Placental Apoptosis Research Articles

Placental apoptotic markers are associated with placental morphometry.

Preeclampsia is a hypertensive disorder affecting both mother and the fetus and is a major cause of maternal and neonatal morbidity and mortality. Abnormal placentation is a common feature in preeclampsia that contributes to placental dysfunction. It is likely that increased homocysteine and oxidative stress influence apoptosis in preeclampsia. Increased placental apoptosis may aggravate the symptoms of preeclampsia through disruption of the placental structure. The current study aims to examine the association between various placental apoptotic markers with placental dimensions and maternal and neonatal characteristics in women with preeclampsia. A total of 80 pregnant women [preeclampsia (n=40); normotensive control (n=40)] were included in the study. Placental characteristics such as its major axis, minor axis, breadth, thickness (at centre, cord insertion and periphery) and trimmed placental weight were recorded.Placental protein levels of caspase-3, caspase-8, BAX and Bcl-2 were estimated by ELISA and gene expression were examined by real time quantitative PCR. Protein levels of proapoptotic markers such as caspase-8 and 3 were higher (p<0.01) in the preeclampsia group compared to control whereas, the level of antiapoptotic marker Bcl-2 (p<0.05) was lower in the preeclampsia group. Caspase-3 and Bcl-2 protein levels were negatively associated with thickness of placenta at cord insertion (p<0.01). Protein levels of caspase-8 and caspase-3 were positively associated with placental MDA levels (p<0.01). Caspase-8 was negatively associated with baby length (p=0.055). This study demonstrates the association of various apoptotic markers with oxidative stress and placental dimensions.

Resveratrol ameliorates toxic effects of cadmium on placental development in mouse placenta and human trophoblast cells.

Cadmium (Cd) is a common heavy metal pollutant. Prenatal exposure to Cd results in adverse effects on fetal development. Placental apoptosis, inflammation, and epigenetic disruption have been implicated in Cd-induced placental toxicity. Resveratrol (Res) is a naturally occurring polyphenol with anti-apoptotic, anti-inflammatory, and epigenetic regulatory activities. In present study, the effects of Res on placental toxicity induced by Cd were evaluated. Pregnant CD-1 mice were fed with base diet containing 0.2% Res started on gestational day 0 (GD0), and intraperitoneally injected with 4.5mg/kg CdCl2 or saline once on GD9. JEG-3 cells were treated with 20 μM Res for 24 hr in the absence or presence of 20 μM CdCl2 for the second 12 hr. The fetal outcomes, the apoptosis in placenta and JEG-3 cells, the expression of inflammatory cytokines and chemokines including tumor necrosis factor-α (TNF-α), interferon-gamma (IFN-γ), monocyte chemoattractant protein 1 (MCP-1), macrophage inflammatory protein-2 (MIP-2) and chemokine (C-X-C motif) ligand 1 (KC), and expression of endoplasmic reticulum (ER) stress markers were evaluated. The expression and activities of DNA methyltransferase (DNMT), and the activation of Akt signaling pathway were detected. Cd exposure resulted in decreased fetal weight and crown-rump length while Res ameliorated these outcomes. Res suppressed Cd-induced apoptosis in placenta and JEG-3 cells, and decreased Cd-induced expression of TNF-α, IFN-γ, MCP-1, MIP-2, and KC in placenta. Cd greatly increased ER stress in placenta in mice, which was partially ameliorated by Res treatment. Res decreased Cd-induced upregulation of DNMT activity and suppressed Cd-induced expression of DNMT3B. Res restored estradiol secretion, enhances activity and protein levels of SIRT1 and inhibited Cd-induced activation of Akt signaling pathway. Res ameliorated Cd-induced placental toxicity and regulated DNMT3 expression and PI3K/Akt pathway activation.

Gestational exposure to environmental cadmium induces placental apoptosis and fetal growth restriction via Parkin-modulated MCL-1 degradation

Heavy metal cadmium (Cd), a classical environmental pollutant, causes placental apoptosis and fetal growth restriction (FGR), whereby the mechanism remains unclear. Here, our human case-control study firstly showed that there was a positive association of Parkin mitochondrial translocation, MCL-1 reduction, placental apoptosis, and all-cause FGR. Subsequently, Cd was administered to establish in vitro and in vivo models of placental apoptosis or FGR. Our models demonstrated that Parkin mitochondrial translocation was observed in Cd-administrated placental trophoblasts. Meaningfully, Parkin siRNA (siR) dramatically mitigated Cd-triggered apoptosis in placental trophoblasts. Mdivi-1 (M-1), an inhibitor for Parkin mitochondrial translocation, mitigated Cd-induced apoptosis in placental trophoblasts, which further ameliorated the effect of attenuated placental sizes in Cd-exposed mice. Furthermore, the interaction of MCL-1 with Parkin or Ub in Cd-stimulated cells was stronger than that in controls. MG132, an inhibitor for proteasome, abolished MCL-1 degradation in Cd-stimulated cells. Importantly, Parkin siR and M-1 memorably abolished the ubiquitin-dependent degradation of MCL-1 in placental trophoblasts. Interestingly, mito-TEMPO and melatonin, two mitochondria-targeted antioxidants, obviously rescued Cd-caused mitochondrial membrane potential (MMP) decrease, Parkin mitochondrial translocation, MCL-1 degradation, and apoptosis in placental trophoblasts. In conclusion, cadmium induces placental apoptosis and FGR via mtROS-mediated Parkin-modulated degradation of MCL-1.

Evaluation of pregnancy outcome in cases of intrauterine growth restriction in relation to placenta apoptosis and doppler indices of the umbilical and uterine arteries

Objective: To assess apoptotic changes in trophoblastic cells in normal term placentae and term placentae complicated by either preeclampsia or intrauterine growth restriction (IUGR). Additionally, we aim to examine the correlation between these apoptotic changes and the Doppler velocity of the umbilical and uterine arteries. Methods: This prospective observational study was conducted on 150 pregnant women, including 100 cases with preeclampsia and 50 controls. Placentas were collected at delivery, and apoptotic changes were examined using light microscopy and immunohistochemical staining. Doppler velocimetries were performed to assess umbilical and uterine artery resistance indices. Pregnancy outcomes and neonatal data were recorded. Results: The incidence of apoptosis in placentae was significantly higher in the preeclampsia group compared to the control group (p&lt;0.001). The umbilical and uterine resistance indices were also significantly higher in the preeclampsia group (p&lt;0.001). There was a positive correlation between the incidence of apoptosis and Doppler resistance indices in the preeclampsia group. Fetal birth weight, Apgar scores at 1 and 5 minutes, and gestational age at delivery were significantly lower in the preeclampsia group (p&lt;0.001). Conclusions: Increased placental apoptosis and abnormal Doppler indices are associated with preeclampsia and adverse pregnancy outcomes.

Increased expression of apoptotic markers in human full-term placenta after exposure to elevated environmental cadmium levels during pregnancy.

Cadmium (Cd), a toxic heavy metal, produces various forms of environmental contaminations and health problems in human. In this study, we aimed to examine the localization of several apoptotic markers in human placentas from pregnant women who were environmentally exposed to Cd. Twelve pregnant women participated in this analysis and they were divided into 2 groups according to their living areas: high-Cd (H-Cd) and low-Cd (L-Cd) groups. After delivery, the placentas were immediately harvested, and the placental width, length, and weight were measured. The placental Cd concentration was determined by using ICP-MS. The expression of three apoptotic markers, cleaved caspase-3, cleaved lamin A/C, and TUNEL, was examined in immunohistochemistry. In results, the placental Cd concentration in the H-Cd group was higher than that in the L-Cd group. In contrast, a significant decrease in the BW (birth weight):PW (placenta weight) ratio representing the placental nutrient transport function was found in the H-Cd group, and an inverse correlation between placental Cd concentration and BW:PW ratio was demonstrated. Additionally, significant elevations in the expression of cleaved caspase-3, cleaved lamin A/C proteins, and TUNEL were shown in the H-Cd placenta. Moreover, positive correlations were found between the placental Cd concentration and the expression of cleaved caspase-3 and TUNEL. Collectively, our findings suggest that the exposure of pregnant women to environmental Cd might induce Cd to be transferred to the body and then accumulated in the placenta, resulting in disturbance of the placental function and eventual apoptosis.

Serum survivin is decreased in women with preeclampsia

ABSTRACT Objective: To evaluate the serum survivin level in preeclampsia. Methods: Eighty-eight pregnancies complicated with preeclampsia and 88 gestational-age (GA)-matched uncomplicated pregnancies were evaluated. Results: Mean serum survivin was detected to be significantly decreased in the early- (EOPE) and late-onset (LOPE) preeclampsia subgroups than the GA-matched control-groups; and were comparable in EOPE- and LOPE-groups after correction for GA. Serum survivin had weak negative correlations with systolic and diastolic arterial blood pressure. Conclusion: The serum survivin level was decreased in preeclamptic patients than the GA-matched controls. More comprehensive studies are needed to clarify the timing and extent of placental apoptosis in preeclampsia.

ELABELA alleviates syncytiotrophoblast hypoxia/reoxygenation injury and preeclampsia-like symptoms in mice by reducing apoptosis

IntroductionPreeclampsia (PE) is associated with increased syncytiotrophoblast apoptosis. ELABELA (ELA) is a circulating hormone secreted by the placenta. Here, we investigated the involvement of ELA in the pathogenesis of PE. MethodsWe measured ELA expression in the placental villi of patients with severe PE and healthy controls. A cellular model of hypoxia and reoxygenation was used to simulate PE hypoxia, and changes in the proliferation and apoptosis of trophoblasts in response to different ELA concentrations were measured. In addition, we used NG-nitro-l-arginine methyl ester (l-NAME) to generate a mouse model of pregnancy-induced hypertension and explore whether ELA can improve the symptoms of PE. ResultsELA expression was decreased in severe PE. ELA promoted the proliferation of BeWo cells and improved the decreased cell proliferation rate after hypoxia/reoxygenation injury. ELA reversed the phenotypes of l-NAME-induced PE mice and regulated the expression of mouse placental apoptosis factors. DiscussionELA reduced apoptosis in BeWo cells and improved PE-like symptoms in mice, suggesting its value as a potential novel treatment for PE.

Cell death mechanisms and their roles in pregnancy related disorders.

Autophagy and apoptosis are catabolic pathways essential for homeostasis. They play a crucial role for normal placental and fetal development. These cell death mechanisms are exaggerated in placental disorders such as preeclampsia, intrauterine growth restriction (IUGR) and gestational diabetes mellitus (GDM). Apoptosis is widely studied, highly controlled and regulated whereas; autophagy is an orderly degradation and recycling of the cellular components. Cellular senescence may be initiated by a variety of stimuli, including hypoxia, oxidative stress, reduction in survival signals and nutrition deprivation. Apoptosis is regulated by two types of pathways intrinsic and extrinsic. Extrinsic pathway is initiated by apoptosis inducing cells such as macrophages, natural killer cells whereas; intrinsic pathway is initiated in response to DNA damage, cell injury and lack of oxygen. In autophagy, the cell or organelles undergo lysosomal degradation. Placental apoptosis increases as the gestation progresses while autophagy plays a role in trophoblast differentiation and invasion. In pregnancy disorders like preeclampsia and IUGR, proapoptotic markers such as caspase 3, 8, BAX are higher and antiapoptotic markers like Bcl-2 are lower. In GDM, apoptotic markers are reduced resulting in increased placental mass and fetal macrosomia. Apoptosis in the pathological pregnancies is also influenced by the reduced levels of micronutrients and long chain polyunsaturated fatty acids resulting in disturbed placental biology. This chapter describes the role of various key molecular events involved in cellular senescence and the various factors influencing them. This will help identify future therapeutic strategies for better management of these processes.

Fas ligand neutralization attenuates hypertension, endothelin-1, and placental inflammation in an animal model of HELLP syndrome.

Neutralization of FasL is linked to suppression of hypertension, placental inflammation, and endothelin system activation in an animal model of hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome. During HELLP syndrome the placenta has been reported to serve as the primary source of Fas ligand (FasL), which has an impact on inflammation and hypertension during pregnancy and is dysregulated in women with severe preeclampsia and HELLP syndrome. We hypothesize that neutralization of FasL during pregnancy in an animal model of HELLP syndrome decreases inflammation and placental apoptosis, improves endothelial damage, and improves hypertension. On gestational day (GD) 12, rats were chronically infused with placental antiangiogenic factors sFlt-1 and sEng to induce HELLP syndrome. To neutralize FasL, MFL4 or FasL antibody was infused into a subset of HELLP or normal pregnant rats on GD13. IgG infusion into another group of NP and HELLP rats on GD13 was used as a control for FasL antibody, and all rats were euthanized on GD19 after blood pressure measurement. Plasma and placentas were collected to assess inflammation, apoptosis, and the degree of placental debris activation of endothelial cells. Administration of MFL4 to HELLP rats significantly decreased blood pressure compared with untreated HELLP rats and HELLP rats infused with IgG and improved the biochemistry of HELLP syndrome. Both circulating and placental FasL were significantly attenuated in response to MFL4 infusion, as were levels of placental and circulating TNFα when compared with untreated HELLP rats and HELLP rats infused with IgG. Endothelial cells exposed to placental debris and media from HP + MFL4 rats secreted significantly less endothelin-1 compared with stimulated endothelial cells from HELLP placentas. Neutralization of FasL is associated with decreased MAP and improvement in placental inflammation and endothelial damage in an animal model of HELLP syndrome.

The Effect of Cigarette Smoke Exposure due to Placental Apoptosis and Gestation Outcomes at Gestation Disorders Mechanism In White Rat (Rattus norvegicus)

The Effect of Cigarette Smoke Exposure due to Placental Apoptosis and Gestation Outcomes at Gestation Disorders Mechanism In White Rat (Rattus norvegicus)

Co‐expression of placental RAGE and g‐H2AX during intrauterine growth restriction and preeclampsia in rodents

Intrauterine growth restriction (IUGR) and preeclampsia (PE) are obstetrics complications associated with poor outcomes for the both the mother and fetus. Although both characteristically differ, both diseases are associated with placental malfunction that stems in part from increased placental apoptosis. DNA double strand breaks (DNA‐DSBs) represent some of the most destructive forms of genomic damage in which both strands of DNA are ruptured. H2AX is a component of the histone octomer and is phosphorylated to form g‐H2AX in response to the sensing of DNA‐DSBs. The receptor for advanced glycation end‐products (RAGE) is a multi‐ligand receptor primarily expressed on cell membranes, where it functions as a progression factor in inflammatory signaling; however, the nuclear isoform of RAGE (nRAGE) has been described as having a crucial role in DNA‐DSBs repair. The purpose of this study was to identify placental DNA damage, placental nRAGE and g‐H2AX expression in a secondhand smoke exposed rodent model of IUGR and a Gas6 induced PE model. Placental and fetal weights were determined at the time of necropsy in the IUGR model. Blood pressure and proteinuria was assessed in the PE model. Characterizing DNA degradation was used to confirm placental DNA damage during these pregnancy complications. Immunohistochemistry was used to determine localization of both molecules in the placenta. Relative to controls we observed: 1) decreased placental and fetal weights (1.4‐fold and 2.3‐fold; p&lt;0.003) during IUGR; 2) significantly increased systolic and diastolic blood pressure and proteinuria (80%; p&lt;0.05) during PE; 3) increased DNA degradation in the IUGR and PE placentas and 4) Increased staining for RAGE and g‐H2AX in the IUGR and PE placentas. These results may provide insight into the physiological relevance of these molecules, and if so, their modification during gestation may help alleviate placental disease.Support or Funding InformationThis work was supported by a grant from the Flight Attendant’s Medical Research Institute (FAMRI, PRR and JAA) and a BYU Mentoring Environment Grant (JAA and PRR).

Maternal curcumin supplementation ameliorates placental function and fetal growth in mice with intrauterine growth retardation†.

Intrauterine growth retardation (IUGR) is a serious reproductive problem in humans. The objective of this study was to investigate the effects of daily maternal curcumin supplementation during pregnancy on placental function and fetal growth in a mouse model of IUGR fed the low-protein (LP) diet. Pregnant mice were divided into four groups: (1) normal protein (19% protein) diet (NP); (2) LP (8% protein) diet; (3) LP diet + 100mg/kg curcumin (LPL); (4) LP diet +400mg/kg curcumin (LPH). The results showed that the LP group decreased fetal weight, placental weight, placental efficiency, serum progesterone level, placental glutathione peroxidase activity activity, blood sinusoids area, and antioxidant gene expression of placenta. In addition, in comparison with the NP group, LP diet increased serum corticosterone level, placental malondialdehyde content, and apoptotic index. Daily curcumin administration decreased the placental apoptosis, while it increased placental efficiency, placental redox balance, blood sinusoids area, and antioxidant-related protein expression in fetal liver. The antioxidant gene expression of placenta and fetal liver was normalized to the NP level after curcumin administration. In conclusion, daily curcumin supplementation could improve maternal placental function and fetal growth in mice with IUGR.

Decreased placental apoptosis and autophagy in pregnancies complicated by gestational diabetes with large-for-gestational age fetuses

IntroductionDysregulation of placental apoptosis and autophagy are observed in pregnancy complications including preeclampsia and fetal growth restriction. However, studies of their changes in the placentas of women with gestational diabetes mellitus (GDM) show inconsistent results. We aimed to compare the changes in apoptosis, autophagy, and Bcl-2 family proteins in the placentas from women with normal pregnancies and those with GDM, with or without large-for-gestational age (LGA) infants and to investigate the effect of hyperglycemia on the changes in apoptosis, autophagy, and Bcl-2 family proteins in primary cytotrophoblastic cells. MethodsVillous tissues were obtained from normal pregnant women and those with GDM, with or without LGA infants. Primary cytotrophoblast cells were isolated from normal term placentas and cultured under standard, hyperglycemic, or hyperosmotic conditions. ResultsCompared to placentas from normal pregnant women, those from GDM women with LGA infants were heavier, had lower beclin-1 and DRAM levels, less M30 and cleaved PARP immunoreactivity, and increased Ki-67 immunoreactivity. These changes were associated with increased Bcl-xL and decreased Bak levels. Increased glucose concentration led to lower ATG5, beclin-1, LC3B-II, p62, and DRAM levels, lower annexin V and M30-positive cell percentages, and less cleaved PARP changes compared with standard culture conditions. Hyperglycemia caused higher Bcl-xL levels and lower Bak and Bad levels than did standard culture conditions. DiscussionThere were differential changes in apoptosis and autophagy between placentas from normal pregnant women and those from GDM women with LGA infants. Bcl-2 family proteins are likely involved in the regulation of these changes.

Effect of maternal omega-3 fatty acids and vitamin E supplementation on placental apoptotic markers in rat model of early and late onset preeclampsia

AimDisturbed placentation results in pregnancy complications like preeclampsia. Placental development is influenced by apoptosis during trophoblast differentiation and proliferation. Increased oxidative stress upregulates placental apoptosis. We have earlier reported increased oxidative stress, lower omega-3 fatty acids and vitamin E levels in women with preeclampsia. Current study examines effect of maternal omega-3 fatty acids and vitamin E supplementation on apoptotic markers across gestation in a rat model of preeclampsia. Main methodsPregnant Wistar rats were randomly assigned to control; early onset preeclampsia (EOP); late onset preeclampsia (LOP); early onset preeclampsia + omega-3 fatty acid + vitamin E supplementation (EOP + O + E) and late onset preeclampsia + omega-3 fatty acid + vitamin E supplementation (LOP + O + E) groups. Animals (Control, EOP, EOP + O + E) were sacrificed at d14 and d20 of gestation while animals (LOP, LOP + O + E) were sacrificed at d20 to collect blood and placentae. Protein and mRNA levels of apoptotic markers were analyzed by ELISA and RT-PCR respectively. Key findingsProtein levels of proapoptotic markers like Bcl-2 associated X-protein (BAX) (p < 0.05), caspase-8 and 3 (p < 0.01 for both) and malondialdehyde (p < 0.01) were higher only in the EOP group as compared to control. However, the antiapoptotic marker, B cell lymphoma 2 (Bcl-2) protein levels were lower in both the subtypes of preeclampsia (p < 0.01 for both). SignificanceOur findings suggest that supplementation was beneficial in reducing the caspase-8 and 3 in early onset preeclampsia but did not normalize BAX and Bcl-2 levels. This has implications for reducing placental apoptosis in preeclampsia.

Tri‐ortho‐cresyl phosphate (TOCP)‐induced reproductive toxicity involved in placental apoptosis, autophagy and oxidative stress in pregnant mice

Tri-ortho-cresyl phosphate (TOCP) has been widely used as plasticizers, and reported causing reproductive toxicity in mammals. However, little is known about the toxic effect on the placenta. In this study, dams were orally administered different doses of TOCP to explore the effect of TOCP on placental development. Results showed that TOCP exposure significantly reduced numbers of implanted embryo, caused atrophy and collapse of ectoplacental cone, and decreased total areas of placenta and numbers of PCNA-positive cells. Expression levels of placental development genes were prominently downregulated in the TOCP-treated groups. Moreover, TOCP administration induced placental apoptosis and autophagy by upregulating P53, Bax, Beclin-1, ratio of LC3 II/LC3 I and Atg5 and downregulating Bcl-2 protein. In addition, TOCP exposure markedly inhibited activities of catalase and superoxide dismutase and increased the production of H2 O2 and malondialdehyde. Collectively, these findings suggest that apoptosis, autophagy and oxidative stress may be involved in the TOCP-induced reproductive toxicity.

The role of insulin-like growth factor 2 receptor-mediated homeobox gene expression in human placental apoptosis, and its implications in idiopathic fetal growth restriction.

Fetal growth restriction (FGR) is caused by poor placental development and function early in gestation. It is well known that placentas from women with FGR exhibit reduced cell growth, elevated levels of apoptosis and perturbed expression of the growth factors, cytokines and the homeobox gene family of transcription factors. Previous studies have reported that insulin-like growth factor-2 (IGF2) interacts with its receptor-2 (IGF2R) to regulate villous trophoblast survival and apoptosis. In this study, we hypothesized that human placental IGF2R-mediated homeobox gene expression is altered in FGR and contributes to abnormal trophoblast function. This study was designed to determine the association between IGF2R, homeobox gene expression and cell survival in pregnancies affected by FGR. Third trimester placentas were collected from FGR-affected pregnancies (n = 29) and gestation matched with control pregnancies (n = 30). Functional analyses were then performed in vitro using term placental explants (n = 4) and BeWo trophoblast cells. mRNA expression was determined by real-time PCR, while protein expression was examined by immunoblotting and immunohistochemistry. siRNA transfection was used to silence IGF2R expression in placental explants and the BeWo cell-line. cDNA arrays were used to screen for downstream targets of IGF2R, specifically homeobox gene transcription factors and apoptosis-related genes. Functional effects of silencing IGF2R were then verified by β-hCG ELISA, caspase activity assays and a real-time electrical cell-impedance assay for differentiation, apoptosis and cell growth potential, respectively. IGF2R expression was significantly decreased in placentas from pregnancies complicated by idiopathic FGR (P < 0.05 versus control). siRNA-mediated IGF2R knockdown in term placental explants and the trophoblast cell line BeWo resulted in altered expression of homeobox gene transcription factors, including increased expression of distal-less homeobox gene 5 (DLX5), and decreased expression of H2.0-Like Homeobox 1 (HLX) (P < 0.05 versus control). Knockdown of IGF2R transcription increased the expression and activity of caspase-6 and caspase-8 in placental explants, decreased BeWo proliferation and increased BeWo differentiation (all P < 0.05 compared to respective controls). This is the first study linking IGF2R placental expression with changes in the expression of homeobox genes that control cellular signalling pathways responsible for increased trophoblast cell apoptosis, which is a characteristic feature of FGR.

Molecular mechanisms of Cisplatin- induced placental toxicity and teratogenicity in rats and the ameliorating role of N-acetyl-cysteine

The aim of the present study is to investigate the molecular mechanisms of Cisplatin- induced placental toxicity and teratogenicity in rats and the ameliorating role of N-acetyl-cysteine (NAC). Cisplatin was administrated intraperitoneally at 5 mg/kg.b.wt as a single dose on the 12th day of gestation while NAC was administered orally throughout gestation either alone or in concomitant injection of Cisplatin at 200 mg/kg.b.wt. Cisplatin + NAC group showed reduction in the elevated morphological, visceral and skeletal abnormalities as well as the morphological and histopathological changes in placenta compared to Cisplatin - treated rats. Importantly, NAC attenuated Cisplatin-induced placental apoptosis through down-regulation of Fas and Caspase-3 genes expression. In conclusion, induction of placental apoptosis by overexpression of Fas and Caspase-3 genes gives a new insight into the mechanism of Cisplatin teratogenicity. The protective role of NAC, on the other hand, was characterized by attenuation of Fas and Caspase-3 genes- mediated apoptosis.

Growth arrest-specific protein-6/AXL signaling induces preeclampsia in rats†.

Preeclampsia (PE) is a complicated obstetric complication characterized by increased blood pressure, decreased trophoblast invasion, and inflammation. The growth arrest-specific 6 (Gas6) protein is known to induce dynamic cellular responses and is elevated in PE. Gas6 binds to the AXL tyrosine kinase receptor and AXL-mediated signaling is implicated in proliferation and migration observed in several tissues. Our laboratory utilized Gas6 to induce preeclamptic-like conditions in pregnant rats. Our objective was to determine the role of Gas6/AXL signaling as a possible model of PE. Briefly, pregnant rats were divided into three groups that received daily intraperitoneal injections (from gestational day 7.5 to 17.5) of phosphate buffered saline (PBS), Gas6, or Gas6+R428 (an AXL inhibitor administered from gestational day 13.5 to 17.5). Animals dispensed Gas6 experienced elevated blood pressure, increased proteinuria, augmented caspase-3-mediated placental apoptosis, and diminished trophoblast invasion. Gas6 also enhanced expression of several PE-related genes and a number of inflammatory mediators. Gas6 further enhanced placental oxidative stress and impaired mitochondrial respiration. Each of these PE-related characteristics was ameliorated in dams and/or their placentae when AXL inhibition by R428 occurred in tandem with Gas6 treatment. We conclude that Gas6 signaling is capable of inducing PE and that inhibition of AXL prevents disease progression in pregnant rats. These results provide insight into pathways associated with PE that could be useful in the clarification of potential therapeutic approaches.

The Role of Anticoagulant Therapy in the Prevention of Preeclampsia Pharmacokinetic and pharmacodynamic mechanisms

Pregnancies complicated with preeclampsia associate a high incidence of intrauterine fetal death, intrauterine growth restriction, premature ruptures of membranes, abruption placentae and prematurity. Understanding the pathogenesis of preeclampsia is mandatory for a correct approach and prevention management of high risk cases. Placental hypoperfusion seems to be a key factor in developing systemic resounding. By placental necrosis and apoptosis, cell-free DNA is released in maternal circulation in early pregnancy, respectively prior 17 weeks of gestation. There is no test, useful in early pregnancy, accurate enough to predict preeclampsia. Various screening test have been proposed in order to predict the development of preeclampsia, but most of them are not sufficiently accurate for general screening. There is a continuous debate regarding the algorithm of administration, doses and timing of low dose aspirin. The initiation moment is crucial, as the administration after the development symptoms and signs of preeclampsia do not interfere with the progression and the severity of the disease. Early initiation of therapy with low dose aspirin, prior the end of the first trimester is important since the pathogenesis mechanisms of preeclampsia take place in the first trimester. The action of acetylsalicylic acid consists in inhibition of COX-1 and COX-2 (cyclooxygenase isoenzymes), necessary for prostaglandin biosynthesis. Preferential inhibition of Thromboxane A2 by low dose aspirin, counterbalance the increased production of thromboxanes characteristic to preeclampsia and modulate the inflammatory process, amplified in pregnant women with preeclampsia.

Time-restricted feeding reduces high-fat diet associated placental inflammation and limits adverse effects on fetal organ development

Maternal nutrition has become a major public health concern over recent years and is a known predictor of adverse long-term metabolic derangement in offspring. Time-restricted feeding (TRF), wherein food consumption is restricted to the metabolically active phase of the day, is a dietary approach that improves metabolic parameters when consuming a high-fat diet (HFD). Here, we tested whether TRF could reduce maternal HFD associated inflammation and thereby mitigate defects in fetal organ developmental. Female rats were kept on following three dietary regimens; Ad libitum normal chow diet (NCD-AL), Ad libitum HFD (HFD-AL) and Time-restricted fed HFD (HFD-TRF) from 5 months prior to mating and continued throughout pregnancy. Rat dams were sacrificed at embryonic day 18.5 (ED18.5) and placental tissues from these rats were processed for the analysis of cellular apoptosis, inflammatory cytokines (TNFα and IL-6), oxidative stress, endoplasmic reticulum (ER) stress and autophagy. Furthermore, fetal hepatic triglyceride (TG) content and fetal lung maturation were assessed at ED18.5. Biochemical analysis revealed that HFD-TRF rat had significantly lower serum TG levels and body weight compared to HFD-AL rats. Additionally, TRF significantly blocked HFD-induced placental apoptosis and inflammation via minimizing cellular stress, and restoring autophagic flux. In addition, fetal hepatosteatosis and delayed fetal lung maturation induced by HFD was significantly ameliorated in HFD-TRF compared to HFD-AL. Collectively, our results suggest that reducing placental inflammation via TRF could prevent adverse fetal metabolic outcomes in pregnancies complicated by maternal obesity.