Apoptotic and non-apoptotic roles of caspases in placenta physiology and pathology.

Caspases, a family of cysteine proteases, are pivotal regulators of apoptosis, the tightly controlled cell death process crucial for eliminating excessive or unnecessary cells during development, including placental development. Collecting research has unveiled the multifaceted roles of caspases in the placenta, extending beyond apoptosis. Apart from their involvement in placental tissue remodeling via apoptosis, caspases actively participate in essential regulatory processes, such as trophoblast fusion and differentiation, significantly influencing placental growth and functionality. In addition, growing evidence indicates an elevation in caspase activity under pathological conditions like pre-eclampsia (PE) and intrauterine growth restriction (IUGR), leading to excessive cell death as well as inflammation. Drawing from advancements in caspase research and placental development under both normal and abnormal conditions, we examine the significance of caspases in both cell death (apoptosis) and non-cell death-related processes within the placenta. We also discuss potential therapeutics targeting caspase-related pathways for placenta disorders.

d-galactose causes embryonic development arrest and placental development disorders in mice by increasing ROS and inhibiting SIRT1/FOXO3a axis.

INTRODUCTION: Does an elevation in d-Galactose (D-Gal) levels within the body contribute to abnormal embryonic development and placental dysfunction during pregnancy? METHODS: Mouse embryos were cultivated to the blastocyst stage under varying concentrations of D-Gal. The blastocyst formation rate was measured, and the levels of reactive oxygen species (ROS), sirtuin 1 (SIRT1), and forkhead box O3a (FOXO3a) in blastocysts were assessed. Mice were intraperitoneally injected with either saline or D-Gal with or without SRT1720. On the 14th day of pregnancy, the fetal absorption rate and placental weight were recorded. Placental levels of superoxide dismutase (SOD) and malondialdehyde (MDA) were determined. The expression of senescence-related factors, such as senescence-associated ß-galactosidase (SA-ß-gal) in the placenta was examined, and the expression of placental SIRT1, FOXO3a and p21 was evaluated by immunohistochemistry and Western blotting. RESULTS: D-Gal adversely affects early embryonic development in vitro, resulting in a decreased blastocyst formation rate. Furthermore, D-Gal downregulates SIRT1 and FOXO3a while increasing ROS levels in blastocysts. Concurrently, D-Gal induces placental dysfunction, characterized by an elevated fetal absorption rate, reduced placental weight, diminished SOD activity, and increased MDA content. The senescence-related factor SA-ß-gal was detected in the placenta, along with altered expression of placental SIRT1, FOXO3a, and p21. The SIRT1 agonist SRT1720 mitigated this damage by increasing SIRT1 and FOXO3a expression. DISCUSSION: The inhibition of early embryonic development and placental dysfunction induced by D-Gal may be attributed to the dysregulation of SIRT1. Activating SIRT1 emerges as a potentially effective strategy for alleviating the adverse effects of D-Gal exposure.

Maternal obesity and placental function: impaired maternal-fetal axis.

The prevalence of maternal obesity rapidly increases, which represents a major public health concern worldwide. Maternal obesity is characteristic by metabolic dysfunction and chronic inflammation. It is associated with health problems in both mother and offspring. Increasing evidence indicates that the placenta is an axis connecting maternal obesity with poor outcomes in the offspring. In this brief review, we have summarized the current data regarding deregulated placental function in maternal obesity. The data show that maternal obesity induces numerous placental defects, including lipid and glucose metabolism, stress response, inflammation, immune regulation and epigenetics. These placental defects affect each other and result in a stressful intrauterine environment, which transduces and mediates the adverse effects of maternal obesity to the fetus. Further investigations are required to explore the exact molecular alterations in the placenta in maternal obesity, which may pave the way to develop specific interventions for preventing epigenetic and metabolic programming in the fetus.

Directed Differentiation of Human Pluripotent Stem Cells to Cytotrophoblast and Syncytiotrophoblast.

Human pluripotent stem cells (hPSCs) form an ideal system to study the formation of placental cells, from an undifferentiated human embryonic stem cell state. The conventional human in vitro model systems to study the human placenta cannot be employed for understanding placental dysfunctions or the development of specialized placental cell types. Hence, human PSCs make an ideal model system to study human placental development and disorders. Here, we describe an efficient and validated protocol to reproducibly study the formation of human cytotrophoblasts (CTBs) and syncytiotrophoblast (STBs) from undifferentiated hPSCs. CTBs are the trophoblast stem cells that can differentiate into specialized placental cell types such as STBs. The multinucleated STB plays vital role in the exchange of nutrients and gases across the placenta and secretes several hormones during pregnancy, such as human chorionic gonadotropin ß (hCGß). Here we describe two methods of seeding the hPSCs: chemical (clumps method) and enzymatic methods (single cells) to differentiate them to CTB and STB, activating BMP (B) signaling and inhibiting ACTIVIN/NODAL and FGF signaling pathways (2i), thus naming our protocol as "B2i" (Sudheer et al., Stem Cells Dev 21:2987-3000, 2012). This protocol forms the perfect model system for understanding in vitro placentation, modeling diseases arising from abnormal placentation that cause complications such as miscarriage, preeclampsia or intrauterine growth restriction (IUGR), and drug discovery for placental disorders.

NaviCenta - The disease map for placental research.

The placenta remains the key organ to pregnancy complications, such as preeclampsia, contrarily the pathophysiology underlying the placental dysfunctions remains elusive. Here, we present our Disease Map "NaviCenta", which is an online resource based on the interactions between tissues, cellular compartments, and molecules that mediate disease-related processes in the placenta. We built cellular and molecular interaction networks based upon manual curation and annotation of publicly available information in the scientific literature, pathways resources, and Omics data. NaviCenta (Navigate the plaCenta) serves as an open access, spatio-temporal, multi-scale knowledge base, and analytical tool for enhanced interpretation and hypothesis testing on various placental disease phenotypes.

Identifying placental metabolic biomarkers of preterm birth using nuclear magnetic resonance of intact tissue samples.

INTRODUCTION: Our understanding of the etiology of preterm birth (PTB) is incomplete; however, recent evidence has found a strong association between placental dysfunction and PTB. Altered placental metabolism may precede placental dysfunction and therefore the study of placental metabolic profiles could identify early biomarkers of PTB. In this study, we evaluated the placental metabolome in PTB in intact tissue samples using nuclear magnetic resonance (NMR) and spectral editing. METHODS: Placental tissue samples were collected from nine term pregnancies and nine preterm pregnancies (<37 weeks' gestation). 1H NMR experiments on unprocessed tissue samples were performed using a high field magnet (500 MHz spectrometer) and a comprehensive multiphase NMR probe. The relative concentrations of 23 metabolites were corrected for gestational age and compared between groups. RESULTS: The relative concentration of valine, glutamate and creatine were significantly decreased while alanine, choline and glucose were elevated in placentas from PTB pregnancies compared to controls (p < 0.05). Multivariate analysis using principal component analysis showed the PTB and control groups were significantly separated (p < 0.0001) and pathway analysis identified perturbations in the glycine, serine and threonine metabolism, aminoacyl-tRNA biosynthesis and valine, leucine and isoleucine biosynthesis pathways. CONCLUSION: PTB is associated with significant alterations in placental metabolism. This study helps improve our understanding of the etiology of PTB. It also highlights the potential for small molecule metabolites to serve as placental metabolic biomarkers to aid in the prediction and diagnosis of PTB. The results can be translated to clinical use via in utero magnetic resonance spectroscopy.

Involvement of oxidative stress in placental dysfunction, the pathophysiology of fetal death and pregnancy disorders.

In brief: Placental oxidative stress contributes to both normal and abnormal placentation during pregnancy. This review discusses the potential consequence of oxidative stress-induced placental dysfunction on pregnancies complicated by fetal death and pregnancies with a high risk of fetal death. Abstract: The placenta is a source of reactive oxygen free radicals due to the oxidative metabolism required to meet the demands of the growing fetus. The placenta has an array of efficient antioxidant defense systems to deal with rising oxidative stress created by free radicals during pregnancy. Properly controlled physiological (low-level) free radical production is a necessary part of cellular signaling pathways and downstream activities during normal placental development; however, poorly controlled oxidative stress can cause aberrant placentation, immune disturbances and placental dysfunction. Abnormal placental function and immune disturbances are linked to many pregnancy-related disorders, including early and recurrent pregnancy loss, fetal death, spontaneous preterm birth, preeclampsia and fetal growth restriction. This review discusses the role of placental oxidative stress in both normal and pathological settings. Finally, based on previously published work, this review presents multiple lines of evidence for the strong association between oxidative stress and adverse pregnancy outcomes, including fetal death and pregnancies with a high risk of fetal death.

Discordant Eosinophilic/T-Cell Chorionic Vasculitis in a Dichorionic Diamniotic Placenta.

Eosinophilic/T-cell chorionic vasculitis (ETCV) is an idiopathic lesion composed of eosinophils, CD3+ T lymphocytes, and histiocytes. In twins, ETCV may affect only one chorionic plate, a feature defined as "discordant". We present a case of ETCV discordance in a diamniotic dichorionic placenta at 38 weeks of gestation, in which the female twin was small for gestational age, weighing 2670 g (25th percentile). The corresponding placental territory presented ETCV in two close chorionic vessels with concordance of the fetal inflammatory response. Immunohistochemistry showed an abundance of CD3+/CD4+/CD25+T lymphocytes, CD68 PG M1+ macrophages, and scattered CD8+ T cells with focal TIA-1 positivity. Granzyme B, CD20 B lymphocytes, and CD56 natural killer cells were negative. High-grade villitis of unknown etiology (VUE) was additionally found and displayed comparable ETCV findings, except for an equivalent ratio of CD4+/CD8+ T cells, but TIA-1 was focally expressed. VUE was associated with chronic histiocytic intervillositis (CHI). The combination of ETCV, VUE, and CHI may have been responsible for reduced fetal growth. Concordance was observed in the ETCV and TIA-1 expression, both in ETCV and in VUE, which is a maternal response. These findings may suggest a common antigen or chemokine pathway to which both mother and fetus accordingly responded.

The Role of Ferroptosis in Placental-Related Diseases.

Ferroptosis is a recently identified form of programmed cell death which is different from apoptosis, pyroptosis, necrosis, and autophagy. It is uniquely defined by redox-active iron-dependent hydroxy-peroxidation of polyunsaturated fatty acid (PUFA)-containing phospholipids and a loss of lipid peroxidation repair capacity. Ferroptosis has recently been implicated in multiple human diseases, such as tumors, ischemia-reperfusion injury, acute kidney injury, neurological diseases, and asthma among others. Intriguingly, ferroptosis is associated with placental physiology and trophoblast injury. Circumstances such as accumulation of lipid reactive oxygen species (ROS) due to hypoxia-reperfusion and anoxia-reoxygenation of trophoblast during placental development, the abundance of trophoblastic iron and PUFA, physiological uterine contractions, or pathological placental bed perfusion, cause placental trophoblasts' susceptibility to ferroptosis. Ferroptosis of trophoblast can cause placental dysfunction, which may be involved in the occurrence and development of placenta-related diseases such as gestational diabetes mellitus, preeclampsia, fetal growth restriction, preterm birth, and abortion. The regulatory mechanisms of trophoblastic ferroptosis still need to be explored further. Here, we summarize the latest progress in trophoblastic ferroptosis research on placental-related diseases, provide references for further understanding of its pathogenesis, and propose new strategies for the prevention and treatment of placental-related diseases.

Transcriptomics-Based Subphenotyping of the Human Placenta Enabled by Weighted Correlation Network Analysis in Early-Onset Preeclampsia With and Without Fetal Growth Restriction.

BACKGROUND: Placental disorders contribute to pregnancy complications, including preeclampsia and fetal growth restriction (FGR), but debate regarding their specific pathobiology persists. Our objective was to apply transcriptomics with weighted gene correlation network analysis to further clarify the placental dysfunction in these conditions. METHODS: We performed RNA sequencing with weighted gene correlation network analysis using human placental samples (n=30), separated into villous tissue and decidua basalis, and clinically grouped as follows: (1) early-onset preeclampsia (EOPE)+FGR (n=7); (2) normotensive, nonanomalous preterm FGR (n=5); (2) EOPE without FGR (n=8); (4) spontaneous idiopathic preterm birth (n=5) matched for gestational age; and (5) uncomplicated term births (n=5). Our data was compared with RNA sequencing data sets from public databases (GSE114691, GSE148241, and PRJEB30656; n=130 samples). RESULTS: We identified 14 correlated gene modules in our specimens, of which most were significantly correlated with birthweight and maternal blood pressure. Of the 3 network modules consistently predictive of EOPE±FGR across data sets, we prioritized a coexpression gene group enriched for hypoxia-response and metabolic pathways for further investigation. Cluster analysis based on transcripts from this module and the glycolysis/gluconeogenesis metabolic pathway consistently distinguished a subset of EOPE±FGR samples with an expression signature suggesting modified tissue bioenergetics. We demonstrated that the expression ratios of LDHA/LDHB and PDK1/GOT1 could be used as surrogate indices for the larger panels of genes in identifying this subgroup. CONCLUSIONS: We provide novel evidence for a molecular subphenotype consistent with a glycolytic metabolic shift that occurs more frequently but not universally in placental specimens of EOPE±FGR.

Cholic acid exposure during late pregnancy causes placental dysfunction and fetal growth restriction by reactive oxygen species-mediated activation of placental GCN2/eIF2α pathway.

Epidemiological studies suggest that fetal growth restriction (FGR) caused by gestational cholestasis is associated with elevated serum cholic acid (CA). Here, we explore the mechanism by which CA induces FGR. Pregnant mice except controls were orally administered with CA daily from gestational day 13 (GD13) to GD17. Results found that CA exposure decreased fetal weight and crown-rump length, and increased the incidence of FGR in a dose-dependent manner. Furthermore, CA caused placental glucocorticoid (GC) barrier dysfunction via down-regulating the protein but not the mRNA level of placental 11ß-Hydroxysteroid dehydrogenase-2 (11ß-HSD2). Additionally, CA activated placental GCN2/eIF2α pathway. GCN2iB, an inhibitor of GCN2, significantly inhibited CA-induced down-regulation of 11ß-HSD2 protein. We further found that CA caused excessive reactive oxygen species (ROS) production and oxidative stress in mouse placentas and human trophoblasts. NAC significantly rescued CA-induced placental barrier dysfunction by inhibiting activation of GCN2/eIF2α pathway and subsequent down-regulation of 11ß-HSD2 protein in placental trophoblasts. Importantly, NAC rescued CA-induced FGR in mice. Overall, our results suggest that CA exposure during late pregnancy induces placental GC barrier dysfunction and subsequent FGR may be via ROS-mediated placental GCN2/eIF2α activation. This study provides valuable insight for understanding the mechanism of cholestasis-induced placental dysfunction and subsequent FGR.

Mitochondrial Dysfunction in the Pathogenesis of Preeclampsia.

PURPOSE OF REVIEW: Preeclampsia complicates 5-10% of all pregnancies and is a leading cause of maternal and perinatal mortality and morbidity. The placenta plays a pivotal role in determining pregnancy outcome by supplying the fetus with oxygen and nutrients and by synthesizing hormones. Placental function is highly dependent on energy supplied by mitochondria. It is well-known that preeclampsia is originated from placental dysfunction, although the etiology of it remains elusive. RECENT FINDINGS: During the last three decades, substantial evidence suggests that mitochondrial abnormality is a major contributor to placental dysfunction. In addition, mitochondrial damage caused by circulating bioactive factors released from the placenta may cause endothelial dysfunction and subsequent elevation in maternal blood pressure. In this review, we summarize the current knowledge of mitochondrial abnormality in the pathogenesis of preeclampsia and discuss therapeutic approaches targeting mitochondria for treatment of preeclampsia.

Metabolomics analysis of placental tissue obtained from patients with fetal growth restriction.

AIM: The aim of this study was to determine whether there was a difference in placental metabolite profiles between patients with fetal growth restriction (FGR) and healthy controls. METHODS: The study included 10 patients with FGR diagnosis with 14 healthy controls with both matched maternal age and body mass index. 1 H HR-MAS NMR spectroscopy data obtained from placental tissue samples of patients with FGR and healthy control group were analyzed with bioinformatics methods. The obtained results of metabolite levels were further validated with the internal standard (IS) quantification method. RESULTS: Principal component analysis (PCA) and the partial least squares discriminant analysis (PLS-DA) score plots obtained with the multivariate statistical analysis of preprocessed spectral data shows a separation between the samples from patients with FGR and healthy controls. Bioinformatics analysis results suggest that the placental levels of lactate, glutamine, glycerophosphocholine, phosphocholine, taurine, and myoinositol are increased in patients with FGR compared to the healthy controls. CONCLUSIONS: Placental metabolic dysfunctions are a common occurrence in FGR.

Imbalances in circulating angiogenic factors in the pathophysiology of preeclampsia and related disorders.

Preeclampsia is a devastating medical complication of pregnancy that can lead to significant maternal and fetal morbidity and mortality. It is currently believed that there is abnormal placentation in as early as the first trimester in women destined to develop preeclampsia. Although the etiology of the abnormal placentation is being debated, numerous epidemiologic and experimental studies suggest that imbalances in circulating angiogenic factors released from the placenta are responsible for the maternal signs and symptoms of preeclampsia. In particular, circulating levels of soluble fms-like tyrosine kinase 1, an antiangiogenic factor, are markedly increased in women with preeclampsia, whereas free levels of its ligand, placental, growth factor are markedly diminished. Alterations in these angiogenic factors precede the onset of clinical signs of preeclampsia and correlate with disease severity. Recently, the availability of automated assays for the measurement of angiogenic biomarkers in the plasma, serum, and urine has helped investigators worldwide to demonstrate a key role for these factors in the clinical diagnosis and prediction of preeclampsia. Numerous studies have reported that circulating angiogenic biomarkers have a very high negative predictive value to rule out clinical disease among women with suspected preeclampsia. These blood-based biomarkers have provided a valuable tool to clinicians to accelerate the time to clinical diagnosis and minimize maternal adverse outcomes in women with preeclampsia. Angiogenic biomarkers have also been useful to elucidate the pathogenesis of related disorders of abnormal placentation such as intrauterine growth restriction, intrauterine fetal death, twin-to-twin transfusion syndrome, and fetal hydrops. In summary, the discovery and characterization of angiogenic proteins of placental origin have provided clinicians a noninvasive blood-based tool to monitor placental function and health and for early detection of disorders of placentation. Uncovering the mechanisms of altered angiogenic factors in preeclampsia and related disorders of placentation may provide insights into novel preventive and therapeutic options.

Bizarre Chorionic-type Trophoblast in Second-trimester and Third-trimester Placentas: Clinicopathologic Characterization of a Placental Pseudoneoplastic Lesion.

Bizarre (atypical/symplastic) cells have been described in various gynecologic normal tissues and benign neoplasms. This type of bizarre cytologic change is usually an incidental finding and is regarded as a benign process. We describe 17 cases of bizarre chorionic-type trophoblast in second-trimester and third-trimester placentas that created concern for an underlying/undersampled or incipient intraplacental trophoblastic neoplasm, predominantly found in intervillous trophoblastic islands (11/17), placental septae (6/17), chorionic plate (1/17), and/or the chorion layer of fetal membranes (2/17). The bizarre trophoblastic cells exhibited sheet-like or nested architecture, had a multifocal/patchy distribution, and/or were present as individual cells within hyaline stroma; they were characterized by large nuclei with smudgy chromatin and occasional intranuclear pseudoinclusions. The degree of atypia was classified as mild (0/17), moderate (3/17), or severe (14/17). Mitotic figures and necrosis were not identified. A dual immunohistochemical stain for trophoblast (hydroxyl-delta-5-steroid dehydrogenase) and a proliferation marker (Ki-67), performed in 15 cases, demonstrated 0% to very low proliferative activity within the bizarre trophoblast (0% to 2% [10/15], 3% to 8% [5/15]). Immunohistochemical stains for fumarate hydratase showed intact/retained expression in the bizarre cells in 7 of 7 cases. Clinical follow-up ranged from 1 to 45 months, and all patients were alive and well without subsequent evidence of a gestational trophoblastic or other neoplasms. We conclude that bizarre chorionic-type trophoblast in second-trimester or third-trimester placentas have the potential to mimic an intraplacental trophoblastic neoplasm but are likely a benign degenerative change. This study expands the spectrum of bizarre cells that occur in the gynecologic tract.

NR4A2 expression is not altered in placentas from cases of growth restriction or preeclampsia, but is reduced in hypoxic cytotrophoblast.

Nuclear Receptor Subfamily 4 Group A Member 2 (NR4A2) transcripts are elevated in the circulation of individuals whose pregnancies are complicated by preterm fetal growth restriction (FGR). In this paper, we show that the cases with preeclampsia (PE) have increased circulating NR4A2 transcripts compared to those with normotensive FGR. We aimed to establish whether the dysfunctional placenta mirrors the increase in NR4A2 transcripts and further, to uncover the function of placental NR4A2. NR4A2 expression was detected in preterm and term placental tissue; expressed higher at term. NR4A2 mRNA expression and protein were not altered in placentas from preterm FGR or PE pregnancies. Hypoxia (1% O2 compared to 8% O2) significantly reduced cytotrophoblast NR4A2 mRNA expression, but not placental explant NR4A2 expression. Silencing cytotrophoblast NR4A2 expression under hypoxia (via short interfering (si)RNAs) did not alter angiogenic Placental Growth Factor, nor anti-angiogenic sFlt-1 mRNA expression or protein secretion, but increased expression of cellular antioxidant, oxidative stress, inflammatory, and growth genes. NR4A2 expression was also not altered in a model of tumour necrosis factor-α-induced endothelial dysfunction, or with pravastatin treatment. Further studies are required to identify the origin of the circulating transcripts in pathological pregnancies, and investigate the function of placental NR4A2.

Human Placental Transcriptome Reveals Critical Alterations in Inflammation and Energy Metabolism with Fetal Sex Differences in Spontaneous Preterm Birth.

A well-functioning placenta is crucial for normal gestation and regulates the nutrient, gas, and waste exchanges between the maternal and fetal circulations and is an important endocrine organ producing hormones that regulate both the maternal and fetal physiologies during pregnancy. Placental insufficiency is implicated in spontaneous preterm birth (SPTB). We proposed that deficits in the capacity of the placenta to maintain bioenergetic and metabolic stability during pregnancy may ultimately result in SPTB. To explore our hypothesis, we performed a RNA-seq study in male and female placentas from women with SPTB (<36 weeks gestation) compared to normal pregnancies (≥38 weeks gestation) to assess the alterations in the gene expression profiles. We focused exclusively on Black women (cases and controls), who are at the highest risk of SPTB. Six hundred and seventy differentially expressed genes were identified in male SPTB placentas. Among them, 313 and 357 transcripts were increased and decreased, respectively. In contrast, only 61 differentially expressed genes were identified in female SPTB placenta. The ingenuity pathway analysis showed alterations in the genes and canonical pathways critical for regulating inflammation, oxidative stress, detoxification, mitochondrial function, energy metabolism, and the extracellular matrix. Many upstream regulators and master regulators important for nutrient-sensing and metabolism were also altered in SPTB placentas, including the PI3K complex, TGFB1/SMADs, SMARCA4, TP63, CDKN2A, BRCA1, and NFAT. The transcriptome was integrated with published human placental metabolome to assess the interactions of altered genes and metabolites. Collectively, significant and biologically relevant alterations in the transcriptome were identified in SPTB placentas with fetal sex disparities. Altered energy metabolism, mitochondrial function, inflammation, and detoxification may underly the mechanisms of placental dysfunction in SPTB.

Elevated Circulating and Placental SPINT2 Is Associated with Placental Dysfunction.

Biomarkers for placental dysfunction are currently lacking. We recently identified SPINT1 as a novel biomarker; SPINT2 is a functionally related placental protease inhibitor. This study aimed to characterise SPINT2 expression in placental insufficiency. Circulating SPINT2 was assessed in three prospective cohorts, collected at the following: (1) term delivery (n = 227), (2) 36 weeks (n = 364), and (3) 24-34 weeks' (n = 294) gestation. SPINT2 was also measured in the plasma and placentas of women with established placental disease at preterm (<34 weeks) delivery. Using first-trimester human trophoblast stem cells, SPINT2 expression was assessed in hypoxia/normoxia (1% vs. 8% O2), and following inflammatory cytokine treatment (TNFα, IL-6). Placental SPINT2 mRNA was measured in a rat model of late-gestational foetal growth restriction. At 36 weeks, circulating SPINT2 was elevated in patients who later developed preeclampsia (p = 0.028; median = 2233 pg/mL vs. controls, median = 1644 pg/mL), or delivered a small-for-gestational-age infant (p = 0.002; median = 2109 pg/mL vs. controls, median = 1614 pg/mL). SPINT2 was elevated in the placentas of patients who required delivery for preterm preeclampsia (p = 0.025). Though inflammatory cytokines had no effect, hypoxia increased SPINT2 in cytotrophoblast stem cells, and its expression was elevated in the placental labyrinth of growth-restricted rats. These findings suggest elevated SPINT2 is associated with placental insufficiency.

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.

MicroRNA-mRNA Networks in Pregnancy Complications: A Comprehensive Downstream Analysis of Potential Biomarkers.

Pregnancy complications are a major cause of fetal and maternal morbidity and mortality in humans. The majority of pregnancy complications initiate due to abnormal placental development and function. During the last decade, the role of microRNAs (miRNAs) in regulating placental and fetal development has become evident. Dysregulation of miRNAs in the placenta not only affects placental development and function, but these miRNAs can also be exported to both maternal and fetal compartments and affect maternal physiology and fetal growth and development. Due to their differential expression in the placenta and maternal circulation during pregnancy complications, miRNAs can be used as diagnostic biomarkers. However, the differential expression of a miRNA in the placenta may not always be reflected in maternal circulation, which makes it difficult to find a reliable biomarker for placental dysfunction. In this review, we provide an overview of differentially expressed miRNAs in the placenta and/or maternal circulation during preeclampsia (PE) and intrauterine growth restriction (IUGR), which can potentially serve as biomarkers for prediction or diagnosis of pregnancy complications. Using different bioinformatics tools, we also identified potential target genes of miRNAs associated with PE and IUGR, and the role of miRNA-mRNA networks in the regulation of important signaling pathways and biological processes.