Preexisting hypertension and pregnancy-induced hypertension reveal molecular differences in placental proteome in rodents.
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ABSTRACT:
SUBMITTER: Mary S
PROVIDER: S-EPMC8616587 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Preeclampsia is a pregnancy-specific disorder of new-onset hypertension. Unfortunately, the most effective treatment is early delivery of the fetus and placenta. Placental ischemia appears central to the pathogenesis of preeclampsia because placental ischemia/hypoxia induced in animals by reduced uterine perfusion pressure (RUPP) or in humans stimulates release of hypertensive placental factors into the maternal circulation. The anti-angiogenic factor soluble fms-like tyrosine kinase-1 (sFlt-1), which antagonizes and reduces bioavailable vascular endothelial growth factor and placental growth factor (PlGF), is elevated in RUPP rats and preeclampsia. Although PlGF and vascular endothelial growth factor are both natural ligands for sFlt-1, vascular endothelial growth factor also has high affinity to VEGFR2 (Flk-1) causing side effects like edema. PlGF is specific for sFlt-1. We tested the hypothesis that PlGF treatment reduces placental ischemia-induced hypertension by antagonizing sFlt-1 without adverse consequences to the mother or fetus. On gestational day 14, rats were randomized to 4 groups: normal pregnant or RUPP±infusion of recombinant human PlGF (180 ?g/kg per day; AG31, a purified, recombinant human form of PlGF) for 5 days via intraperitoneal osmotic minipumps. On day 19, mean arterial blood pressure and plasma sFlt-1 were higher and glomerular filtration rate lower in RUPP than normal pregnant rats. Infusion of recombinant human PlGF abolished these changes seen with RUPP along with reducing oxidative stress. These data indicate that the increased sFlt-1 and reduced PlGF resulting from placental ischemia contribute to maternal hypertension. Our novel finding that recombinant human PlGF abolishes placental ischemia-induced hypertension, without major adverse consequences, suggests a strong therapeutic potential for this growth factor in preeclampsia.
| S-EPMC4786447 | biostudies-other
Project description:Assisted reproductive technology (ART)-treated women exhibit increased risk of premature delivery compared to fertile women. We evaluated whether ART treatment modalities increase prematurity and whether placental abnormalities and pregnancy-induced hypertensive (PIH) disorders mediate these risks. This retrospective study of ART-treated and fertile deliveries (2004-2017) used an ART-cycle database linked to Massachusetts birth certificates and hospital discharges. Outcomes of late preterm birth (LPTB: 34-36 weeks gestation) and early preterm birth (EPTB: <34 weeks gestation) were compared with term deliveries (≥37 weeks gestation) in ART-treated (linked to the ART database) and fertile (no indicators of infertility or ART) deliveries. ART treatments with autologous oocyte, donor oocyte, fresh or frozen embryo transfer (FET), intracytoplasmic sperm injection (ICSI) and no-ICSI were separately compared to the fertile group. Adjusted odds ratios (AOR) were calculated with multivariable logistic regression: placental abnormalities or PIH were quantified in the pathway as mediators. There were 218,320 deliveries: 204,438 fertile and 13,882 ART-treated. All treatment types increased prematurity (AOR 1.31-1.58, LPTB; AOR 1.34-1.48, EPTB). Placental abnormalities mediated in approximately 22% and 38% of the association with LPTB and EPTB, respectively. PIH mediated 25% and 33% of the association with LPTB and EPTB in FET and donor oocyte cycles, more than other treatments (<10% LPTB and <13% EPTB). ART-treatment and all ART modalities increased LPTB and EPTB when compared with fertile deliveries. Placental abnormalities modestly mediated associations approximately equally, while PIH was a stronger mediator in FET and donor oocyte cycles. Reasons for differences require exploration.
| S-EPMC8070757 | biostudies-literature
Project description:Maternal infections are implicated in a variety of complications during pregnancy, including pregnancy loss, prematurity, and increased risk of neurodevelopmental disorders in the child. Here, we show in mice that even mild innate immune activation by low-dose lipopolysaccharide in early pregnancy causes hemorrhages in the placenta and increases the risk of pregnancy loss. Surviving fetuses exhibit hypoxia in the brain and impaired fetal neurogenesis. Maternal Toll-like receptor 4 signaling is a critical mediator of this process, and its activation is accompanied by elevated proinflammatory cytokines in the placenta. We evaluated the role of tumor necrosis factor-? (TNF-?) signaling and show that TNF receptor 1 (TNFR1) is necessary for the illness-induced placental pathology, accompanying fetal hypoxia, and neuroproliferative defects in the fetal brain. We also show that placental TNFR1 in the absence of maternal TNFR1 is sufficient for placental pathology to develop and that a clinically relevant TNF-? antagonist prevents placental pathology and fetal loss. Our observations suggest that the placenta is highly sensitive to proinflammatory signaling in early pregnancy and that TNF-? is an effective target for preventing illness-related placental defects and related risks to the fetus and fetal brain development.
| S-EPMC3124299 | biostudies-literature
Project description:Group B Streptococcus (GBS) is a pathobiont that can ascend to the placenta and cause adverse pregnancy outcomes, in part through production of the toxin β-hemolysin/cytolysin (β-h/c). Innate immune cells have been implicated in the response to GBS infection, but the impact of β-h/c on their response is poorly defined. We show that GBS modulates innate immune cell states by subversion of host inflammation through β-h/c, allowing worse outcomes. We used an ascending mouse model of GBS infection to measure placental cell state changes over time following infection with a β-h/c-deficient and isogenic wild type GBS strain. Transcriptomic analysis suggests that β-h/c-producing GBS elicit a worse phenotype through suppression of host inflammatory signaling in placental macrophages and neutrophils, and comparison of human placental macrophages infected with the same strains recapitulates these results. Our findings have implications for identification of new targets in GBS disease to support host defense against pathogenic challenge.
| S-EPMC9996236 | biostudies-literature
Project description:BackgroundIntrahepatic cholestasis of pregnancy (ICP) is a pregnancy-associated liver disease with potentially deleterious consequences for the fetus, particularly when maternal serum bile-acid concentration >40 μM. However, the etiology and pathogenesis of ICP remain elusive. To reveal the underlying molecular mechanisms for the association of maternal serum bile-acid level and fetal outcome in ICP patients, DNA microarray was applied to characterize the whole-genome expression profiles of placentas from healthy women and women diagnosed with ICP.MethodsThirty pregnant women recruited in this study were categorized evenly into three groups: healthy group; mild ICP, with serum bile-acid concentration ranging from 10-40 μM; and severe ICP, with bile-acid concentration >40 μM. Gene Ontology analysis in combination with construction of gene-interaction and gene co-expression networks were applied to identify the core regulatory genes associated with ICP pathogenesis, which were further validated by quantitative real-time PCR and histological staining.ResultsThe core regulatory genes were mainly involved in immune response, VEGF signaling pathway and G-protein-coupled receptor signaling, implying essential roles of immune response, vasculogenesis and angiogenesis in ICP pathogenesis. This implication was supported by the observed aggregated immune-cell infiltration and deficient blood vessel formation in ICP placentas.ConclusionsOur study provides a system-level insight into the placental gene-expression profiles of women with mild or severe ICP, and reveals multiple molecular pathways in immune response and blood vessel formation that might contribute to ICP pathogenesis.
| S-EPMC4105836 | biostudies-literature
Project description:BackgroundIt is hypothesized that male fetuses prioritize growth, resulting in increased mortality, whereas females reduce growth in the presence of adversity. Preeclampsia reflects a chronic condition, in which fetuses have the opportunity to adjust growth. If females reduce their growth in response to preeclampsia, but males attempt to maintain growth at the cost of survival, we predict that differences in birthweight between preeclamptic and non-preeclamptic pregnancies will be greater among females, whereas differences in mortality will be greater among males.MethodsWe analysed data from the Centers for Disease Control and Prevention. We compared pregnancies with pregnancy-associated hypertension (PAH) and controls.ResultsThe difference in birthweight between pregnancies affected by PAH and controls varied by fetal sex and gestational age. Among pregnancies of White individuals, at 34-35 weeks, the difference between PAH and controls was higher among females, as predicted. However, this pattern was reversed earlier in pregnancy and around term. Such variation was not significant in Black pregnancies. In both Black and White pregnancies, early in gestation, males had lower odds of death in PAH pregnancies, but higher odds of death in control pregnancies, counter to our prediction. Later, males had higher odds of death in PAH and controls, although the increased odds of death in males was not higher in PAH pregnancies than in controls. Overall, the difference in birthweight between surviving and non-surviving infants was greater in males than in females, opposite to our prediction.ConclusionsThe impact of PAH on birthweight and survival varies widely throughout gestation. Differences in birthweight and survival between male and female PAH and controls are generally not consistent with the hypothesis that males prioritize fetal growth more than females, and that this is a cause of increased mortality in males.
| S-EPMC10783718 | biostudies-literature
Project description:Preeclampsia is characterized by reduced placental perfusion with placental ischemia and hypertension during pregnancy. Preeclamptic women also exhibit a heightened inflammatory state and greater number of neutrophils in the vasculature compared to normal pregnancy. Since neutrophils are associated with tissue injury and inflammation, we hypothesized that neutrophils are critical to placental ischemia-induced hypertension and fetal demise. Using the reduced uteroplacental perfusion pressure (RUPP) model of placental ischemia-induced hypertension in the rat, we determined the effect of neutrophil depletion on blood pressure and fetal resorptions. Neutrophils were depleted with repeated injections of polyclonal rabbit anti-rat polymorphonuclear leukocyte (PMN) antibody (antiPMN). Rats received either antiPMN or normal rabbit serum (Control) on 13.5, 15.5, 17.5, and 18.5 days post conception (dpc). On 14.5 dpc, rats underwent either Sham surgery or clip placement on ovarian arteries and abdominal aorta to reduce uterine perfusion pressure (RUPP). On 18.5 dpc, carotid arterial catheters were placed and mean arterial pressure (MAP) was measured on 19.5 dpc. Neutrophil-depleted rats had reduced circulating neutrophils from 14.5 to 19.5 dpc compared to Control, as well as decreased neutrophils in lung and placenta on 19.5 dpc. MAP increased in RUPP Control vs Sham Control rats, and neutrophil depletion attenuated this increase in MAP in RUPP rats without any effect on Sham rats. The RUPP-induced increase in fetal resorptions and complement activation product C3a were not affected by neutrophil depletion. Thus, these data are the first to indicate that neutrophils play an important role in RUPP hypertension and that cells of the innate immune system may significantly contribute to pregnancy-induced hypertension.
| S-EPMC4509576 | biostudies-literature
Project description:Genome-wide signatures of convergent evolution are widely expected but rarely revealed in animals. Subterranean rodent genome and transcriptome data produced by next-generation sequencing facilitate the use of phylogenetic methods to infer non-synonymous and synonymous substitution rates within coding regions, which can reveal changes at the molecular level that are correlated with the dramatic shift from a terrestrial to subterranean habitat.Our study used previously sequenced genome or transcriptome data of two subterranean rodents, the blind mole rat and naked mole rat, and their terrestrial relatives, the mouse and guinea pig, to investigate the genetic basis of rodent subterranean adaptation. An analysis of 4996 orthologous genes revealed that the substitution pace of coding sequences was significantly slower in the blind mole rat than in the mouse, and slower in the naked mole rat than in the guinea pig. The dN/dS ratio was significantly higher in the blind mole rat than in the mouse and in the naked mole rat than in the guinea pig. These patterns are most likely related to the longer generation time and lower effective population size of subterranean rodents caused by subterranean ecological constraints. We also identified some genes and gene ontology (GO) categories that might be candidates for adaptation to subterranean life.Our study reveals a case of subterranean convergent evolution in rodents that is correlated with change in the pace and mode of molecular evolution observed at the genome scale. We believe that this genomic signature could have also evolved in other cases of subterranean convergence. Additionally, the genes that displayed the most radical changes in their patterns of evolution and their associated GO categories provide a strong basis for further comparative and functional studies, and potentially reveal molecular signatures of adaptation to subterranean life.
| S-EPMC4683706 | biostudies-literature
Project description:Preeclampsia is a prevalent pregnancy complication characterized by new-onset maternal hypertension and inflammation, with placental ischemia as the initiating event. Studies of others have provided evidence for the importance of lymphocytes in placental ischemia-induced hypertension; however, the contributions of B1 versus B2 lymphocytes are unknown. We hypothesized that peritoneal B1 lymphocytes are important for placental ischemia-induced hypertension. As an initial test of this hypothesis, the effect of anti-CD20 depletion on both B-cell populations was determined in a reduced utero-placental perfusion pressure (RUPP) model of preeclampsia. Anti-murine CD20 monoclonal antibody (5 mg/kg, Clone 5D2) or corresponding mu IgG2a isotype control was administered intraperitoneally to timed pregnant Sprague-Dawley rats on gestation day (GD)10 and 13. RUPP or sham control surgeries were performed on GD14, and mean arterial pressure (MAP) was measured on GD19 from a carotid catheter. As anticipated, RUPP surgery increased MAP and heart rate and decreased mean fetal and placental weight. However, anti-CD20 treatment did not affect these responses. On GD19, B-cell populations were enumerated in the blood, peritoneal cavity, spleen, and placenta with flow cytometry. B1 and B2 cells were not significantly increased following RUPP. Anti-CD20 depleted B1 and B2 cells in peritoneum and circulation but depleted only B2 lymphocytes in spleen and placenta, with no effect on circulating or peritoneal IgM. Overall, these data do not exclude a role for antibodies produced by B cells before depletion but indicate the presence of B lymphocytes in the last trimester of pregnancy is not critical for placental ischemia-induced hypertension.NEW & NOTEWORTHY The adaptive and innate immune systems are implicated in hypertension, including the pregnancy-specific hypertensive condition preeclampsia. However, the mechanism of immune system dysfunction leading to pregnancy-induced hypertension is unresolved. In contrast to previous reports, this study reveals that the presence of classic B2 lymphocytes and peritoneal and circulating B1 lymphocytes is not required for development of hypertension following third trimester placental ischemia in a rat model of pregnancy-induced hypertension.
| S-EPMC6843018 | biostudies-literature
Project description:RationalePulmonary hypertension (PH) is characterized by progressive increase in pulmonary artery pressure leading to right ventricular (RV) hypertrophy, RV failure, and death. Current treatments only temporarily reduce severity of the disease, and an ideal therapy is still lacking.ObjectivesEstrogen pretreatment has been shown to attenuate development of PH. Because PH is not often diagnosed early, we examined if estrogen can rescue preexisting advanced PH.MethodsPH was induced in male rats with monocrotaline (60 mg/kg). At Day 21, rats were either treated with 17-β estradiol or estrogen (E2, 42.5 μg/kg/d), estrogen receptor-β agonist (diarylpropionitrile, 850 μg/kg/d), or estrogen receptor α-agonist (4,4',4"-[4-Propyl-(1H)-pyrazole-1,3,5-triyl] trisphenol, 850 μg/kg/d) for 10 days or left untreated to develop RV failure. Serial echocardiography, cardiac catheterization, immunohistochemistry, Western blot, and real-time polymerase chain reaction were performed.Measurements and main resultsEstrogen therapy prevented progression of PH to RV failure and restored lung and RV structure and function. This restoration was maintained even after removal of estrogen at Day 30, resulting in 100% survival at Day 42. Estradiol treatment restored the loss of blood vessels in the lungs and RV. In the presence of angiogenesis inhibitor TNP-470 (30 mg/kg) or estrogen receptor-β antagonist (PHTPP, 850 μg/kg/d), estrogen failed to rescue PH. Estrogen receptor-β selective agonist was as effective as estrogen in rescuing PH.ConclusionsEstrogen rescues preexisting severe PH in rats by restoring lung and RV structure and function that are maintained even after removal of estrogen. Estrogen-induced rescue of PH is associated with stimulation of cardiopulmonary neoangiogenesis, suppression of inflammation, fibrosis, and RV hypertrophy. Furthermore, estrogen rescue is likely mediated through estrogen receptor-β.
| S-EPMC3208600 | biostudies-literature