Preeclampsia (PE) is a severe gestational disorder characterized by hypertension and proteinuria, with a subset of cases exhibiting an immune-driven phenotype marked by placental overexpression of proinflammatory cytokines and chronic inflammatory damage, profoundly impacting fetal development. To elucidate the pathophysiology of this PE subtype, we established an inflammation-driven PE mouse model via lipopolysaccharide (LPS) intraperitoneal injection, systematically evaluating histopathological changes in maternal heart, liver, lung, kidney, and placenta, and integrating transcriptomic profiling to uncover molecular mechanisms. LPS administration robustly induced maternal hypertension and proteinuria, hallmarks of PE, without significantly altering organ or fetal weights. Histological analyses revealed pronounced inflammatory damage in the maternal lung, kidney, and placenta, with the lung exhibiting the most severe pathology, characterized by inflammatory cell infiltration, alveolar wall thickening, and interstitial edema-challenging the conventional focus on placental and renal primacy in PE. Placental labyrinth and junctional zones displayed extensive structural disruption and necrosis, indicating functional impairment. Transcriptomic analysis identified 27 inflammation-related genes consistently upregulated across tissues, with protein-protein interaction networks pinpointing Il1β, Il6, Ccl5, Ccl2, Cxcl10, Tlr2, and Icam1 as hub genes. Quantitative PCR validation confirmed Tlr2 as a central regulator, evidenced by significant upregulation of Tlr2 in lung, kidney, and placenta of LPS-induced PE mice, while Cxcl10 exhibited placenta-specific upregulation, suggesting a synergistic inflammatory axis in placental pathology. These findings highlight the lung as a critical, yet underappreciated, target in inflammation-driven PE, reframe the multi-organ inflammatory landscape of the disease, and nominate Tlr2 and Cxcl10 as potential diagnostic biomarkers and therapeutic targets, offering new avenues for precision intervention in PE.
Animals ; Female ; Pregnancy ; Mice ; Pre-Eclampsia/genetics* ; Inflammation ; Lipopolysaccharides/adverse effects* ; Disease Models, Animal ; Transcriptome ; Placenta/pathology* ; Phenotype

Preeclampsia and intrauterine growth restriction (IUGR) of the fetus are the two most common pregnancy complications worldwide, affecting 5%-10% of pregnant women. Preeclampsia is associated with significantly increased maternal and fetal morbidity and mortality. Hypoxia-induced uteroplacental dysfunction is now recognized as a key pathological factor in preeclampsia and IUGR. Reduced oxygen supply (hypoxia) disrupts mitochondrial and endoplasmic reticulum (ER) function. Hypoxia has been shown to alter mitochondrial reactive oxygen species (ROS) homeostasis and induce ER stress. Hypoxia during pregnancy is associated with excessive production of ROS in the placenta, leading to oxidative stress. Oxidative stress occurs in a number of human diseases, including high blood pressure during pregnancy. Studies have shown that uterine placental tissue/cells in preeclampsia and IUGR show high levels of oxidative stress, which plays an important role in the pathogenesis of both the complications. This review summarizes the role of hypoxia-induced mitochondrial oxidative stress and ER stress in the pathogenesis of preeclampsia/IUGR and discusses the potential therapeutic strategies targeting oxidative stress to treat both the pregnancy complications.
Pregnancy ; Female ; Humans ; Placenta ; Fetal Growth Retardation/etiology* ; Pre-Eclampsia/pathology* ; Reactive Oxygen Species ; Hypoxia/pathology* ; Pregnancy Complications/pathology* ; Endoplasmic Reticulum Stress

Paraganglioma in pregnancy is an extremely rare condition and its diagnosis is often delayed because the clinical symptoms can mimic those of preeclampsia or gestational hypertension. Here, we report the case of a 32-year-old, gravida 2, para 1 woman who presented with severe headache, palpitation, and sweating at 37 weeks' gestation. Although emergent cesarean section was performed on the assumption of severe preeclampsia, blood pressure fluctuated and heart rate remained tachycardiac. We suspected that she might have thromboembolic lesion in the chest or pheochromocytoma. Chest and abdominal computed tomography revealed a 4 cm mass in the left para-aortic space. Serum and urinary catecholamine levels were found to be significantly increased. She underwent laparoscopic mass removal and the pathology confirmed paraganglioma. When typical paroxysmal hypertension is accompanied by headache, palpitation, and sweating during pregnancy, adrenal tumors should be considered.
Adult ; Blood Pressure ; Cesarean Section ; Diagnosis ; Female ; Headache ; Heart Rate ; Humans ; Hypertension ; Hypertension, Pregnancy-Induced ; Paraganglioma ; Paraganglioma, Extra-Adrenal* ; Pathology ; Pheochromocytoma ; Pre-Eclampsia* ; Pregnancy ; Sweat ; Sweating ; Thorax

OBJECTIVETo investigate the relationship between polymorphisms of the growth arrest specific 6 (GAS6) gene and severe preeclampsia in a South West Han Chinese population.

METHODSBlood samples from 167 patients with severe preeclampsia and 312 normal pregnant women as controls from Han Chinese in Chengdu area were analyzed by polymerase chain reaction-restriction fragment length polymorphisms.

RESULTSC and T allele frequencies for +1332C/T site were 85.63% and 14.37% in the patient group, respectively, and 78.04% and 21.96% in control group, respectively. The TT genotype and variant T allelic frequencies of the +1332C/T polymorphism were significantly lower in patients with severe preeclampsia than in the control group (both P<0.05), and the odds ratio for the risk of severe preeclampsia was 0.602 (95%CI: 0.401-0.904) in carriers for the variant T allele (χ=6.045, P=0.014). G and A allele frequencies for 834+7G/A site were 72.75% and 27.25% in case group, respectively, and 74.36% and 25.64% in control group, respectively. The genotype and allele frequencies of the 834+7G/A polymorphism in patients with severe preeclampsia and controls showed no significant differences (both P>0.05). In addition, there was no significant association between the polymorphisms and blood pressure levels in the patient or control groups.

CONCLUSIONThe variant GAS6+1332 T allele is associated with a decreased risk for severe preeclampsia in a South West Han Chinese population. On the other hand, the 834+7G/A polymorphism has no effect on the severe preeclampsia.

Adult ; Alleles ; Asian Continental Ancestry Group ; genetics ; China ; Female ; Gene Frequency ; Genetic Predisposition to Disease ; ethnology ; genetics ; Genotype ; Humans ; Intercellular Signaling Peptides and Proteins ; genetics ; Polymerase Chain Reaction ; Polymorphism, Single Nucleotide ; Pre-Eclampsia ; ethnology ; genetics ; pathology ; Pregnancy ; Risk Factors ; Severity of Illness Index ; Young Adult

Epstein-Barr virus (EBV), a common pathogen in humans, is suspected as the cause of multiple pregnancy-related pathologies including depression, preeclampsia, and stillbirth. Moreover, transmission of EBV through the placenta has been reported. However, the focus of EBV infection within the placenta has remained unknown to date. In this study, we proved the expression of latent EBV genes in the endometrial glandular epithelial cells of the placenta and investigated the cytological characteristics of these cells. Sixty-eight placentas were obtained from pregnant women. Tissue microarray was constructed. EBV latent genes including EBV-encoding RNA-1 (EBER1), Epstein-Barr virus nuclear antigen 1 (EBNA1), late membrane antigen (LMP1), and RPMS1 were detected with silver in situ hybridization and/or mRNA in situ hybridization. Nuclear features of EBV-positive cells in EBV-infected placenta were compared with those of EBV-negative cells via image analysis. Sixteen placentas (23.5%) showed positive expression of all 4 EBV latent genes; only the glandular epithelial cells of the decidua showed EBV gene expression. EBV infection status was not significantly correlated with maternal, fetal, or placental factors. The nuclei of EBV-positive cells were significantly larger, longer, and round-shaped than those of EBV-negative cells regardless of EBV-infection status of the placenta. For the first time, evidence of EBV gene expression has been shown in placental tissues. Furthermore, we have characterized its cytological features, allowing screening of EBV infection through microscopic examination.
Decidua ; Depression ; Epithelial Cells ; Epstein-Barr Virus Infections ; Female ; Gene Expression ; Herpesvirus 4, Human* ; Humans* ; Image Cytometry ; In Situ Hybridization ; Mass Screening ; Membranes ; Pathology ; Placenta* ; Pre-Eclampsia ; Pregnant Women ; RNA, Messenger ; Silver ; Stillbirth ; Virus Latency

Axl encodes the tyrosine-protein kinase receptor, participating in the proliferation and migration of many cells. This study examined the role of Axl in functions of endothelial progenitor cells (EPCs). Axl was detected by RT-PCR and Western blotting in both placentas and EPCs from normal pregnancy and preeclampsia patients. The Axl inhibitor, BMS777-607, was used to inhibit the Axl signalling pathway in EPCs. Cell proliferation, differentiation, migration and adhesion were measured by CCK-8 assay, cell differentiation assay, Transwell assay, and cell adhesion assay, respectively. Results showed the expression levels of Axl mRNA and protein were significantly higher in both placentas and EPCs from preeclampsia patients than from normal pregnancy (P<0.05). After treatment with BMS777-607, proliferation, differentiation, migration and adhesion capability of EPCs were all significantly decreased. Our study suggests Axl may play a role in the function of EPCs, thereby involving in the pathogenesis of preeclampsia.
Adult ; Aminopyridines ; pharmacology ; Blood Pressure ; Case-Control Studies ; Cell Adhesion ; drug effects ; Cell Differentiation ; drug effects ; Cell Movement ; drug effects ; Cell Proliferation ; drug effects ; Female ; Fetal Blood ; cytology ; enzymology ; Gene Expression Regulation ; Gestational Age ; Human Umbilical Vein Endothelial Cells ; drug effects ; enzymology ; pathology ; Humans ; Placenta ; metabolism ; physiopathology ; Pre-Eclampsia ; blood ; genetics ; physiopathology ; Pregnancy ; Primary Cell Culture ; Protein Kinase Inhibitors ; pharmacology ; Proto-Oncogene Proteins ; antagonists & inhibitors ; genetics ; metabolism ; Pyridones ; pharmacology ; RNA, Messenger ; antagonists & inhibitors ; genetics ; metabolism ; Receptor Protein-Tyrosine Kinases ; antagonists & inhibitors ; genetics ; metabolism ; Stem Cells ; drug effects ; enzymology ; pathology

Conflicting results on the influences of histologic chorioamnionitis (HC) on neonatal morbidities might be partly originated from using different definition of HC. The aim of this study was to determine the relationship between HC and neonatal morbidities using definition of HC that reflects the site and extent of inflammation. This was a retrospective cohort study of 261 very low birth weight (VLBW) infants admitted at a tertiary academic center. Based on the site of inflammation, HC was categorized: any HC; amnionitis; funisitis; amnionitis+funisitis. The extent of inflammation in each site was reflected by sub-defining high grade (HG). The incidences of morbidities in infants with and without HC were compared. The bronchopulmonary dysplasia (BPD) rate was significantly higher in infants with amnionitis and the severe retinopathy of prematurity (ROP) rate was significantly higher in infants with any HC and funisitis. After adjustment for both gestational age and birth weight, the respiratory distress syndrome (RDS) rate was significantly lower in infants with all categories of HC except for HG amnionitis and HG funisitis, which are not associated with lower RDS rate. HG amnionitis was significantly associated with increased BPD rate but the association of HC with severe ROP disappeared. In conclusion, HC is significantly associated with decreased RDS and HG amnionitis with increased BPD while lacking association with other neonatal morbidities in VLBW infants. The association with HC and neonatal morbidities differs by the site and extent of chorioamnionitis.
Adult ; Birth Weight ; Bronchopulmonary Dysplasia/complications/*epidemiology ; Chorioamnionitis/classification/*epidemiology/pathology ; Cohort Studies ; Female ; Gestational Age ; Humans ; Infant, Newborn ; *Infant, Very Low Birth Weight ; Neutrophil Infiltration/immunology ; Placenta/pathology ; Pre-Eclampsia/*epidemiology/pathology ; Pregnancy ; Respiratory Distress Syndrome, Newborn/complications/*epidemiology ; Retinopathy of Prematurity/complications/*epidemiology ; Retrospective Studies ; Tertiary Care Centers

BACKGROUNDPreeclampsia is a multifactorial disease during pregnancy. Dysregulated lipid metabolism may be related to some preeclampsia. We investigated the relationship between triglycerides (TGs) and liver injury in different preeclampsia-like mouse models and their potential common pathways.

METHODSPreeclampsia-like models (Nw-nitro-L-arginine-methyl ester [L-NAME], lipopolysaccharide [LPS], apolipoprotein C-III [Apo] transgnic mice + L-NAME, β2 glycoprotein I [βGPI]) were used in four experimental groups: L-NAME (LN), LPS, Apo-LN and βGPI, respectively, and controls received saline (LN-C, LPS-C, Apo-C, βGPI-C). The first three models were established in preimplantation (PI), early-, mid- and late-gestation (EG, MG and LG). βGPI and controls were injected before implantation. Mean arterial pressure (MAP), 24-hour urine protein, placental and fetal weight, serum TGs, total cholesterol (TC) and pathologic liver and trophocyte changes were assessed.

RESULTSMAP and proteinuria were significantly increased in the experimental groups. Placenta and fetal weight in PI, EP and MP subgroups were significantly lower than LP. Serum TGs significantly increased in most groups but controls. TC was not different between experimental and control groups. Spotty hepatic cell necrosis was observed in PI, EG, MG in LN, Apo-LN and βGPI, but no morphologic changes were observed in the LPS group. Similar trophoblastic mitochondrial damage was observed in every experimental group.

CONCLUSIONSEarlier preeclampsia onset causes a higher MAP and urine protein level, and more severe placental and fetal damage. Preeclampsia-like models generated by varied means lead to different changes in lipid metabolism and associated with liver injury. Trophoblastic mitochondrial damage may be the common terminal pathway in different preeclampsia-like models.

Animals ; Cholesterol ; blood ; Disease Models, Animal ; Female ; Fetal Weight ; physiology ; Liver ; injuries ; Male ; Mice ; Mice, Inbred C57BL ; Mitochondrial Diseases ; blood ; pathology ; Placenta ; metabolism ; Pre-Eclampsia ; blood ; pathology ; Pregnancy ; Triglycerides ; blood ; Trophoblasts ; pathology

OBJECTIVETo explore the pathologic features and prognosis of early and late onset severe preeclampsia.

METHODSAn observational study was conducted in 178 cases of severe preeclampsia collected during January 2010 to December 2014 from Haidian Maternal and Child Health Hospital.The cases were divided into two groups according to the onset of gestational age of the severe preeclampsia, with 54 cases of namely early onset (onset ≤ 34 weeks) and 124 cases of late onset (onset >34 weeks). Clinical characteristics of the patients, perinatal outcome and the pathologic characteristics of the placentas in each group were evaluated.

RESULTSDecidual vascular disease, placental infarction, abruptio placentae and placental villi dysplasia were seen in both groups. The incidence of placental villi dysplasia was the highest, followed by placental infarction. Incidence of severe decidual vascular disease of early and late onset severe decidual vascular disease were 16.7% (9/54) and 5.6% (7/124), respectively.Incidence of placental infarction of early and late onset severe preeclampsia were 48.1% (26/54) and 61.3% (76/124). Incidence of placental villi dysplasia of early and late onset severe preeclampsia were 79.6% (43/54) and 50.8% (63/124). Incidence of Severe decidual vascular disease, placental infarction and placental villi dysplasia were significantly different between early and late onset severe preeclampsia cases (P<0.05), while there was no difference in decidual vascular disease and placenta thrombi (P>0.05). Fetal survival rate of every group was 81.5% (44/54) and 93.5% (116/124). Incidence of fetal growth retardation was 55.6% (30/54) and 38.7% (48/124). The fetal survival rate and incidence of fetal growth retardation were different between two groups (P<0.05).

CONCLUSIONSThe incidence of decidual vascular disease and placental villi dysplasia in early onset severe preeclampsia is higher than those in late onset severe preeclampsia. Neonatal outcome and prognosis in early onset severe preeclampsia are worse than those in late onset severe preeclampsia.

Chorionic Villi ; pathology ; Female ; Fetus ; Gestational Age ; Humans ; Placenta ; pathology ; Placenta Diseases ; epidemiology ; pathology ; Pre-Eclampsia ; epidemiology ; pathology ; Pregnancy

Acute atherosis is unique vascular changes of the placenta associated with poor placentation. It is characterized by subendothelial lipid-filled foam cells, fibrinoid necrosis of the arterial wall, perivascular lymphocytic infiltration, and it is histologically similar to early-stage atherosclerosis. Acute atherosis is rare in normal pregnancies, but is frequently observed in non- transformed spiral arteries in abnormal pregnancies, such as preeclampsia, small for gestational age (SGA), fetal death, spontaneous preterm labor and preterm premature rupture of membranes. In preeclampsia, spiral arteries fail to develop physiologic transformation and retain thick walls and a narrow lumen. Failure of physiologic transformation of spiral arteries is believed to be the main cause of uteroplacental ischemia, which can lead to the production of anti-angiogenic factors and induce endothelial dysfunction and eventually predispose the pregnancy to preeclampsia. Acute atherosis is more frequently observed in the spiral arteries of the decidua of the placenta (parietalis or basalis) than in the decidual or myometrial segments of the placental bed. The presence and deeper location of acute atherosis is associated with poorer pregnancy outcomes, more severe disease, earlier onset of preeclampsia, and a greater frequency of SGA neonates in patients with preeclampsia. Moreover, the idea that the presence of acute atherosis in the placenta may increase the risk of future cardiovascular disease in women with a history of preeclampsia is of growing concern. Therefore, placental examination is crucial for retrospective investigation of pregnancy complications and outcomes, and accurate placental pathology based on universal diagnostic criteria in patients with abnormal pregnancies is essential for clinicopathologic correlation.
Arteries* ; Atherosclerosis ; Cardiovascular Diseases ; Cholesterol ; Decidua ; Female ; Fetal Death ; Foam Cells ; Gestational Age ; Humans ; Infant, Newborn ; Ischemia ; Membranes ; Necrosis ; Obstetric Labor, Premature ; Pathology ; Placenta ; Placentation ; Pre-Eclampsia ; Pregnancy ; Pregnancy Complications ; Pregnancy Outcome ; Retrospective Studies ; Rupture