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.

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.

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.

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.

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.

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.

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.

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.

Transient ischemic attack (TIA) is a brief episode of neurological dysfunction caused by focal brain ischemia, typically lasting less than one hour without acute infarction. Preeclampsia, a multisystem hypertensive disorder occurring in pregnancy, significantly heightens the risk of stroke, particularly during the postpartum period. This case report details a 34-year-old Sub-Saharan African woman, gravida 4 para 4, who experienced a TIA characterized by right-sided weakness and slurred speech 13 days after delivering a baby by cesarean section. Upon presentation to the emergency department with symptoms suggesting a minor stroke, clinical examination revealed hypertension and neurological deficits. Imaging studies clarified the absence of acute intracranial pathology but indicated hypoperfusion in the right frontal white matter and significant chronic sinusitis. The patient's elevated blood pressure and clinical conditions were consistent with postpartum preeclampsia. Management included dual antiplatelet therapy and antihypertensives alongside seizure prophylaxis. The patient's neurological symptoms resolved within 24 hours, and she was discharged on supportive medications, with follow-up arrangements established for various specialties. This case emphasizes the need for careful monitoring of postpartum women for signs of preeclampsia and cerebrovascular events, particularly in high-risk populations. It highlights the interaction between these conditions and the importance of collaborative multidisciplinary care. Further research is warranted to explore the link between chronic sinusitis and postpartum preeclampsia.

Preeclampsia (PE) contributes to maternal and fetal mortality and morbidity. Supplementation with L-arginine, the precursor of nitric oxide, has not proven effective, possibly due to extensive arginine catabolism in the splanchnic bed. Citrulline is converted by the kidney to L-arginine. Citrulline, therefore, could be a more effective nitric oxide donor in the treatment of PE.

The study aimed to determine whether oral L-citrulline supplementation would prolong the delay between diagnosis and delivery in preeclamptic females.

A total of 115 females with monofetal preeclamptic pregnancy were enrolled before 36 weeks of gestation in a multicenter randomized, double-blind trial: 58 received oral L-citrulline supplementation, and 57 received placebo. The duration of pregnancy, neonatal and maternal outcomes, and soluble fms-like tyrosine kinase 1/placental growth factor ratio, an index of placental dysfunction, were monitored.

Gestational age at inclusion was similar in both groups. The duration of pregnancy between inclusion and delivery was unaltered (hazard ratio: 0.90; 95% confidence interval: 0.62, 1.31). Neither neonatal weight nor pregnancy outcome differed between groups. Liver enzymes were higher on the day of delivery in the treated, compared to the placebo group (65.1 compared with 33.2 UI and 70.4 compared with 33.7 UI for alanine aminotransferase and aspartate aminotransferase, respectively, (estimate: 5.92; 95% confidence interval: 1.09, 10.74). Systolic blood pressure (BP) was higher at delivery in the citrulline group compared with the control group (P = 0.015), whereas the diastolic BP showed no difference. We did not find any difference in neonatal outcomes nor soluble fms-like tyrosine kinase 1/placental growth factor ratio.

The current trial found no benefit of oral L-citrulline supplementation to females with PE regarding either the duration of pregnancy, fetal growth, or maternal and neonatal outcomes. Systolic BP and liver enzymes levels were found to increase at delivery in the treated group. L-citrulline oral supplementation does not seem to be a promising candidate as a therapeutic intervention in pregnancies with PE. This trial was registered at CITRUPE as NCT02801695.

Aging and pregnancy are often considered opposites in a woman's biological timeline. Aging is defined by a gradual decline in the functional capabilities of an organism over its lifetime, while pregnancy is characterized by the presence of the transient placenta, which fosters the cellular fitness necessary to support fetal growth. However, in the context of preeclampsia, pregnancy and aging share common hallmarks, including clinical complications, altered cellular phenotypes, and heightened oxidative stress. Furthermore, women with pregnancies complicated by preeclampsia tend to experience age-related disorders earlier than those with healthy pregnancies. Klotho, a gene discovered fortuitously in 1997 by researchers studying aging mechanisms, is primarily expressed in the kidneys but also to a lesser extent in several other tissues, including the placenta. The Klotho protein is a membrane-bound protein that, upon cleavage by ADAM10/17, is released into the circulation as soluble Klotho (sKlotho) where it plays a role in modulating oxidative stress. This review focuses on the involvement of sKlotho in the development of preeclampsia and age-related disorders, as well as the expression of the recently discovered Mytho gene, which has been associated with skeletal muscle atrophy.

Preeclampsia is a hypertensive disorder of pregnancy characterized by systemic endothelial dysfunction. The pathophysiology of preeclampsia remains incompletely understood. This study used human venous endothelial cell (EC) transcriptional profiling to investigate potential novel mechanisms underlying EC dysfunction in preeclampsia.

Venous ECs were isolated from postpartum patients with severe preeclampsia and those with normotensive pregnancy using a J wire-based technique in the antecubital vein followed by CD144 (vascular endothelial cadherin) magnetic bead isolation. Venous EC transcriptomes were compared between preeclamptic and normotensive individuals. Differentially expressed genes were carried forward for genetic validation using expression quantitative trait loci from the Genotype-Tissue Expression project as exposures for vascular-specific Mendelian randomization. Functional validation of the top candidate was performed in human umbilical vein ECs using gain- and loss-of-function genetic approaches.

Seventeen individuals with preeclampsia and 7 normotensive controls were included. Pairwise analysis yielded 14 protein-coding genes nominally differentially expressed in participants with preeclampsia. Mendelian randomization revealed a significant association between higher genetically predicted METAP1 (methionyl aminopeptidase 1) expression in aortic and tibial arterial tissues and greater risk of preeclampsia. METAP1 overexpression in human umbilical vein ECs decreased angiogenesis, with a 66% decrease in tube formation (P=7.9×10-3) and 72% decrease in cell proliferation (P=2.9×10-2). Furthermore, METAP1 overexpression decreased VEGFA expression and increased expression of multiple preeclampsia-related genes, for example, FLT1, INHBA, and IL1B. Conversely, METAP1 knockdown produced opposite effects on tube formation, cell proliferation, and inflammation-related gene expression.

In a cohort of early postpartum individuals, we observed greater METAP1 expression in venous ECs of women with preeclampsia versus normotensive delivery. Mendelian randomization supported a causal relationship between greater vascular METAP1 expression and higher preeclampsia risk, and functional experiments demonstrated antiangiogenic and proinflammatory effects of METAP1 in human ECs consistent with alterations observed in preeclampsia. Ex vivo EC transcriptomics can identify novel mechanisms underlying preeclampsia pathophysiology, with implications for prevention and treatment.

Vascular endothelial growth factor receptor inhibitors (VEGFRis) improve cancer patient survival by inhibiting tumor angiogenesis. However, VEGFRis induce treatment-limiting hypertension which has been associated with impaired vascular endothelial cell (EC) function and kidney damage. The mineralocorticoid receptor (MR) regulates blood pressure (BP) via its effects on the vasculature and the kidney. Thus, we interrogated the role of the MR in EC dysfunction, renal impairment, and hypertension in a mouse model of VEGFRi-induced hypertension using sorafenib.

EC dysfunction in mesenteric arterioles was assessed by immunoblotting for phosphorylation of endothelial nitric oxide synthase (eNOS) at serine 1177. Renal damage was measured by assessing glomerular endotheliosis histologically. BP was measured using implanted radiotelemetry.

Six days of sorafenib treatment significantly impaired mesenteric resistance vessel EC function, induced renal damage, and increased BP. Pharmacologic MR blockade with spironolactone prevented the sorafenib-induced decline in eNOS phosphorylation and renal glomerular endotheliosis, without affecting systolic BP (SBP) or diastolic BP. Mice with the MR knocked out specifically in ECs (EC-MR-KO) were protected from sorafenib-induced EC dysfunction and glomerular endotheliosis, whereas smooth muscle cell-specific MR (SMC-MR) knockout mice were not. Neither EC-MR nor SMC-MR knockout affected the degree to which sorafenib increased SBP or diastolic BP.

These results reveal that the MR, specifically in EC but not in SMCs, is necessary for VEGFRi-induced renal and vascular injury. While ineffective at lowering SBP, these data suggest potential therapeutic benefits of MR antagonists, like spironolactone, to protect the vasculature and the kidneys from VEGFRi-induced injury.

Preeclampsia (PE) is an unusual multisystem condition that occurs during pregnancy and is characterized by maternal endothelial dysfunction and damage to various organs. The catabolism of L-tryptophan (Trp) is involved in various biological activities, including healthy pregnancy. Our previous work revealed that PE significantly elevated the concentration of indole-3-lactic acid (ILA), a Trp derivative, during the third trimester of pregnancy. However, the effects of ILA on the occurrence of PE and its influence on fetoplacental vascular functionality remain unknown.

Twenty-five Trp metabolites were detected in maternal serum. The effects of ILA on the functions of human umbilical vein endothelial cells (HUVECs) were examined. Furthermore, a soluble fms-like tyrosine kinase-1 (sFlt-1) induced PE-like mouse model was established and treated with ILA.

We found that the ratio of ILA to Trp gradually increased as pregnancy progressed. PE did not significantly change the concentration of ILA during either the first or second trimester. Moreover, as an aryl hydrocarbon receptor (AhR) ligand, ILA promoted HUVEC proliferation, migration and tube formation through the PI3K/AKT signaling pathway after AhR activation. Importantly, ILA administration alleviated sFlt-1-induced PE-like symptoms in mice. Similarly, our in vitro study demonstrated that ILA significantly relieved sFlt-1-induced HUVEC dysfunction by increasing the VEGFA and PIGF levels.

These data strongly suggest that PE-elevated ILA in the third trimester is a protective mechanism against vascular dysfunction. Therefore, we propose that ILA is a novel and promising therapeutic approach for the treatment of PE that promotes endothelial cell functions.

EMCN (endomucin), an endothelial-specific glycocalyx component, was found to be highly expressed by the endothelium of the renal glomerulus. We reported an anti-inflammatory role of EMCN and its involvement in the regulation of VEGF (vascular endothelial growth factor) activity through modulating VEGFR2 (VEGF receptor 2) endocytosis. The goal of this study is to investigate the phenotypic and functional effects of EMCN deficiency using the first global EMCN knockout mouse model.

Global EMCN knockout mice were generated by crossing EMCN-floxed mice with ROSA26-Cre mice. Flow cytometry was used to analyze infiltrating myeloid cells in the kidneys. The ultrastructure of the glomerular filtration barrier was examined by transmission electron microscopy, whereas urinary albumin, creatinine, and total protein levels were analyzed from freshly collected urine samples. Expression and localization of EMCN, EGFP (enhanced green fluorescent protein), CD45 (cluster of differentiation 45), CD31, CD34, podocin, and albumin were examined by immunohistochemistry. Mice were weighed regularly, and their systemic blood pressure was measured using a noninvasive tail-cuff system. Glomerular endothelial cells and podocytes were isolated by fluorescence-activated cell sorting for RNA sequencing. Transcriptional profiles were analyzed to identify differentially expressed genes in both endothelium and podocytes, followed by gene ontology analysis. Protein levels of EMCN, albumin, and podocin were quantified by Western blot.

The EMCN-/- mice exhibited increased infiltration of CD45+ cells, with an increased proportion of Ly6GhighLy6Chigh myeloid cells and higher VCAM-1 (vascular cell adhesion molecule 1) expression. EMCN-/- mice displayed albuminuria with increased albumin in the Bowman's space compared with the EMCN+/+ littermates. Glomeruli in EMCN-/- mice revealed fused and effaced podocyte foot processes and disorganized endothelial fenestrations. We found no significant difference in blood pressure between EMCN knockout mice and their wild-type littermates. RNA sequencing of glomerular endothelial cells revealed downregulation of cell-cell adhesion and MAPK (mitogen-activated protein kinase)/ERK (extracellular signal-regulated kinase) pathways, along with glycocalyx and extracellular matrix remodeling. In podocytes, we observed reduced VEGF signaling and alterations in cytoskeletal organization. Notably, there was a significant decrease in both mRNA and protein levels of podocin, a key component of the slit diaphragm.

Our study demonstrates a critical role of the endothelial marker EMCN in supporting normal glomerular filtration barrier structure and function by maintaining glomerular endothelial tight junction and homeostasis and podocyte function through endothelial-podocyte crosstalk.

Postpartum hemorrhage (PPH) is the leading cause of maternal mortality worldwide, which is often attributed to retained placenta (RP) after delivery. There are no biomarkers currently used to predict a risk of developing RP/PPH prior to labor. The objective of this study was to determine relationships between placental biomarkers measured in the first and second trimesters and proxy measures of postpartum blood loss relative to preeclampsia status in the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be (nuMoM2b) dataset. 2,192 participants had placental analytes drawn during the first and second trimesters (9-13 and 16-22 weeks gestation, respectively); the outcome was a composite of retained placenta and/or PPH requiring blood transfusion (RP/PPH). Using Kruskal-Wallis tests, median differences in levels of soluble fms-like tyrosine kinase-1 (sFlt-1), placental growth factor (PlGF), sFlt-1/PlGF ratio, soluble endoglin (sEng), beta subunit of human chorionic gonadotropin (β-hCG), inhibin A (INHA), and pregnancy-associated protein-A (PAPP-A) were assessed between women with (n=67) and without (n=2125) RP/PPH overall and stratified by preeclampsia status. Women with RP/PPH had significantly higher median levels of sEng, β-hCG, INHA, PAPP-A in the second trimester and sFlt-1was higher in both first and second trimesters, which was observed again when stratifying by preeclampsia status. Our findings indicate that biomarkers associated with angiogenesis, particularly when measured in the second trimester, are important targets for further study of RP and/or PPH pathophysiology and potential risk screening development.

Hypertensive disorders of pregnancy represent an escalating global health concern with increasing incidence in low- to middle-income countries and high-income countries alike. The current lack of methods to detect the subclinical stages of preeclampsia (PE) and fetal growth restriction (FGR), two common vascular disorders of pregnancy, limits treatment options to minimize acute- and long-term adverse outcomes for both mother and child. To determine whether impaired maternal cardiovascular or uteroplacental vascular function precedes the onset of PE and/or FGR (PE-FGR), we used noninvasive techniques to obtain serial measurements of maternal cardiac output (CO), stroke volume (SV), systemic vascular resistance (SVR), and uterine and fetal arterial resistance at gestational weeks 10-16, 20-24, and 30-34 for 79 maternal-infant pairs in La Paz-El Alto, Bolivia (3,850 m), where the chronic hypoxia of high altitude increases the incidence of PE and FGR. Compared with controls (n = 55), PE-FGR cases (n = 24) had lower SV, higher SVR, and greater uterine artery resistance at 10-16 wk. In addition, fetuses of women with lower SV and higher SVR at 10-16 wk showed evidence of brain sparing at 30-34 wk and had lower birth weights, respectively. Although the trajectory of SV and SVR across pregnancy was similar between groups, PE-FGR cases had a comparatively blunted rise in CO from the first to the third visit. Impaired maternal central hemodynamics and increased uteroplacental resistance precede PE-FGR onset, highlighting the potential use of such measures for identifying high-risk pregnancies at high altitudes.NEW & NOTEWORTHY In this prospective study of maternal central hemodynamics at high altitude, pregnancies later affected by preeclampsia (PE) and/or fetal growth restriction (FGR) show elevated systemic and uterine vascular resistance and reduced stroke volume as early as 10-16 wk gestation. Maternal hemodynamic assessments could facilitate early detection of high-risk pregnancies, improving resource allocation and reducing adverse outcomes. We propose an integrated model linking maternal cardiovascular performance to placental insufficiency, enhancing the understanding of PE-FGR in high-altitude settings.

Single-cell RNA-seq (scRNA-seq) revolutionized our understanding of tissue complexity in health and disease and revealed massive transcriptional dysregulation across placental cell classes in early-onset, but not late-onset preeclampsia (PE). However, the multinucleated syncytium is largely inaccessible to cell dissociation. Nuclei isolation and single-nuclei RNA-seq may be preferable in the placenta; not least considering compatibility with long-term tissue storage. Yet, nuclei contain a subsample of the cells' transcriptional profile. Mature transcripts critical to cellular function and disease may be missed.

We analyzed placenta from pregnancies using single-cell and single-nuclei RNA-seq. The datasets comprise 45,836 cells and 27,078 nuclei, from 10 to 7 early-onset preeclampsia (EPE) cases and 3 and 2 early idiopathic controls (ECT), respectively. We compared the methods' sensitivities, cell type detection, differential gene expression in PE, and performed histological validations.

Mature syncytiotrophoblast were sampled ∼50x more efficiently after nuclei extraction. Yet, scRNA-seq was more sensitive in detection of genes, molecules and mature transcripts. In snRNA-seq, nuclei of all placental cell classes suffered ambient trophoblast contamination. Transcripts from extravillous trophoblast, stroma, vasculature and immune cells were profiled less comprehensively by single-nuclei RNA-seq (snRNA-seq), restricting cell-type detection. In EPE, we found dysregulation of angiogenic actors FLT1/PGF both in prefused syncytiotrophoblast after cell extraction, and mature syncytiotrophoblast after nuclei isolation. Disease-related stress and inflammation were undetected from nuclei.

scRNA-seq has important advantages over snRNA-seq for comprehensive transcriptomics studies of the placenta, especially to understand cell-type resolved dysregulation in pathologies. Yet, to address the dilemma of an underrepresented syncytium, studies benefit from complementary nuclei extraction.

Preeclampsia is a serious pregnancy complication that can lead to life-threatening conditions such as seizures, strokes, and even death. A dysregulated inflammatory response in the placenta plays a crucial role in the development of preeclampsia. Cordycepin, known for its anti-inflammatory and antioxidant properties, was the focus of this study, which aimed to investigate its effects on preeclampsia.

A preeclampsia-like rat model was established via tail vein injection of lipopolysaccharides (LPS) at a dose of 1 μg/kg in pregnant rats. These rats were then treated with cordycepin at doses of 5, 25, or 50 mg/kg from embryonic day 6 (E6) today 18 (E18). Systolic blood pressures and urinary protein levels were monitored, and pregnancy outcomes, such as fetal body length and weight, were measured. The expression of target genes or proteins was assessed by qPCR, ELISA, and Western blot.

Our findings revealed that cordycepin significantly reduced systolic blood pressure and proteinuria in preeclampsia-like rats. Additionally, cordycepin improved pregnancy outcomes, as shown by increased fetal body length and weight. The treatment also lowered serum sFlt-1 levels, elevated PIGF levels, decreased placental pro-inflammatory cytokine levels (IL-1β, TNF-α, IL-6, MCP-1, and MIP-2), and raised levels of anti-inflammatory cytokine IL-10 level in preeclampsia-like rats. Furthermore, cordycepin helped restore macrophage population imbalances, increasing M1-type macrophage markers (iNOS, TNF-α, and IL-1β) and reducing M2-type macrophage markers (Arg 1, IL-10, and TGF-β).

This study suggests that cordycepin alleviates LPS-induced preeclampsia by reducing placental inflammation and correcting the M1/M2 macrophage imbalance, offering potential therapeutic benefits for managing preeclampsia.

Hypertension (HTN), often dubbed the "silent killer," poses a significant global health challenge, affecting over 1.3 billion individuals. Despite advances in treatment, effective long-term blood pressure (BP) control remains elusive, necessitating novel therapeutic approaches. Poor control of BP remains a leading cause of cardiovascular morbidity and mortality worldwide and is becoming an even larger global health problem due to the aging population, rising rates of obesity, poorer dietary patterns and overall cardiometabolic health, and suboptimal rates of patient adherence and optimal BP control. Ribonucleic acid interference (RNAi) technology, which leverages the body's natural gene-silencing mechanism, has emerged as a promising strategy for several diseases and has recently been tested for its antihypertensive effects. We systematically reviewed peer-reviewed articles from databases including PubMed, EMBASE, and Scopus for studies examining RNAi's role in managing HTN, focusing on mechanisms, clinical utility, and safety profile. Key early-phase trials of some RNAi-leading candidate drugs are detailed. Also highlighted are challenges such as target specificity, delivery mechanisms, durability of effect, and immunogenicity. We conclude by summarizing how RNAi has a significant potential role in HTN therapy due to their unique benefits, such as long-term duration of action, infrequent dosing, and lack of major side effects.