Preeclampsia (PE) is characterized as de novo hypertension (HTN) with end-organ damage, especially in the brain. PE is hypothesized to be caused by placental ischemia. PE affects ~5-8% of USA pregnancies and increases the risk for HTN and cerebrovascular diseases (CVD) later in life. We hypothesize that blood pressure (BP), cerebral oxidative stress, and cerebral inflammation will increase in postpartum (PP) placental ischemic dams.

Placental ischemia was induced in pregnant Sprague Dawley dams, utilizing reduced uterine perfusion pressure (RUPP) surgery. At 6 weeks PP (~3 human years), BP was measured via carotid catheterization, and cerebral oxidative stress and inflammation were assessed via ELISAs, biochemical assays, and Western blots.

BP, cerebral pro-inflammatory cytokines (TNF-α and IL-6), and GFAP (a marker of astrocyte activity) were increased in PP RUPP dams. Cerebral hydrogen peroxide (H2O2) was also increased in PP RUPP dams, and had a strong correlation with PP RUPP BP, proinflammatory cytokines (TNF- α and IL-6), and GFAP astrocyte activation.

PP RUPP dams have increased BP, cerebral oxidative stress, and cerebral inflammation at 6 weeks postpartum. These changes in cerebral inflammation and oxidative stress may contribute to the pathology and development of HTN and CVDs in postpartum dams.

Microplastic (MP) pollution is an emerging environmental concern with potential health risks, yet its impact on pregnancy remains largely unexplored. This study investigated the effects of polystyrene microplastic (PS-MP) exposure on placental function and its role in preeclampsia (PE) pathogenesis. Pregnant rats were exposed to PS-MP, which induced PE-like symptoms including elevated blood pressure, increased proteinuria, and altered expression of angiogenic factors. Transcriptomic and molecular analyses revealed PS-MP triggered ferroptosis in placental trophoblast cells by activating the HIF-1α/TFRC axis, resulting in iron overload and oxidative stress. PS-MP exposure impaired trophoblast migration, invasion, and angiogenesis; these effects were ameliorated by ferroptosis inhibition. These findings identified PS-MP-induced ferroptosis as a critical mechanism underlying placental dysfunction, highlighting PS-MP as a potential environmental risk factor for PE. Understanding the impact of MP on pregnancy provides crucial insights into their reproductive toxicity and underscores the need for further research on mitigating their effects.

Preeclampsia is a pregnancy-specific syndrome, linked to oxidative stress, affecting 5-8% of pregnancies, with no effective treatment available. Here, diaryl-hydrazones have been designed, synthesized, and investigated as mitochondria-targeting antioxidants to reduce placental oxidative stress and mitigate preeclampsia symptoms. The design, based on density functional theory studies, revealed that conjugated electron structure with the NH-motif appeared to explain their effect. Thirty compounds were synthesized and tested in three assays, where they exhibited excellent radical scavenging activity, significantly greater than that of the standard, Trolox. Based on the data, eight compounds were selected for cell-based assays. Oxidative stress was induced in human trophoblast cells and assessed whether the compounds reduced downstream antiangiogenic responses using ascorbic acid and MitoTEMPO as standards. The pretreatment with the hydrazones reduced mitochondrial superoxide and sFLT-1 production in H2O2-exposed trophoblast cells, indicating that mitochondrial oxidative stress and the anti-angiogenic response can be alleviated by these compounds.

Vascular endothelial growth factor (VEGF) signaling is a critical regulator of vasculogenesis, angiogenesis, and lymphangiogenesis, processes that are vital for the development of vascular and lymphatic systems, tissue repair, and the maintenance of homeostasis. VEGF ligands and their receptors orchestrate endothelial cell proliferation, migration, and survival, playing a pivotal role in dynamic vascular remodeling. Dysregulated VEGF signaling drives diverse pathological conditions, including tumor angiogenesis, cardiovascular diseases, and ocular disorders. Excessive VEGF activity promotes tumor growth, invasion, and metastasis, while insufficient signaling contributes to impaired wound healing and ischemic diseases. VEGF-targeted therapies, such as monoclonal antibodies and tyrosine kinase inhibitors, have revolutionized the treatment of diseases involving pathological angiogenesis, offering significant clinical benefits in oncology and ophthalmology. These therapies inhibit angiogenesis and slow disease progression, but they often face challenges such as therapeutic resistance, suboptimal efficacy, and adverse effects. To further explore these issues, this review provides a comprehensive overview of VEGF ligands and receptors, elucidating their molecular mechanisms and regulatory networks. It evaluates the latest progress in VEGF-targeted therapies and examines strategies to address current challenges, such as resistance mechanisms. Moreover, the discussion includes emerging therapeutic strategies such as innovative drug delivery systems and combination therapies, highlighting the continuous efforts to improve the effectiveness and safety of VEGF-targeted treatments. This review highlights the translational potential of recent discoveries in VEGF biology for improving patient outcomes.

Proteomics has emerged as a transformative tool in biomedical research, enabling comprehensive characterization of protein profiles in complex biological systems. In preeclampsia (PE) research, quantitative proteomic analyses of plasma and serum have revealed critical insights into disease mechanisms and potential biomarkers. Through a systematic review of 17 studies (2009-2024), we identified 561 differentially expressed plasma/serum proteins (p < 0.05) in PE patients versus healthy controls, with 122 proteins consistently replicated across ≥2 independent studies. Stratified analysis by clinical subtype (early-vs. late-onset PE) demonstrated both concordant and divergent protein expression patterns, reflecting heterogeneity in PE pathophysiology, methodological variations (e.g., sample processing, proteomic platforms), and differences between discovery-phase and targeted validation studies. The trimester-specific biomarker panels proposed here offer a framework for future large-scale, multicenter validation. By integrating advanced proteomic technologies with standardized preanalytical and analytical protocols, these findings advance opportunities for early prediction (first-trimester biomarker signatures); mechanistic insight (complement system involvement); and personalized management (subtype-specific therapeutic targets). This work underscores the potential of proteomics to reshape PE research, from molecular discovery to clinical translation, ultimately improving outcomes for this leading cause of maternal and perinatal morbidity.

The incidence of dementia, and specifically, Alzheimer's disease, is higher in women than men, even in middle age, making it possible to rule out lifespan differences between men and women as a contributing factor. Thus, it is plausible that pregnancy experience, which is unique to women, may play a contributing role. In this review, we discuss the different hypertensive disorders of pregnancy (HDP), Alzheimer's and vascular dementia, clinical, epidemiological, and preclinical studies that link a history of HDP with dementia. We also present potential mechanisms linking HDP, Alzheimer's, and vascular dementia. Several key symptoms that are shared among the disorders are presented as potential underlying mechanisms that link the adverse pregnancy disorder with the long-term postpartum neurological changes. Further, we present limitations of the existing literature, gaps, and opportunities for further research.

The US Food and Drug Administration recently approved the ratio of soluble FMS-like tyrosine kinase 1 (sFlt-1) to placental growth factor (PlGF) using the Thermo Fisher Scientific B·R·A·H·M·S KRYPTOR autoanalyzer-the first preeclampsia marker used for clinical testing. We evaluated the analytical precision of the sFlt-1 and PlGF assays, focusing on the effects of PlGF imprecision on the sFlt-1 to PlGF ratio interpretation and clinical reliability for preeclampsia risk assessment.

We measured sFlt-1 and PlGF on the KRYPTOR instrument using a homogeneous sandwich fluoroimmunoassay. Between-day precision was assessed using 3 levels of commercial quality control (QC) materials and analyzed over 3 months. In all, 180 samples obtained from 161 hospitalized pregnant women were analyzed to assess the relationship between PlGF levels and the sFlt-1 to PlGF ratio.

The sFlt-1 assay demonstrated good precision (coefficient of variation (s/x̄) × 100 [CV] = approximately 3.0%) across all QC levels, while the PlGF assay exhibited higher imprecision, particularly at low QC levels (CV = 7.7%-11.3%). Long-term QC monitoring revealed a downward drift in PlGF values, with improved stability after reagent lot changes. Despite higher imprecision at lower PlGF levels (23.1-34.7 ng/L), the clinical interpretation of the sFlt-1 to PlGF ratio remained robust because low PlGF consistently correlated with ratios well above the critical cutoff of 40.

Despite the suboptimal precision observed at low QC levels and potential drifts in PlGF results, the sFlt-1 to PlGF ratio remains a reliable tool for preeclampsia risk assessment. This study highlights the need for critical evaluation of analytical performance beyond FDA approval and the importance of assessing the potential impact of assay imprecision on patient care for individual biomarkers.

Hypertensive disorders of pregnancy (HDP) is assumed to be triggered by incomplete remodeling of the decidual spiral arteries. We examined the lymphocyte subsets and identified immune differences in the spiral arteries between HDP and normal pregnancies, and between remodeled and non-remodeled arteries such as the muscular artery and acute atherosis. One hundred seventy-three patients with HDP diagnosed at our hospital between 2008 and 2017 were included. Patients with a normal course of delivery and patients with premature birth after 34 weeks without pathological changes and abnormalities in the pregnancy course were included in the control group. The infiltrating lymphocytes were evaluated using immunohistochemistry. Acute atherosis was observed in 56 patients (32.4%) of all HDP patients. In patients that presented HDP with acute atherosis, the density of CD8+ T cells and CD4+ T cells was higher in the acute atherosis than those in the non-remodeled muscular artery. CD4+ T cells were more abundant in the non-remodeled muscular artery compared to the remodeled artery. In control patients, the density of CD4+ T cells was higher in the non-remodeled muscular artery than that in the remodeled artery; there was no difference in the density of CD56+ natural killer cells. There was no difference in the density of CD3+ T cells and CD56+ natural killer cells in the remodeled artery between patients presenting HDP with acute atherosis and control patients. These immune differences may cause changes in local cytokine balance around the spiral artery, contributing to the development of HDP.

Preeclampsia is a leading cause of maternal and fetal morbidity and mortality, with obesity recognised as a significant risk factor. However, the direct contribution of obesity to the pathophysiology underpinning preeclampsia remains unclear.

This study aimed to develop and characterise a diet-induced obese mouse model with superimposed preeclampsia to better understand the impact of obesity on disease pathogenesis.

Female mice were fed either standard rodent chow or a high-fat diet from weaning. At 8 weeks of age, mice were mated. Pregnant mice were treated with L-NG-Nitro arginine methyl ester (L-NAME; to block nitric oxide production) from gestational day (D)7.5 to D17.5 to induce a preeclampsia-like phenotype. Blood pressure was measured on D14.5 and D17.5, followed by the collection of maternal and fetal tissues for histological, biochemical, and molecular analyses.

Obese dams exhibited significantly increased body, fat pad, and liver weights compared to lean controls. While L-NAME induced hypertension in the control mice, contrary to expectations, the L-NAME-induced hypertension was partially attenuated in obese dams, with significantly lower systolic and diastolic blood pressures at D14.5 and reduced systolic pressure at D17.5. Fetal weights were comparable between groups, however, placentas were significantly heavier with obesity. Endothelial function, inflammatory markers, and renal gene expression patterns suggested distinct physiological adaptations in obese preeclamptic-like mice.

These findings challenge the prevailing assumption that obesity drives hypertension, endothelial dysfunction, and inflammatory markers. The differential vascular and physiological responses observed in the obese dams highlight the complexity of obesity-preeclampsia interactions and underscore the need for refined preclinical models to disentangle mechanistic contributions. This work has implications for personalised management strategies and targeted therapeutic interventions in obese pregnancies at risk of preeclampsia.

Soluble Fms-like Tyrosine kinase-1 (sFLT1) is a native inhibitor of VEGF, best known for its antiangiogenic effects in preeclampsia. sFLT1 also reduces chronic inflammation and promotes tissue repair. In experimental diabetic nephropathy, we previously found that sFLT1 ameliorates kidney fibrosis and reduces the infiltration of macrophages. How sFLT1 regulates inflammation is still incompletely understood. Based on the direct association of sFLT1 with various cell types, we here studied whether sFLT1 interacts with macrophages to modulate inflammation.

Using various macrophage cell lines, sFLT1 cell surface binding was detected with flow cytometry. Enzyme studies, mass spectrometry and RNAseq were employed to identify potential sFLT1 cell surface interactors and effects of sFLT1 on macrophage signaling.

Soluble FLT1 binds to primary macrophages, THP-1 and RAW264.7 macrophages in vitro. Alternative activation with IL-4 increases sFLT1 binding in THP-1 macrophages, whereas proinflammatory activation with IFN-γ and LPS decreases binding. Binding of sFLT1 depends on heparan sulphates, and colocalizes with the membrane heparin sulfate proteoglycan neuropilin-1. Incubation with sFLT1 reduces the gene expression of chemokine receptors.

Our results show that sFLT1, while typically associated with angiogenesis, also directly interacts with macrophages. Alternative activation of macrophages by IL-4 strongly increases binding of sFLT1 to the cell surface membrane, possibly via the VEGF co-receptor neuropilin-1. Considering sFLT1's anti-inflammatory effects in animal studies, our findings indicate a novel function for sFLT1 to directly control anti-inflammatory macrophage function.

Worldwide, hypertensive disorders of pregnancy (HDP) are a leading cause of maternal and neonatal morbidity and mortality (Semin Perinatol 2009;33:130-7). This is especially true in the United States where preeclampsia is a leading cause of premature births (Hypertens Pregnancy 2016;35:510-9 and Lancet 2008;371:164-75). Moreover, this disorder is costly due to the financial burden of the health services needed to care for mothers with preeclampsia and their very often preterm infants (Am J Obstet Gynecol 2017;217:235-6). Recently, placental biomarkers have been shown to aid in assessment of the risk of severe preeclampsia. In 2023, the FDA approved the use of soluble feline McDonough sarcoma (fms)-like tyrosine kinase-1 to placental growth factor ratio (sFlt-1/PlGF) as an additional tool for preeclampsia risk assessment between 23 and 35 weeks' gestation in high-risk patients in the United States. Use of these biomarkers will improve maternal and fetal/neonatal outcomes and may assist in decreasing the healthcare burden of these patients by adding to risk assessment and the current diagnosis and management of pregnancies with HDP.

The pathophysiology of preeclampsia stems from abnormal placentation that results in an imbalance of pro- and antiangiogenic factors leading to endothelial and vascular dysfunction and the clinical syndrome of preeclampsia (J Clin Invest 2003;111:649-58). The role of the sFlt-1/PlGF in the prediction of progression to preeclampsia has been demonstrated in multiple studies.

The goal of this review is to demonstrate the role of placental biomarkers (sFlt-1 and PlGF) in the pathophysiology of preeclampsia, with an emphasis on clinical applications and cost-effectiveness in the United States, using real-world applications as examples.

Inflammatory bowel disease (IBD) often presents during the fertile age and may affect pregnancy outcomes. Both IBD and selected pregnancy complications involve oxidative stress. Soluble FMS-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) serve as biomarkers of placental insufficiency, while free thiols (FT) reflect systemic oxidative stress. This study aimed to assess the dynamics of FT, sFlt-1, and PlGF before, during, and shortly after pregnancy, and their relationships with disease- and pregnancy outcomes in patients with IBD.

This retrospective cohort study included pregnant women with and without IBD. FTs were measured with colorimetric detection; sFlt-1 and PlGF were measured using immunofluorescent assays. Extensive clinical data were collected, including pregnancy complications and IBD parameters.

A total of 40 patients and 14 non-IBD controls participated, covering 57 IBD and 14 control pregnancies. Serum FT levels were significantly lower in patients with ulcerative colitis during pregnancy (p = 0.007) and decreased compared to pre-conceptional levels (p = 0.005), indicating increased oxidative stress. sFlt-1/PlGF ratios were higher in patients with small-for-gestational-age infants (p = 0.015). Post-pregnancy FT levels were lower in patients experiencing disease exacerbations during pregnancy (p = 0.046), whereas sFlt-1/PlGF ratios were numerically higher (p = 0.063). IBD severity correlated with lower FT levels regarding surgical history (p = 0.066) and biologic use (p = 0.033).

This study demonstrates increased systemic oxidative stress in patients with IBD during pregnancy, as reflected by lower FT levels compared to pre-conceptional values and non-IBD controls. Prospective validation is required to evaluate the utility of these biomarkers in predicting pregnancy complications and informing clinical decisions.

The microvascular system is essential for delivering oxygen and nutrients to tissues while removing metabolic waste. During pregnancy, the uteroplacental microvascular system undergoes extensive remodeling to meet the increased demands of the fetus. Key adaptations include vessel dilation and increases in vascular volume, density, and permeability, all of which ensure adequate placental perfusion while maintaining stable maternal blood pressure. Structural and functional abnormalities in the uteroplacental microvasculature are associated with various gestational complications, posing both immediate and long-term risks to the health of both mother and infant. In this review, we describe the changes in uteroplacental microvessels during pregnancy, discuss the pathogenic mechanisms underlying diseases such as preeclampsia, fetal growth restriction, and gestational diabetes, and summarize current clinical and research approaches for monitoring microvascular health. We also provide an update on research models for gestational microvascular complications and explore solutions to several unresolved challenges. With advancements in research techniques, we anticipate significant progress in understanding and managing these diseases, ultimately leading to new therapeutic strategies to improve maternal and fetal health.

Fetal growth restriction (FGR) is a major cause of neonatal morbidity and mortality. This study investigates the potential of gelsolin (GSN), an actin-regulating protein with anti-inflammatory properties, as a biomarker for early late-onset FGR detection and predicting adverse neonatal outcomes.

In a prospective, cross-sectional study conducted at Ankara Etlik City Hospital, maternal blood samples were collected from 1016 pregnant individuals at 11-14 weeks gestation. After exclusion criteria were applied, 64 late-onset FGR patients and 72 controls were analyzed. Serum GSN levels were assessed via ELISA, and statistical analyses were conducted to determine correlations with late-onset FGR and neonatal outcomes. ROC curve analysis was performed to identify optimal GSN cut-off values.

GSN levels were significantly higher in the late-onset FGR group compared to controls (4.396 ± 3.39 ng/mL vs. 0.925 ± 0.43 ng/mL; p < 0.001). A GSN cut-off of 0.999 ng/mL predicted late-onset FGR with a sensitivity of 78.1 % and specificity of 66.7 % (AUC = 0.852). A higher GSN cut-off of 3.863 ng/mL predicted adverse neonatal outcomes within the late-onset FGR group with a sensitivity of 63.4 % and specificity of 60.9 % (AUC = 0.703).

Elevated first trimester GSN levels are associated with late-onset FGR and adverse neonatal outcomes. Monitoring GSN could serve as an early, non-invasive screening tool for high-risk pregnancies, facilitating timely intervention and specialized care. This study provides evidence supporting GSN as a promising biomarker in late-onset FGR prediction, contributing to the improvement of maternal-fetal healthcare.

Elevated maternal serum sFLT1 (soluble fms-like tyrosine kinase 1) has a key role in the pathophysiology of preeclampsia. We sought to determine the relationship between the maternal and fetal genome and maternal levels of sFLT1 at 12, 20, 28, and 36 weeks of gestational age (wkGA).

We studied a prospective cohort of nulliparous women (3968 mother-child pairs). We related maternal and fetal genotype to the adjusted sFLT1 Z score and sFLT1:placental growth factor (PlGF) ratio Z score at each wkGA and the change in the Z score between 28 and 36 wkGA (Δ36-28). We studied genetic variants from a previous fetal genome-wide association study of preeclampsia and an externally defined polygenic score from a maternal genome-wide association study of preeclampsia.

Four variants from the fetal preeclampsia genome-wide association study were positively associated with sFLT1 and sFLT1:PlGF Z score at 36 wkGA, and FLT1 enhancer single-nucleotide polymorphisms were associated with increased Δ36-28 of sFLT1. The associations were specific for the fetal genome or stronger for the fetal than the maternal genome. An increased risk of preeclampsia based on the maternal polygenic score for preeclampsia was associated with lower levels of sFLT1 and sFLT1:PlGF ratio in the first trimester and a greater Δ36-28 for sFLT1.

The current data are consistent with a causal association between sFLT1 released by the placenta in late pregnancy and the pathophysiology of preeclampsia. The data are also consistent with maternal components to the protective effect of high sFLT1 in the first trimester and the rise in third-trimester sFLT1 levels and preeclampsia.

The objective of this study was to evaluate total circulating PlGF (placental growth factor) and free PlGF concentrations to provide insights into the mechanisms of decreased PlGF noted in preeclampsia and fetal growth restriction.

We conducted a retrospective single-center study in pregnant women receiving care for suspected preeclampsia or fetal growth restriction. Serum angiogenic proteins (sFLT1 [soluble fms-like tyrosine kinase] and free PlGF) were measured on an automated platform as part of standard-of-care. Total PlGF concentrations in the serum were directly measured using a validated biochemical procedure that dissociated circulating sFLT1 and PlGF complexes. Small for gestational age (SGA) was defined by birthweight ≤10th percentile.

Of the 407 women studied, 155 women did not develop preeclampsia or SGA (control group), 111 women developed SGA without preeclampsia (SGA group), 71 women developed preeclampsia without SGA (preeclampsia group), and 70 developed preeclampsia and SGA (preeclampsia+SGA group). Despite reductions in free PlGF levels (229 [158-321] pg/mL), total PlGF levels were not reduced in the preeclampsia group (1020 [738-1444] pg/mL) compared with the control group (1077 [763-1595] pg/mL). In contrast, the total PlGF levels were significantly reduced in the SGA group (744 [462-1161] pg/mL; P<0.0001) and the preeclampsia +SGA group (616 [349-917] pg/mL; P<0.0001) compared with the control group (1077 [763-1595] pg/mL).

Placental dysfunction associated with preeclampsia, characterized by reduced free PlGF levels but unchanged total PlGF, is driven by excessive placental production of sFLT1. Placental dysfunction associated with SGA, marked by reductions in both free and total PlGF, is mediated by decreased placental PlGF production.

Pre-eclampsia is a severe pregnancy complication affecting 5-8% of pregnancies worldwide, marked by high blood pressure and organ damage typically occurring after 20 weeks of gestation. It is a leading cause of maternal and fetal morbidity and mortality. Though its exact cause is unknown, it involves placental abnormalities and improper blood vessel development. Risk factors include a history of pre-eclampsia, chronic hypertension, diabetes, obesity, and autoimmune disorders. Symptoms include high blood pressure, proteinuria, headaches, vision changes, and abdominal pain. Untreated, it can lead to seizures, stroke, preterm birth, or death. Delivery is the definitive treatment, with management strategies such as monitoring and blood pressure control. Pre-eclampsia significantly increases long-term cardiovascular disease (CVD) risks, including hypertension, ischemic heart disease, and stroke, linked to shared mechanisms like endothelial dysfunction and inflammation. Women with severe or recurrent pre-eclampsia have heightened risks, often developing chronic hypertension within a decade postpartum. It also impacts offspring, with daughters at elevated risk for pre-eclampsia and CVD. Hypertensive disorders of pregnancy, including pre-eclampsia, induce changes like left ventricular hypertrophy and diastolic dysfunction, raising risks for heart failure with preserved ejection fraction and coronary atherosclerosis. Overlapping with peripartum cardiomyopathy, pre-eclampsia underscores a spectrum of pregnancy-related cardiovascular disorders. Long-term monitoring and lifestyle interventions are crucial for managing risks, with research into genetic and biological mechanisms offering the potential for targeted prevention.

The physiological function of beta 2 glycoprotein I (β2GPI) itself is not well understood, other than that it is a primary antigen to anti-phospholipid antibodies in the autoimmune disease antiphospholipid syndrome. β2GPI is a soluble blood protein that is predominantly synthesized in hepatocytes. Why is the expression of β2GPI observed in the placenta despite its abundance in the circulating blood of healthy individuals? Does the placenta produce a specific-acting β2GPI?. β2GPI was recently shown to adopt two interconvertible biochemical confirmations based on the integrity of disulfide bonds: oxidized and reduced. The present study investigates the physiological function of β2GPI in trophoblast cells, with a focus on the reduced and oxidized forms of β2GPI under the hypothesis that placental β2GPI has a different activity from circulating β2GPI. Endogenous β2GPI secretion in trophoblast cells were predominantly in the reduced form, while those in HepG2 liver cells were mainly in the oxidized form. Progesterone increased reduced-β2GPI in both the trophoblast and liver cells. Oxidized-β2GPI significantly inhibited trophoblast cell migration and increased placental soluble fms-like tyrosine kinase-1 (sFlt-1). Furthermore, excess sFlt-1 significantly increased oxidized-β2GPI secretion in HepG2 cells. Circulating oxidized-β2GPI levels were significantly higher in women with pre-eclampsia than in those without pre-eclampsia. Therefore, oxidized-β2GPI may contribute to the pathogenesis of pre-eclampsia. Under oxidative stress, the excessive oxidation of β2GPI and/or excessive placental sFlt-1 may trigger a negative spiral between trophoblast and liver cells.

Failures in uterine spiral artery remodeling can lead to placental defects and subsequent preeclampsia, a leading cause of fetal and maternal mortality during pregnancy. N6-methyladenosine (m6A), the most abundant mRNA modification, is dysregulated in samples with preeclampsia. However, whether and how m6A regulates uterine spiral artery remodeling and leads to subsequent preeclampsia in vivo remains unexplored. In this study, we generated two m6A deficiency mouse models: one with a trophoblast-specific knockout of the m6A methyltransferase gene Mettl3, and another with a methyltransferase enzyme mutation. Using these models, we demonstrated that m6A deficiency impaired extravillous trophoblasts (EVTs) infiltration into the uterine spiral arteries, and the remodeling of the spiral arteries in vivo. We further showed that m6A inhibition induced preeclampsia-like symptoms. Mechanistically, we revealed that the m6A modification of FGF2 mRNA, which encodes a secreted peptide implicated in preeclampsia, facilitated its expression. Notably, administration of the FGF2 peptide largely restored EVTs invasion and uterine spiral artery remodeling in m6A-deficient mice. Our findings underscore the importance of m6A in facilitating uterine spiral artery remodeling and prove the pathological mechanisms in vivo, suggesting a new therapeutic approach for preeclampsia caused by m6A deficiency.

The placenta plays an essential role facilitating nutrient, gas and waste exchange between the maternal and fetal systems for optimal fetal growth. When placental development is impaired and the placenta dysfunctional, serious pregnancy complications such as fetal growth restriction and preeclampsia may arise. Previously, phosphoglucomutase-5 (PGM5) transcripts were found to be highly elevated in the blood of patients whose pregnancies were complicated by fetal growth restriction and preeclampsia. As both conditions feature placental insufficiency, here we aimed to characterise PGM5 levels in the healthy and dysfunctional placenta. PGM5 expression was detectable in all placental samples across gestation, in cases of preterm preeclampsia, fetal growth restriction and controls. PGM5 mRNA expression was significantly downregulated in the pathological placentas compared to controls, but PGM5 protein production was not dysregulated. Isolated cytotrophoblast and placental explant tissue exposed to hypoxia (modelling placental dysfunction) demonstrated significantly increased PGM5 expression, but again did not change protein levels. Silencing PGM5 expression under hypoxic conditions in primary cytotrophoblast did not alter anti-angiogenic sFLT-1 secretion but increased expression of multiple genes associated with cell growth, apoptosis and oxidative stress, whilst also increasing cell viability. Expression of PGM5 in all placental samples assessed suggests that PGM5 has functions in the placenta. However, further investigation could be performed to explore the discrepancies in protein and mRNA expression, as well as the precise function of PGM5 in the placenta, and whether altered PGM5 levels may be important for placental development.

This study analyzed longitudinal trajectories of soluble Flt1 (sFlt1) levels, placenta growth factor (PlGF) levels, and sFlt1:PlGF ratios in a cohort of pregnant patients with systemic lupus erythematosus (SLE).

Blood samples were collected (14-18, 24-26, 30-32, 34-36, and 38-40 weeks), stored at -80°C, and evaluated for serum levels of sFlt1, PlGF, and sFlt1:PlGF ratios. Patients were classified as inactive SLE (Systemic Lupus Erythematosus Pregnancy Disease Activity Index [SLEPDAI] <4), active disease (SLEPDAI ≥4), or preeclampsia (PE). Medians and interquartile ranges were calculated for each group, and linear models with random effects were used.

A total of 527 samples were obtained from 163 patients, and all patients were subsequently classified as having inactive disease (109 patients [66.9%]), active disease (33 patients [20.2%]), and inactive disease with PE (21 patients [12.9%]). In exploratory analysis, patients with PE had higher mean serum levels of sFlt1 and sFlt1:PlGF ratios and lower PlGF levels than patients with inactive and active SLE (P = 0.01 to P < 0.001). Using linear models with random effects, there was no significant differences in mean serum levels of these angiogenic markers comparing inactive and active disease. Patients with PE showed a marked increase in sFlt1 levels from the 24th week, constantly low PlGF levels from the 14th week, and progressive increase of sFlt1:PlGF ratio during pregnancy. All these differences were statistically significant compared to the groups without PE.

Pregnant patients with SLE who developed PE had higher sFlt1 levels and sFlt1:PlGF ratios and lower PlGF levels, and these last two changes were detected at the beginning of second trimester, before clinical manifestation. SLE activity did not interfere with longitudinal behavior of these angiogenic markers.

Exosomes play a role in cell communication by transporting content between cells. Here, we tested whether renal podocyte-derived exosomes affect the injury of glomerular endothelial cells in lupus nephritis (LN). We found that exosomes containing high levels of high mobility group protein B1 (HMGB1) were released from podocytes in patients with LN, BALB/c mice injected with pristane (which induces lupus-like disease in mice), and cultured human renal glomerular endothelial cells (HRGECs) treated with LN plasma. In vitro, GW4869 (an inhibitor of exosome biogenesis/release) or exosome removal alleviated the injury of HRGECs induced by LN plasma. Additionally, leptomycin B or knockdown of HMGB1 in podocyte-derived exosomes reduced endothelial cell injury and the expression of tripartite motif-containing protein 27 (TRIM27). Knockdown or overexpression of TRIM27 attenuated or promoted the damage of HRGECs treated with LN plasma. In vivo, knockdown of HMGB1 in podocytes ameliorated the injury of glomerular endothelial cells in a mouse model of LN. Furthermore, the injection of podocyte-derived exosomes into mice caused glomerular endothelial cell dysfunction. In conclusion, our study revealed that podocyte-derived exosomes may mediate the injury of glomerular endothelial cells seen in LN.

Preeclampsia, one of the great obstetrical syndromes, manifests through diverse maternal and fetal complications and remains a leading contributor to adverse perinatal outcomes. In this review, we describe our work on single-cell and single-nuclei RNA sequencing to elucidate the molecular mechanisms that underlie early- and late-onset preeclampsia. Analysis of 46 cell types, encompassing approximately 90,000 cells from placental tissues collected after delivery, demonstrated cellular dysregulation in early-onset preeclampsia, whereas late-onset preeclampsia showed comparatively subtle changes. These findings were observed in all cell lines, including all types of trophoblast, lymphoid, myeloid, stromal, and endothelial cells. Key findings in early-onset preeclampsia included disrupted syncytiotrophoblast and extravillous trophoblast angiogenic signaling, characterized by an up-regulation of FLT1 and down-regulation of PGF, consistent with an angiogenic imbalance. The stromal and vascular compartments exhibited stress-induced transcriptomic shifts. Both endothelial cells and pericytes showed evidence of stress, including up-regulation of heat shock proteins and markers of apoptosis. In addition, the inflammation- and stress-responsive states were more abundant in early-onset preeclampsia than in matched controls. Inflammatory pathways were markedly up-regulated in both the maternal and fetal immune cells; for example, we observed a marked increase in pro-inflammatory cytokines, including secreted phosphoprotein 1 and C-X-C motif chemokine ligand 2 and 3. Conversely, late-onset preeclampsia retained adaptive placental features with localized dysregulation of extracellular matrix remodeling and angiogenic markers, underscoring its possible maternal cardiovascular etiology. Single-cell and single-nuclei RNA sequencing investigations of placental tissues support the proposed classification of preeclampsia into a placental dysfunction type, primarily presenting early in pregnancy, and a maternal cardiovascular maladaptation type, primarily presenting later in pregnancy, each with distinct biomarkers, risk factors, and therapeutic targets. The early-onset preeclampsia findings advocate for interventions that target angiogenic pathways, such as RNA-based therapies that target specific cells of the placenta, to modulate soluble fms-like tyrosine kinase-1 levels. In contrast, late-onset preeclampsia management may benefit from maternal cardiovascular optimization, including individualized antihypertensive and metabolic treatments. These results underscore the heterogeneity of preeclampsia, emphasizing the need for individualized diagnostic and therapeutic strategies. This molecular atlas of preeclampsia advances our understanding of the complex interplay among elements of the maternal-placental-fetal array, thereby bridging clinical phenotypes and cellular mechanisms. Future research should focus on integrating these insights into longitudinal studies to develop precision medicine approaches for preeclampsia to enhance outcomes for mothers and neonates.

Melatonin is mainly secreted by the pineal gland during darkness and regulates biological rhythms through its receptors in the suprachiasmatic nucleus of the hypothalamus. In addition, it also plays a role in the reproductive system by affecting the function of the hypothalamic-pituitary-gonadal axis, and by acting as a free radical scavenger thus contributing to the maintenance of the optimal physiological state of the gonads. Besides, melatonin can freely cross the placenta to influence fetal development. However, there is still a lack of overall understanding of the role of melatonin in the reproductive cycle of female mammals.

Here we focus the role of melatonin in female reproduction from follicular development to delivery as well as the relationship between melatonin and lactation. We further summarize the potential role of melatonin in the treatment of preeclampsia, polycystic ovary syndrome, endometriosis, and ovarian aging.

Understanding the physiological role of melatonin in female reproductive processes will contribute to the advancement of human fertility and reproductive medicine research.

Placentation is a key process that is tightly regulated that ensures the normal placenta and fetal development. Preeclampsia (PE) is a hypertensive pregnancy‑associated disorder characterized by increased oxidative stress and inflammation. STAT3 signaling plays a key role in modulating important processes such as cell proliferation, differentiation, invasion and apoptosis. The present review aimed to analyse the role of STAT3 signaling in PE pregnancies, discuss the main natural and synthetic compounds involved in modulation of this signaling both in vivo and in vitro and summarize the main cellular modulators of this signaling to identify possible therapeutic targets and treatments to improve the outcome of PE pregnancies.

Preeclampsia (PE) is a pregnancy-specific complication that begins with hypertension and proteinuria and seriously threatens the health of pregnant women and fetuses. Abnormal expression of amniotic fluid-derived exosomal miR-146a-5p was observed in PE. However, the role of human amniotic fluid-derived exosomes (AF-Exos) and miR-146a-5p in PE remains unclear.

We determined the miR-146a-5p expression pattern in the AF-Exos. AF-Exos, Cobalt chloride (CoCl2) and miR-146a-5p mimic were added to trophoblast cell lines HTR-8/SVneo and JEG-3, respectively. Then the proliferation and migration function of HTR-8/SVneo and JEG-3 cells were examined. The expression of miR-146a-5p, HIF-1α and FLT-1 in HTR-8/SVneo and JEG-3 cells were detected by RT-qPCR and western blotting. Finally, we determined the effect of AF-Exos in PE rat models.

MiR-146a-5p was down-regulated in AF-Exos of PE compared to normal. Co-cultured with normal AF-Exos significantly promoted proliferation and migration of HTR-8/SVneo and JEG-3 cells. CoCl2 inhibited proliferation and migration of HTR-8/SVneo and JEG-3 cells, while miR-146a-5p mimic reversed them by suppressing HIF-1α/FLT-1 expression. After treatment of AF-Exos, the blood pressure and 24-h urinary protein of PE rats were substantially decreased, the quality of fetuses and placenta exhibited improved, and HIF-1α/FLT-1 expression of placenta, sFlt-1 and sEng levels of blood, were substantial suppressed.

The study provided experimental evidence for the protective effects of normal AF-Exos on ameliorating preeclampsia phenotypes, and miR-146a-5p may act an important role in enhancing the proliferation and migration of trophoblast cells by targeting HIF-1α.

Central precocious puberty (CPP) is one of the common endocrine diseases in pediatrics. However, the molecular mechanisms regulating development of CPP have remained unclear. The purpose of this study was to discover the key pathways and hub genes related to CPP.

We analyzed two public datasets (GSE7142 and GSE8310) to identify differentially expressed genes in the progression of CPP. Then, we screened out overlapping differential genes from these two datasets and performed a series of bioinformatics analyses to explore promising targets and molecule mechanism of CPP.

We identified 30 down-regulated overlapping DEGs between GSE7142 (CPP/no CPP) and GSE8130 (EP/JUV) datasets and 17 down-regulated overlapping DEGs between GSE7142 (CPP/no CPP) and GSE8130 (LP/JUV) datasets. KEGG signaling pathway shows that calcium signaling pathway is suppressed continuously in early and late pubertal of CPP patients. MAPK signaling pathway also plays an important role in the occurrence and development of CPP. Eventually, we screened out 2 hub genes (FGFR2 and FLT1) highly related to CPP, which may provide a new directions for the diagnosis and treatment of CPP.

While further validation is needed, we provide useful and novel information to explore potential signaling pathways and candidate genes for CPP diagnosis and treatment options.

Preeclampsia is a multifactorial disorder that only occurs during pregnancy. Several genome-wide association studies (GWASs) have revealed potential susceptible variants associated with preeclampsia in different populations. GWASs findings in other ethnicities must be replicated in order to confirm the observed genotype-phenotype association. Here, we performed a replication study to investigate the association of three previously reported genome-wide signals, including FLT1rs4769612, FTO rs1421085, and ZNF831 rs259983, with preeclampsia in the Iranian population. A total of 600 subjects were recruited for this study. The maternal group included 200 preeclamptic patients and 200 healthy normotensive pregnant women. The fetal group included 100 individuals born of preeclamptic pregnancies and 100 individuals born from healthy pregnancies. The tetra-primer amplification refractory mutation system-polymerase chain reaction (TP-ARMS PCR) technique was used for genotyping the rs4769612, rs1421085, and rs259983 variants. The fetal genotype of rs4769612 (FLT1) was associated with preeclampsia risk under the recessive inheritance model. Moreover, fetal rs1421085 (FTO) increased the risk of preeclampsia under dominant and over-dominant inheritance models. Regarding ZNF831 rs259983, only the maternal genotype was associated with preeclampsia under the dominant model, and no association was detected between the fetal genotype and the disease risk. Although the present results showed discrepancies with previous studies considering the association of maternal or fetal genotypes with preeclampsia, all three studied polymorphisms were related to the disease risk in the Iranian population. Based on our study, rs4769612, rs1421085, and rs259983 were associated with the risk of preeclampsia in the Iranian population.

Cells cross the placenta during pregnancy, resulting in proliferation of semiallogeneic cells in the mother and fetus decades later. This phenomenon, termed microchimerism, is documented across mammalian species, implying an evolutionary benefit. Still, short- and long-term effects remain uncertain. Here, we review the dynamics of microchimerism of fetal, maternal, and mother of the proband origin in relation to increasing gestational age and pregnancy complications associated with placental dysfunction including preeclampsia, fetal growth restriction, preterm labor, recurrent miscarriage, and diabetes. We use the two-stage model of preeclampsia as a framework. We recently published a series of papers independently linking increased fetal microchimerism to markers of placental dysfunction (stage 1), severe maternal hypertension (stage 2) and poor glucose control. Placental dysfunction may influence the intrinsic properties of fetal stem cells. Mesenchymal and hematopoietic stem cells isolated from cord blood during preeclampsia display reduced proliferative potential in vitro. Moreover, preeclampsia is shown to disrupt paracrine signaling in mesenchymal stem cells of the umbilical cord. Undesired properties in cells transferred to the mother could have profound negative effects on maternal health. Finally, recent studies indicate that microchimerism is involved in inducing maternal-fetal tolerance. Disruption of this process is associated with pregnancy complications. Long term, the persistence of microchimerism is necessary to sustain specific regulatory T cell populations in mice. This likely plays a role in the proband's future pregnancies and long-term maternal and offspring health. Current evidence indicates that advancements in our understanding of microchimerism could be instrumental in promoting reproductive and long-term health.

sFLT-1 has been implicated in the pathogenesis of HDP. We aimed to examine the role of maternal and fetal polymorphisms in risk of HDP and severe-spectrum disease.

Cases of HDP (143) and controls (169) from mother-baby dyads were recruited at the Los Angeles County Women's and Children's Hospital (WCH). Cases of severe disease (99) and controls (31) from mother-father-baby triads were recruited through HELLP syndrome websites. Four sFLT-1 SNPs (rs7993594, rs3751395, rs7983774, and rs664393) were genotyped. Data was analyzed using a log-linear regression model in the Haplin package in R.

Maternal double dose of the A allele (rs7993594) exhibited a nominally significant increased risk of HDP (RR = 3.52, 95% CI 1.08, 11.20). In the severe-spectrum cohort, a marginally significant protective effect among mothers carrying infants with a single dose of the A allele (rs7993594) was observed (RR = 0.59, 95% CI 0.36, 0.98) and double-dose maternal carriage of the G-t-G-G haplotype increased risk of severe disease (RR = 4.13, 95% CI 1.22, 13.80).

The maternal rs7993594 A allele appears to be associated with increased risk of HDP. Double-dose maternal carriage of the G-t-G-G haplotype increased risk of severe disease whereas the fetal rs7983774 A allele appears to be associated with decreased risk.

Scleroderma renal crisis (SRC) is a major vascular complication of systemic sclerosis (SSc), associated with high morbidity and mortality. In this retrospective study, we evaluated the potential prognostic and diagnostic roles of angiogenesis molecules, placental growth factor (PlGF), soluble fms-like tyrosine kinase 1 (sFlt-1) and sFlt1/PlGF ratio as biomarkers in SRC.

Sera samples from 27 patients with a history of SRC (SSc-SRC+) were collected following event occurence. Biomarker levels were assessed using an electrochemiluminescence immunoassay and compared with age- and sex-matched patients with SSc-SRC- (n = 24), hemolytic uremic syndrome (HUS) (n = 27), malignant hypertension (MHT) (n = 22), and donors (n = 61). Areas under the receiver-operating-characteristic curves (AUC) were used to evaluate diagnostic accuracy. Long-term dialysis risk was evaluated using a Cox model.

The median (interquartile range [IQR]) PlGF (pg/ml) was significantly higher in the serum of patients with SSc-SRC+ (42.1 [21.4-51.8]) compared with donors (14.7 [11.8-17.9]), those with SSc-SRC- (18.5 [14.7-21.5]) (P < 0.0001), those with HUS (22.8 [19.5-29.6]), and those with MHT (25.5 [17.2-39.3]) (P < 0.0001). In a multivariate regression adjusting for multiple confounders, PlGF was associated with higher SRC risk with an odds ratio of 1.08 [1.01-1.22], (P = 0.034). A PlGF level above 24.5 pg/ml revealed an AUC of 0.81 (confidence interval [0.68-0.94]), a specificity of 95%, and a sensitivity of 67% for SRC diagnosis. Eleven patients with SSc-SRC+ reached end-stage kidney failure with significantly higher PlGF (42.9 [22.4-78.2]) compared with patients who were dialysis-free (19.7 [15.6-29.7], P = 0.03).

Serum PlGF may identify the risk of SRC occurrence among patients with SSc with a good specificity and represents a potential tool for long-term dialysis risk evaluation.

Preeclampsia (PE) is a gestational complication affecting 5% to 10% of all pregnancies. PE is characterized by hypertension and endothelial dysfunction, whose etiology involves, among other factors, alterations in the extracellular matrix (ECM) that can compromise vascular remodeling and trophoblast invasion, ie, processes essential for placental development. Endothelial dysfunction is caused by release of antiangiogenic factors, mainly a soluble fms-like tyrosine kinase-1 (sFlt-1), which antagonizes two endothelial angiogenic factors, the vascular endothelial growth factor (VEGF) and placental growth factor (PLGF). This angiogenic imbalance contributes to clinical symptoms including hypertension and multisystem dysfunction. This review aims to summarize recent advances in understanding PE, particularly with altered ECM components such as heparan sulfate proteoglycans, the glycosidase heparanase, fibronectin, collagen XVIII (endostatin), and metalloproteases. This comprehensive narrative review was conducted on PubMed from 1994 to 2024, focusing on articles on the pathophysiology of PE, particularly endothelial dysfunction caused by ECM modifications. The data shows a reduced expression of matrix metalloproteinases, increased collagen fragment XVIII, and significant changes in fibronectin associated with PE. Furthermore, endothelial dysfunction was associated with increased degradation of heparan sulfate chains from proteoglycans and increased sFlt-1. Understanding these ECM modifications is crucial for developing potential new therapeutic interventions that improve maternal and fetal outcome in PE.

Cytomegalovirus (CMV) infection during pregnancy is the leading cause of congenital infection subsequent to viral transplacental transmission. CMV placental infection can contribute to the development of adverse outcomes likely through placental dysfunction. This case report shows the potential utility of angiogenic markers, such as placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1), in assessing CMV-related placental involvement and monitoring the effect of antiviral therapy on placental function, and highlights the possibility of integrating these markers into the clinical management of CMV infection.

Preeclampsia (PE) is a major cause of maternal mortality and morbidity, affecting 3-6% of pregnancies worldwide and ranking among the top six causes of maternal deaths in the U.S. PE typically develops after 20 weeks of gestation and is characterized by new-onset hypertension and/or end-organ dysfunction, with or without proteinuria. Current management strategies for PE emphasize early diagnosis, blood pressure control, and timely delivery. For prevention, low-dose aspirin (81 mg/day) is recommended for high-risk women between 12 and 28 weeks of gestation. Magnesium sulfate is also advised to prevent seizures in preeclamptic women at risk of eclampsia. Emerging management approaches include antiangiogenic therapies, hypoxia-inducible factor suppression, statins, and supplementation with CoQ10, nitric oxide, and hydrogen sulfide donors. Black women are at particularly high risk for PE, potentially due to higher rates of hypertension and cholesterol, compounded by healthcare disparities and possible genetic factors, such as the APOL1 gene. This review explores current and emerging strategies for managing PE and addresses the underlying causes of health disparities, offering potential solutions to improve outcomes.

Preeclampsia (PE) is a serious pregnancy complication that contributes to maternal and perinatal morbidity and mortality. Understanding its pathogenesis and revealing predictive biomarkers are essential for guiding treatment decisions. In order to explore the global changes of serum metabolites in PE patients and identify potential predictive biomarkers for suspected PE patients (pregnant women who had already shown PE-related symptoms in the middle to late stages of pregnancy, but were not yet confirmatively diagnosed as PE.), a large-scale serum metabolomic analysis was conducted in this study with a prospective cohort of 328 suspected PE patients in the middle or late pregnancy stages, as well as a retrospective cohort of 30 healthy pregnant women and 30 PE patients. Using liquid chromatography mass spectrometry (LC - MS), serum metabolomic profiling revealed that the development of PE was closely associated with disturbed amino acid metabolism. Moreover, a panel of seven predictive biomarkers including 2-methyl-3-hydroxy-5-formylpyridine-4-carboxylate, gamma-glutamyl-leucine, 2-hydroxyvaleric acid, LysoPC(16:1(9Z)/0:0), PC(DiMe(13,5)/MonoMe(13,5)), ADP-D-glycero-beta-D-manno-heptose and phenylalanyl-tryptophan were identified for PE development by performing multiple statistical analysis and LASSO regression analysis. The combination of these biomarkers showed promise in the prediction of PE development for suspected PE patients, with an AUC of 0.753 and 0.885 for the discovery and validation cohorts, respectively. These findings highlight the potential of large-scale prospective metabolomic studies combined with machine learning algorithms in identifying key biomarkers for predicting PE development, while retrospective metabolomics studies provide insights into the pathogenesis of PE.

Preeclampsia is a complex pregnancy condition marked by hypertension and organ dysfunction, posing significant risks to maternal and fetal health. This study investigates the role of energy metabolism-associated genes in preeclampsia development and identifies potential early diagnostic biomarkers.

Preeclampsia datasets from Gene Expression Omnibus were analyzed for batch correction, normalization, and differential expression. Enrichment analyses using gene ontology, Kyoto Encyclopedia of Genes and Genomes, and gene set enrichment were performed. Protein-protein interaction networks were constructed to identify key genes, and regulatory networks involving transcription factors, miRNAs, and RNA-binding proteins were established. Differential expression was validated with receiver operating characteristic curve analyses, and immune infiltration was assessed.

Six energy metabolism-related genes were identified. Enrichment analyses revealed their involvement in glycolysis, gluconeogenesis, lipid transport, bone remodeling, and glucagon secretion. Key differentially expressed genes included CRH(Corticotropin-Releasing Hormone), LEP(Leptin), PDK4(Pyruvate Dehydrogenase Kinase Isozyme 4), SPP1(Secreted Phosphoprotein 1), and SST(Somatostatin). PDK4 exhibited moderate accuracy in receiver operating characteristic analysis. Immune infiltration analysis indicated significant differences between preeclampsia and control samples. qRT-PCR confirmed LEP and CRH increased, while SPP1 expression in preeclampsia samples.

Dysregulated energy metabolism-related genes may contribute to preeclampsia through metabolic and immune changes. Identifying these genes aids in understanding preeclampsia's molecular basis and early diagnosis. Future studies should validate these markers in larger cohorts and explore targeted treatments.

Preeclampsia is a significant cause of maternal and fetal morbidity and mortality, particularly in low- and middle-income countries like South Africa.

The aim of our study was to investigate the association between placental growth factor (PlGF) and soluble FMS-like tyrosine kinase-1 (sFlt-1) in South African preeclamptic women of African ancestry, comorbid with HIV infection.

The study population consisted of women attending a regional hospital in Durban, South Africa, stratified by pregnancy type (normotensive pregnant and preeclampsia) and HIV status. Preeclampsia was defined as new-onset hypertension and proteinuria. DNA was obtained from whole blood. The SNPs of interest were rs722503 in sFlt-1 and rs4903273 in PlGF.

Our findings suggest that single nucleotide polymorphisms of rs722503 analysis show no significant associations between the genotypic frequencies of rs722503 variants and preeclampsia risk in either HIV-negative or HIV-positive groups of women of African ancestry. Similarly, the rs493273 polymorphism showed no significant association with preeclampsia risk in either HIV-negative or HIV-positive pregnant women. Additionally, comparisons of dominant, recessive, and over-dominant allele models did not reveal significant associations. These findings suggest that these genetic variants may not significantly contribute to preeclampsia development in this African ancestry population. However, significant differences were observed in the rs4903273 genotype frequencies between normotensive and preeclamptic women, regardless of HIV status, over dominant alleles AA + GG vs AG showed a significant difference [OR = 2.706; 95% Cl (1.199-5.979); adjusted p = 0.0234*], also in normotensive compared to EOPE (OR = 2.804; 95% Cl (1.151-6.89) p = 0.0326* and LOPE (OR = 2.601; 95% Cl (1.0310-6.539) p = 0.0492*), suggesting that they may be the potential role of this variant in preeclampsia susceptibility.

The findings suggest that the rs722503 and rs493273 polymorphisms do not significantly contribute to preeclampsia susceptibility in HIV-negative or HIV-positive pregnant women. However, the rs4903273 genotype frequencies showed notable differences between normotensive and preeclamptic women, indicating a potential association with preeclampsia development in the African ancestry population irrespective of HIV status.