsia with 6,663 cases and eclampsia with 452cases), systolic blood pressure (SBP) and diastolic blood pressure (DBP) (both 757,601 participants) from published available genome-wide association studies (GWAS). The single nucleotide polymorphisms (SNPs) associated with UL phenotype were used as instrumental variables, and hypertension, three sub-types of HDP, SBP and DBP were used as outcomes. The inverse-variance weighted (IVW) method was employed as the primary method of causal inference. Heterogeneity was assessed using Cochran's Q test, and sensitivity analyses were conducted using MR-Egger regression and MR pleiotropy residual sum and outlier (MR-PRESSO) tests to evaluate the pleiotropy of instrumental variables. PhenoScanner search was used to remove confounding SNP. Robustness and reliability of the results were assessed using methods such as the weighted median and weighted mode. Results: The IVW analysis revealed a positive correlation between genetically predicted UL and SBP [odds ratio (OR)= 1.67, 95% confidence interval (CI):1.24~2.25, P = 0.0007], and no statistical association was found between UL and hypertension, HDP, or DBP. The MR-Egger regression suggested that the above causal relationships were not affected by horizontal pleiotropy. The weighted median method and weighted model produced similar results to the IVW. Conclusion: Based on large-scale population GWAS data, our MR analysis suggested a causal relationship between UL and SBP. Therefore, women with UL, especially pregnant women, should pay attention to monitoring their blood pressure levels. For patients with hypertension who already have UL, interventions for UL may serve as potential therapeutic methods for managing blood pressure.

Causal effects of hypertensive disorders of pregnancy on future gynecologic tumors: A two-sample Mendelian randomization study.

BACKGROUND: Numerous observational studies have investigated the potential link between hypertensive disorders of pregnancy (HDPs) and the subsequent risks of gynecologic tumors, yet the findings have been inconsistent. In this study, we utilized Mendelian randomization (MR) approach to assess the influence of HDPs on the future risks of ovarian, cervical, endometrial, and breast cancer and uterine fibroids, controlling for confounding factors. METHODS: The genome-wide association studies (GWAS) summary data relevant to HDPs was obtained from the FinnGen databases (10,736 cases and 136,325 controls). Gynecologic tumor outcomes were extracted from the IEU Open GWAS project and UK Biobank (47,690 cases and 1, 092,073 controls). The inverse variance weighted (IVW) approach was selected as the principal method for MR analysis, supplemented by MR-Egger, weighted median, weighted model, simple model methods, MR pleiotropy residual sum and outlier (MR-PRESSO) test, and leave-one-out method. Multivariate MR (MVMR) analysis was conducted after adjusting systolic blood pressure (SBP), body mass index (BMI) and type 2 diabetes mellitus (T2DM). RESULTS: Our univariate MR analysis (UVMR) results revealed no significant relationship between HDPs and the risks of ovarian cancer (odds ratio [OR] = 0.924, p = 0.360), cervical cancer (OR = 1.230, p = 0.738), endometrial cancer (OR = 1.006, p = 0.949), uterine fibroids (OR = 1.155, p = 0.158), and breast cancer (OR = 0.792, p = 0.241) by IVW test. Similar results were observed in gestational hypertension and preeclampsia/eclampsia. Additionally, our study detected neither heterogeneity nor pleiotropy. MVMR analysis also provided no evidence of a causal association between HDPs and common gynecologic tumors after adjusting SBP, BMI, and T2DM. CONCLUSION: We discovered no causal relationship between HDPs and ovarian, cervical, endometrial, breast cancer, and uterine fibroids in European populations. However, present analysis did not explore the effect of HDPs on the subtypes of gynecologic tumors across varied ethnic populations, which may require additional research.

SIRT5-mediated PRKAA2 succinylation ameliorates apoptosis of human placental trophoblasts in hypertensive disorder complicating pregnancy.

PURPOSE: Hypertensive disorder complicating pregnancy (HDCP) is a serious clinical disorder syndrome during pregnancy. This study aims at finding novel targets for HDCP therapy. METHODS: HDCP-related mRNAs were firstly screened out and subjected to gene enrichment analysis. We chose protein kinase AMP-activated catalytic subunit alpha 2 (PRKAA2) as the research object. Thirty-nine HDCP patients at 32 to 40 weeks of gestation were selected as the HDCP group, and 39 normal controls who received cesarean section delivery at 37-42 weeks of pregnancy were enrolled in this study. Chorionic villi samples were collected within 30 min of delivery. The apoptosis of isolated placental trophoblasts was monitored to investigate the regulatory role of PRKAA2. RESULTS: PRKAA2 expression was further proven to be enhanced in the placental tissues of HDCP patients compared with that of normal puerpera. Subsequently, the results of flow cytometry analysis and western blot indicated that PRKAA2 overexpression accelerated primary placental cell apoptosis, while its knockdown attenuated cell apoptosis. Mechanistically, we determined that the level of PRKAA2 succinylation was elevated in the placental tissue of HDCP patients. Through in vitro succinylation assay and mutagenesis, we confirmed that sirtuin 5 (SIRT5) interacts with PRKAA2 at K69 and K260 to induce PRKAA2 desuccinylation. SIRT5 regulated primary HDCP cell apoptosis through PRKAA2. Finally, the animal study revealed that PRKAA2 elevates the systolic blood pressure of HDCP rat model. CONCLUSION: Our findings indicated that SIRT5-mediated PRKAA2 succinylation modulates placental cell apoptosis in HDCP, suggesting that PRKAA2 is a potential therapeutic target for HDCP treatment.

The Molecular Basis of the Augmented Cardiovascular Risk in Offspring of Mothers with Hypertensive Disorders of Pregnancy.

The review examines the impact of maternal preeclampsia (PE) on the cardiometabolic and cardiovascular health of offspring. PE, a hypertensive disorder of pregnancy, is responsible for 2 to 8% of pregnancy-related complications. It significantly contributes to adverse outcomes for their infants, affecting the time of birth, the birth weight, and cardiometabolic risk factors such as blood pressure, body mass index (BMI), abdominal obesity, lipid profiles, glucose, and insulin. Exposure to PE in utero predisposes offspring to an increased risk of cardiometabolic diseases (CMD) and cardiovascular diseases (CVD) through mechanisms that are not fully understood. The incidence of CMD and CVD is constantly increasing, whereas CVD is the main cause of morbidity and mortality globally. A complex interplay of genes, environment, and developmental programming is a plausible explanation for the development of endothelial dysfunction, which leads to atherosclerosis and CVD. The underlying molecular mechanisms are angiogenic imbalance, inflammation, alterations in the renin-angiotensin-aldosterone system (RAAS), endothelium-derived components, serotonin dysregulation, oxidative stress, and activation of both the hypothalamic-pituitary-adrenal axis and hypothalamic-pituitary-gonadal axis. Moreover, the potential role of epigenetic factors, such as DNA methylation and microRNAs as mediators of these effects is emphasized, suggesting avenues for future research and therapeutic interventions.

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.

Expression of long non-coding RNA GAS5 by first trimester screening predicts the occurrence of gestational hypertension and pre-eclampsia.

AIMS: Hypertensive disorders of pregnancy (HDP) is a unique disease during gestational period, which is detrimental to pregnancy outcome. This study examined the clinical significance of long non-coding RNA GAS5 in gestational hypertension (GH) and preeclampsia (PE), aiming to explore potential biomarkers for the disease detection. METHODS: 180 pregnant women with HPD including 90 cases with GH and 90 cases with PE, and another 100 healthy pregnant women were enrolled. Serum GAS5 levels were measured by RT-qPCR method. The diagnostic performance of GAS5 was assessed in GH and PE through plotting receiver operating characteristic (ROC) curve. Logistic regression was applied for the identification of independent factors. RESULTS: Elevated serum GAS5 was identified in GH patients, and its diagnostic performance in discriminating GH cases from healthy people was determined by ROC curve. Serum GAS5 was positively associated with SBP, DBP, LDL-C and CRP values. Cases with PE had an increased serum GAS5 level relative to those with GH. Serum GAS5 was identified to be an independent predictor for PE, and can differentiate PE cases from GH ones. with a good diagnositc performance. Cases with high levels of serum GAS5 had a high risk of poor pregnancy outcomes. CONCLUSION: Elevated serum GAS5 could serve as an effective diagnostic biomarker in discriminating GH patients from healthy people by first trimester screening. Detection of serum GAS5 level has a certain predictive value for PE.

Parental genetically predicted liability for coronary heart disease and risk of adverse pregnancy outcomes: a cohort study.

BACKGROUND: Adverse pregnancy outcomes (APO) may unmask or exacerbate a woman's underlying risk for coronary heart disease (CHD). We estimated associations of maternal and paternal genetically predicted liability for CHD with lifelong risk of APOs. We hypothesized that associations would be found for women, but not their male partners (negative controls). METHODS: We studied up to 83,969‬ women (and up to 55,568‬ male partners) from the Norwegian Mother, Father and Child Cohort Study or the Trøndelag Health Study with genotyping data and lifetime history of any APO in their pregnancies (1967-2019) in the Medical Birth Registry of Norway (miscarriage, stillbirth, hypertensive disorders of pregnancy, gestational diabetes, small for gestational age, large for gestational age, and spontaneous preterm birth). Maternal and paternal genetic risk scores (GRS) for CHD were generated using 148 gene variants (p-value < 5 × 10-8, not in linkage disequilibrium). Associations between GRS for CHD and each APO were determined using logistic regression, adjusting for genomic principal components, in each cohort separately, and combined using fixed effects meta-analysis. RESULTS: One standard deviation higher GRS for CHD in women was related to increased risk of any hypertensive disorders of pregnancy (odds ratio [OR] 1.08, 95% confidence interval [CI] 1.05-1.10), pre-eclampsia (OR 1.08, 95% CI 1.05-1.11), and small for gestational age (OR 1.04, 95% CI 1.01-1.06). Imprecise associations with lower odds of large for gestational age (OR 0.98, 95% CI 0.96-1.00) and higher odds of stillbirth (OR 1.04, 95% CI 0.98-1.11) were suggested. These findings remained consistent after adjusting for number of total pregnancies and the male partners' GRS and restricting analyses to stable couples. Associations for other APOs were close to the null. There was weak evidence of an association of paternal genetically predicted liability for CHD with spontaneous preterm birth in female partners (OR 1.02, 95% CI 0.99-1.05), but not with other APOs. CONCLUSIONS: Hypertensive disorders of pregnancy, small for gestational age, and stillbirth may unmask women with a genetically predicted propensity for CHD. The association of paternal genetically predicted CHD risk with spontaneous preterm birth in female partners needs further exploration.

Integrative Placental Multi-Omics Analysis Reveals Perturbed Pathways and Potential Prognostic Biomarkers in Gestational Hypertension.

BACKGROUND: Gestational hypertension (GH) is a severe complication that occurs after 20 weeks of pregnancy; however, its molecular mechanisms are not yet fully understood. OBJECTIVE: Through this case-control discovery phase study, we aimed to find disease-specific candidate placental microRNAs (miRNAs) and metabolite markers for differentiating GH by integrating next-generation sequencing and metabolomics multi-omics analysis of placenta. Using small RNA sequencing and metabolomics of placental tissues of healthy pregnant (HP, n = 24) and GH subjects (n = 20), the transcriptome and metabolome were characterized in both groups. RESULTS: The study identified a total of 44 downregulated placental miRNAs which includes three novel, three mature and 38 precursor miRNAs. Six miRNAs including three mature (hsa-miR-181a-5p, hsa-miR-498-5p, and hsa-miR-26b-5p) and three novel (NC_000016.10_1061, NC_000005.10_475, and NC_000001.11_53) were considered for final target prediction and functional annotation. Integrative analysis of differentially expressed miRNAs and metabolites yielded five pathways such as purine, glutathione, glycerophospholipid, inositol phosphate and ß-alanine to be significantly perturbed in GH. We present fourteen genes (LPCAT1, LPCAT2, DGKH, PISD, GPAT2, PTEN, SACM1L, PGM2, AMPD3, AK7, AK3, CNDP1, IDH2, and ODC1) and eight metabolites (xanthosine, xanthine, spermine, glycine, CDP-Choline, glyceraldehyde 3-phosphate, ß-alanine, and histidine) with potential to distinguish GH and HP. CONCLUSION: The differential expression of miRNAs, their target genes, altered metabolites and metabolic pathways in GH patients were identified for the first time in our study. Further, the altered miRNAs and metabolites were integrated to build their inter-connectivity network. The findings obtained from our study may be used as a valuable source to further unravel the molecular pathways associated with GH and also for the evaluation of prognostic markers.

Associations of hypertensive disorders of pregnancy with cognition, dementia, and brain structure: a Mendelian randomization study.

BACKGROUND: Observational studies have found associations between hypertensive disorders of pregnancy and an increased risk of cognitive dysfunction and reduced brain volume. However, the results of observational studies may have been influenced by confounding factors. This study applied two-sample Mendelian randomization (MR) to explore the causal associations of hypertensive disorders of pregnancy with cognition, dementia, and brain structure. METHODS: Summary data on hypertensive disorders of pregnancy and their main subtypes, cognition, dementia, and brain structure were obtained from recent European genome-wide association studies. We computed the inverse-variance weighted, MR-Egger, and weighted median MR estimates. Cochran's Q statistics and the MR-Egger intercept test were used to quantify the heterogeneity and horizontal pleiotropy of the instrumental variables. RESULTS: Genetically predicted preeclampsia or eclampsia was inversely associated with gray matter volume [beta = -0.072; 95% confidence interval (CI) = -0.131 to -0.014; P  = 1.53 × 10 -2 ]; possibly with brain volume (beta = -0.064; 95% CI = -0.117 to -0.012; P  = 1.68 × 10 -2 ). However, the association of hypertensive pregnancy disorders or gestational hypertension with brain structure was not significant. We did not find any significant association between hypertensive disorders of pregnancy, gestational hypertension, or preeclampsia or eclampsia and cognition and dementia-related outcomes. CONCLUSION: This study provided genetic evidence supporting an association between preeclampsia or eclampsia and reduced brain volume. This supports the view of PE as a risk factor for gray matter volume reduction.

Hypertensive disorders of pregnancy and cardiovascular disease risk: a Mendelian randomisation study.

OBJECTIVE: Observational studies show that hypertensive disorders of pregnancy (HDPs) are related to unfavourable maternal cardiovascular disease (CVD) risk profiles later in life. We investigated whether genetic liability to pre-eclampsia/eclampsia and gestational hypertension is associated with CVD risk factors and occurrence of CVD events. METHODS: We obtained genetic associations with HDPs from a genome-wide association study and used individual participant data from the UK Biobank to obtain genetic associations with CVD risk factors and CVD events (defined as myocardial infarction or stroke). In our primary analysis, we applied Mendelian randomisation using inverse-variance weighted regression analysis in ever pregnant women. In sensitivity analyses, we studied men and nulligravidae to investigate genetic liability to HDPs and CVD risk without the ability to experience the underlying phenotype. RESULTS: Our primary analysis included 221 155 ever pregnant women (mean age 56.8 (SD 7.9) years) with available genetic data. ORs for CVD were 1.20 (1.02 to 1.41) and 1.24 (1.12 to 1.38) per unit increase in the log odds of genetic liability to pre-eclampsia/eclampsia and gestational hypertension, respectively. Furthermore, genetic liability to HDPs was associated with higher levels of systolic and diastolic blood pressure and younger age at hypertension diagnosis. Sensitivity analyses revealed no statistically significant differences when comparing the findings with those of nulligravidae and men. CONCLUSIONS: Genetic liability to HDPs is associated with higher CVD risk, lower blood pressure levels and earlier hypertension diagnosis. Our study suggests similar findings in ever pregnant women, nulligravidae and men, implying biological mechanisms relating to HDPs are causally related to CVD risk.

Trophoblast cellular adhesion molecule expression regulated by different genes and their correlation with pregnancy-induced hypertension.

It was to study trophoblast cell (TC) adhesion molecules regulated by different genes in the placental tissue (PT) of patients with pregnancy-induced hypertension (PIH), and the correlation with the severity of PIH. 42 patients with PIH (13 cases in the mild PIH group, 11 cases in the moderate PIH group, and 18 cases in the severe PIH group) and 40 patients with normal pregnancy (NP group) were included. mRNA and protein levels in matrix metalloproteinase (MMP)-9, MMP-2, tissue inhibitor of metalloproteinases (TIMP)-1, and TIMP-2 of all patients were determined by semi-quantitative polymerase chain reaction (PCR) and Western blotting (WB), respectively. Compared to the NP group, MMP-9 and MMP-2 mRNA levels as well as their proteins in PT significantly decreased in PIH groups (P<0.05). MMP-9 mRNA was greatly lower in the severe PIH group than mild PIH group (P<0.05). MMP-2 mRNA in moderate and severe PIH groups was much lower than NP and mild PIH groups, and that in the severe PIH group was considerably lower than the moderate PIH group (P<0.05). TIMP-1 mRNA and its protein highly increased in PT in PIH groups than NP group (P<0.05). TIMP-2 mRNA was remarkably higher in the severe PIH group than in the NP group (P<0.05). mRNA and proteins of MMP-9 and MMP-2 decreased in PT of PIH patients, while TIMP-1 mRNA and its protein increased, which were correlated with the severity of PIH. MMP-9, MMP-2, and TIMP-1 were involved in the pathogenesis of PIH by regulating the infiltration of TCs.

Circulating inflammatory cytokines and hypertensive disorders of pregnancy: a two-sample Mendelian randomization study.

Background: Hypertensive disorders of pregnancy (HDP) pose a significant risk to maternal and fetal well-being; however, the etiology and pathogenesis of HDP remain ambiguous. It is now widely acknowledged that inflammatory response and the immune system are closely related to HDP. Previous research has identified several inflammatory cytokines are associated with HDP. This study applied Mendelian randomization (MR) analysis to further assess causality. Methods: Patients with HDP who participated in the MR analysis presented with four types of HDP: pre-eclampsia or eclampsia (PE); gestational hypertension (GH); pre-existing hypertension complicating pregnancy, childbirth and the puerperium (EH); and pre-eclampsia or poor fetal growth (PF). A two-sample MR analysis was used to analyze the data in the study. The causal relationship between exposure and outcome was analyzed with inverse variance weighting (IVW), MR Egger, weighted median, weighted mode, and simple mode methods, where IVW was the primary method employed. Results: Our MR analysis demonstrated a reliable causative effect of Interleukin-9 (IL-9) and macrophage migration inhibitory factor (MIF) on reducing HDP risk, while macrophage inflammatory protein 1-beta (MIP1b), Interleukin-13 (IL-13), and Interleukin-16 (IL-16) were associated with promoting HDP risk. Conclusions: This study demonstrated that IL-9, MIF, MIP1b, IL-13, and IL-16 may be cytokines associated with the etiology of HDP, and that a number of inflammatory cytokines are probably involved in the progression of HDP. Additionally, our study revealed that these inflammatory cytokines have causal associations with HDP and may likely be potential therapeutic targets for HDP.

Gut microbiota and hypertensive disorders in pregnancy: evidence from the Mendelian randomization study.

BACKGROUND: Recent studies have shown that gut microbiota (GM) is related to hypertensive disorders in pregnancy (HDP). However, the causal relationship needs to be treated with caution due to confounding factors and reverse causation. METHODS: We obtained genetic variants from genome-wide association studies including GM (N = 18,340) in MiBioGen Consortium as well as HDP (7,686 cases/115,893 controls) and specific subtypes in FinnGen Consortium. Then, Inverse variance weighted, maximum likelihood, weighted median, MR-Egger, and MR.RAPS methods were applied to examine the causal association. Reverse Mendelian randomization (RMR) and multivariable MR were performed to confirm the causal direction and adjust the potential confounders, respectively. Furthermore, sensitivity analyses including Cochran's Q statistics, MR-Egger intercept, MR-PRESSO global test, and the leave-one-out analysis were conducted to detect the potential heterogeneity and horizontal pleiotropy. RESULTS: The present study found causalities between eight gut microbial genera and HDP. The HDP-associated gut microbial genera identified by MR analyses varied in different subtypes. Specifically, our study found causal associations of LachnospiraceaeUCG010, Olsenella, RuminococcaceaeUCG009, Ruminococcus2, Anaerotruncus, Bifidobacterium, and Intestinibacter with GH, of Eubacterium (ruminantium group), Eubacterium (ventriosum group), Methanobrevibacter, RuminococcaceaeUCG002, and Tyzzerella3 with PE, and of Dorea and RuminococcaceaeUCG010 with eclampsia, respectively. CONCLUSIONS: This study first applied the MR approach to detect the causal relationships between GM and specific HDP subtypes. Our findings may promote the prevention and treatment of HDP targeted on GM and provide valuable insights to understand the mechanism of HDP in different subtypes from the perspective of GM.

The role and expression of pro/antiangiogenic factors and microRNAs in gestational hypertension and pre-eclampsia.

OBJECTIVE: Pre-eclampsia and gestational hypertension are two common hypertensive disorders of pregnancy with pre-eclampsia accounting for high foetal and maternal morbidity and mortality rate. These disorders have an unknown aetiology and their hypertensive and end-organ pathophysiology may present too late in pregnancy. This makes the identification of early detection and differentiation markers vital. MicroRNAs have strongly been associated with pregnancy and their imbalance has been associated with the angiogenic dysregulation seen in pre-eclampsia. This study assesses the expression of pro- and antiangiogenic factors and their corresponding microRNAs in the maternal circulation of patients with pre-eclampsia and gestational hypertension. STUDY DESIGN: We analyzed angiogenic factors expression (sEng, TGF-ß, VEGF) normalized against housekeeping gene ß-actin and microRNAs (miRs: 210, 29B, 126) normalized against miR U6, potentially associated with pre-eclampsia and gestational hypertension using the targeted qPCR technique. These analytes were examined from early-onset (<34 weeks) (EOPE) (n = 12), late-onset (>34 weeks) (LOPE) (n = 12) pre-eclampsia, gestational hypertension (GH) (n = 12) and two gestationally matched normotensive groups (NG1 and 2) (n = 12) each in South African women of African ancestry. Group comparisons of experimental vs. control groups were assessed using t-test analysis for significance and represented as fold change expression. RESULTS: The relative expression in group comparisons showed significant (p < 0.05) fold change of VEGF, TGF-ß, sEng and miR126 in the EOPE vs. NG1. The GH vs. NG1 exhibited significant changes in VEGF, TGF-ß, miR126, miR210 and miR29B. The LOPE vs. NG2 showed significant relative expression in all the angiogenic factors (VEGF, TGF-ß and sEng). The GH vs. NG2 showed significant expression in VEGF and miR29B. The LOPE vs. EOPE showed significant fold changes in VEGF and miR210. Finally, only the GH vs. EOPE showed significant differences in miR210 and miR29B (p < 0.05). CONCLUSION: This study provides better insights into angiogenic factors and microRNAs specificity to the subtypes of gestational hypertensive disorders in pregnancy. Relative expression analysis of angiogenic factors and microRNAs showed possible novel characteristics of gestational hypertension, and potential common molecular and pathological profiles with pre-eclampsia. Furthermore, we postulate that sEng and miR29B could be early detection markers for pre-eclampsia and gestational hypertension, respectively.

Fatty acids and pregnancy-induced hypertension: a Mendelian randomization study.

BACKGROUND: It is well known that pregnancy-induced hypertension (PIH) contributes significantly to the mortality rates of both mothers and babies during pregnancy. The relationship between fatty acids (FAs) and PIH remains debatable, with the causality between the two yet to be definitively established. METHODS: Two-sample univariable and multivariable Mendelian Randomization (MR) analyses were executed, based on pooled data from Genome-Wide Association Studies (GWAS), to investigate any causal impact of FAs on PIH. A suite of methods was employed to assess causality, including inverse variance weighting (IVW), weighted median, MR Egger, simple mode, and weighted mode. Subsequently, the data underwent a sensitivity analysis (using Leave-One-Out analysis), a heterogeneity test (with MR-PRESSO and Cochran's Q test), as well as a multiple validity test (using MR-Egger regression). In multivariable analyses, fatty acids were first grouped to observe the effect of individual FAs on PIH. Subsequently, factors such as diabetes, high blood pressure, and body mass index (BMI) were incorporated into a multivariable examination of the impact of each FA on PIH. During this process, the IVW, weighted median, MR-Lasso, and MR-Egger methods were employed. RESULTS: A systematic investigation was conducted into the causal impact of each FA on PIH. The findings indicated that Polyunsaturated Fatty Acids (PUFA), Omega3, the ratio of Omega6 to Omega3, and Docosahexaenoic Acid (DHA) have a causal relationship with PIH. Increases in PUFA, Omega3, and DHA could potentially reduce the risk of PIH, while an increase in the Omega6/Omega3 ratio could heighten the risk. The impacts of other FAs (including Total Fatty Acids, Monounsaturated Fatty Acids (MUFA), Saturated Fatty Acids (SFA), and Omega 6) on PIH were not substantiated by the MR analysis. In the univariate leave-one-out analysis, rs174564 was identified in PUFA, Omega3, and DHA as having a significant role. The tests with MR-Egger and MR-PRESSO found that the results were not influenced by pleiotropy and heterogeneity. After adjusting for BMI, Diabetes Mellitus, and pre-existing hypertension in the multivariable analysis, the results mirrored those obtained univariable. CONCLUSION: The research implies that elevated levels of circulating PUFA, DHA, and Omega3 may serve as a protective mechanism against PIH, while higher Omega6/Omega3 ratios could potentially increase the risk of PIH. These findings may inform clinical strategies for PIH prevention.

Natriuretic Peptide Signaling in Uterine Biology and Preeclampsia.

Endometrial decidualization is a uterine process essential for spiral artery remodeling, embryo implantation, and trophoblast invasion. Defects in endometrial decidualization and spiral artery remodeling are important contributing factors in preeclampsia, a major disorder in pregnancy. Atrial natriuretic peptide (ANP) is a cardiac hormone that regulates blood volume and pressure. ANP is also generated in non-cardiac tissues, such as the uterus and placenta. In recent human genome-wide association studies, multiple loci with genes involved in natriuretic peptide signaling are associated with gestational hypertension and preeclampsia. In cellular experiments and mouse models, uterine ANP has been shown to stimulate endometrial decidualization, increase TNF-related apoptosis-inducing ligand expression and secretion, and enhance apoptosis in arterial smooth muscle cells and endothelial cells. In placental trophoblasts, ANP stimulates adenosine 5'-monophosphate-activated protein kinase and the mammalian target of rapamycin complex 1 signaling, leading to autophagy inhibition and protein kinase N3 upregulation, thereby increasing trophoblast invasiveness. ANP deficiency impairs endometrial decidualization and spiral artery remodeling, causing a preeclampsia-like phenotype in mice. These findings indicate the importance of natriuretic peptide signaling in pregnancy. This review discusses the role of ANP in uterine biology and potential implications of impaired ANP signaling in preeclampsia.