Signaling Pathways in Pregnancy

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Signaling".

Deadline for manuscript submissions: 31 May 2024 | Viewed by 22338

Special Issue Editors


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Guest Editor
Department of Experimental and Clinical Medicine, Università Politecnica delle Marche, 60126 Ancona, Italy
Interests: placenta; morphology; immunohistochemistry; confocal microscope; gestation; development; cell proliferation; cell differentiation; preeclampsia; gestational diseases; extracellular matrix molecules

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Guest Editor
Department of Experimental and Clinical Medicine, Università Politecnica delle Marche, 60126 Ancona, Italy
Interests: pregnancy complications; preeclampsia; preterm birth; ovarian cancer; early marker of pregnancy complications; oxidative stress; chemoresistance
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Special Issue Information

Dear Colleagues,

Placental villous tree development and differentiation are regulated by a number of growth factors, their receptors and other types of molecules that regulate placental cell proliferation, differentiation, migration and invasion. Achieving the correct balance of these factors in the activation of different pathways by regulating the expression of certain genes is critical for a successful pregnancy.

Genetic factors can contribute to impaired placental development, leading to a series of pregnancy pathologies, i.e., preeclampsia (PE), fetal growth restriction (FGR), gestational trophoblastic diseases (GTD) and gestational diabetes mellitus (GDM).

Furthermore, external factors, such as microbial agents, chemicals and natural compounds, can also affect placental development and function by altering signaling pathways, which can lead to pregnancy complications.

Many of these disorders/pathologies result in increased maternal and fetal mortality and morbidity and can lead to life-long health implications for both mother and child.

In this Special Issue, we provide an overview of the signaling pathways involved in placental development in normal and pathological conditions. We are inviting submissions of original research articles, reviews and mini-reviews on topics relevant to any aspect of placental physiology, biochemistry or molecular biology.

Prof. Dr. Daniela Marzioni
Dr. Giovanni Tossetta
Guest Editors

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Keywords

  • cell signaling
  • proliferation
  • differentiation
  • invasion
  • placentation
  • placenta
  • trophoblast
  • preeclampsia
  • fetal growth restriction
  • gestational diabetes mellitus

Published Papers (12 papers)

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Editorial

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3 pages, 210 KiB  
Editorial
Signaling Pathways in Pregnancy
by Giovanni Tossetta and Daniela Marzioni
Cells 2022, 11(9), 1385; https://doi.org/10.3390/cells11091385 - 20 Apr 2022
Cited by 2 | Viewed by 1375
Abstract
We are pleased to present this Special Issue of Cells, entitled ‘Signaling Pathways in Pregnancy’ [...] Full article
(This article belongs to the Special Issue Signaling Pathways in Pregnancy)

Research

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12 pages, 1988 KiB  
Article
Dilation of Pregnant Rat Uterine Arteries with Phenols from Extra Virgin Olive Oil Is Endothelium-Dependent and Involves Calcium and Potassium Channels
by Milena Esposito, Mariacarmela Gatto, Marilyn J. Cipolla, Ira M. Bernstein and Maurizio Mandalà
Cells 2024, 13(7), 619; https://doi.org/10.3390/cells13070619 - 02 Apr 2024
Viewed by 568
Abstract
During pregnancy, uterine vasculature undergoes significant circumferential growth to increase uterine blood flow, vital for the growing feto-placental unit. However, this process is often compromised in conditions like maternal high blood pressure, particularly in preeclampsia (PE), leading to fetal growth impairment. Currently, there [...] Read more.
During pregnancy, uterine vasculature undergoes significant circumferential growth to increase uterine blood flow, vital for the growing feto-placental unit. However, this process is often compromised in conditions like maternal high blood pressure, particularly in preeclampsia (PE), leading to fetal growth impairment. Currently, there is no cure for PE, partly due to the adverse effects of anti-hypertensive drugs on maternal and fetal health. This study aimed to investigate the vasodilator effect of extra virgin olive oil (EVOO) phenols on the reproductive vasculature, potentially benefiting both mother and fetus. Isolated uterine arteries (UAs) from pregnant rats were tested with EVOO phenols in a pressurized myograph. To elucidate the underlying mechanisms, additional experiments were conducted with specific inhibitors: L-NAME/L-NNA (10−4 M) for nitric oxide synthases, ODQ (10−5 M) for guanylate cyclase, Verapamil (10−5 M) for the L-type calcium channel, Ryanodine (10−5 M) + 2-APB (3 × 10−5 M) for ryanodine and the inositol triphosphate receptors, respectively, and Paxilline (10−5 M) for the large-conductance calcium-activated potassium channel. The results indicated that EVOO-phenols activate Ca2+ signaling pathways, generating nitric oxide, inducing vasodilation via cGMP and BKCa2+ signals in smooth muscle cells. This study suggests the potential use of EVOO phenols to prevent utero-placental blood flow restriction, offering a promising avenue for managing PE. Full article
(This article belongs to the Special Issue Signaling Pathways in Pregnancy)
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17 pages, 8291 KiB  
Article
The Impact of SLC2A8 RNA Interference on Glucose Uptake and the Transcriptome of Human Trophoblast Cells
by Aleksandra Lipka, Łukasz Paukszto, Victoria C. Kennedy, Amelia R. Tanner, Marta Majewska and Russell V. Anthony
Cells 2024, 13(5), 391; https://doi.org/10.3390/cells13050391 - 24 Feb 2024
Viewed by 768
Abstract
While glucose is the primary fuel for fetal growth, the placenta utilizes the majority of glucose taken up from the maternal circulation. Of the facilitative glucose transporters in the placenta, SLC2A8 (GLUT8) is thought to primarily function as an intracellular glucose transporter; however, [...] Read more.
While glucose is the primary fuel for fetal growth, the placenta utilizes the majority of glucose taken up from the maternal circulation. Of the facilitative glucose transporters in the placenta, SLC2A8 (GLUT8) is thought to primarily function as an intracellular glucose transporter; however, its function in trophoblast cells has not been determined. To gain insight into the function of SLC2A8 in the placenta, lentiviral-mediated RNA interference (RNAi) was performed in the human first-trimester trophoblast cell line ACH-3P. Non-targeting sequence controls (NTS RNAi; n = 4) and SLC2A8 RNAi (n = 4) infected ACH-3P cells were compared. A 79% reduction in SLC2A8 mRNA concentration was associated with an 11% reduction (p ≤ 0.05) in ACH-3P glucose uptake. NTS RNAi and SLC2A8 RNAi ACH-3P mRNA were subjected to RNAseq, identifying 1525 transcripts that were differentially expressed (|log2FC| > 1 and adjusted p-value < 0.05), with 273 transcripts derived from protein-coding genes, and the change in 10 of these mRNAs was validated by real-time qPCR. Additionally, there were 147 differentially expressed long non-coding RNAs. Functional analyses revealed differentially expressed genes involved in various metabolic pathways associated with cellular respiration, oxidative phosphorylation, and ATP synthesis. Collectively, these data indicate that SLC2A8 deficiency may impact placental uptake of glucose, but that its likely primary function in trophoblast cells is to support cellular respiration. Since the placenta oxidizes the majority of the glucose it takes up to support its own metabolic needs, impairment of SLC2A8 function could set the stage for functional placental insufficiency. Full article
(This article belongs to the Special Issue Signaling Pathways in Pregnancy)
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28 pages, 4728 KiB  
Article
Biomarkers of Affective Dysregulation Associated with In Utero Exposure to EtOH
by Nune Darbinian, Nana Merabova, Gabriel Tatevosian, Mary Morrison, Armine Darbinyan, Huaqing Zhao, Laura Goetzl and Michael Edgar Selzer
Cells 2024, 13(1), 2; https://doi.org/10.3390/cells13010002 - 19 Dec 2023
Viewed by 1108
Abstract
Introduction: Children with fetal alcohol spectrum disorders (FASD) exhibit behavioral and affective dysregulation, including hyperactivity and depression. The mechanisms are not known, but they could conceivably be due to postnatal social or environmental factors. However, we postulate that, more likely, the affective dysregulation [...] Read more.
Introduction: Children with fetal alcohol spectrum disorders (FASD) exhibit behavioral and affective dysregulation, including hyperactivity and depression. The mechanisms are not known, but they could conceivably be due to postnatal social or environmental factors. However, we postulate that, more likely, the affective dysregulation is associated with the effects of EtOH exposure on the development of fetal serotonergic (5-HT) and/or dopaminergic (DA) pathways, i.e., pathways that in postnatal life are believed to regulate mood. Many women who use alcohol (ethanol, EtOH) during pregnancy suffer from depression and take selective serotonin reuptake inhibitors (SSRIs), which might influence these monoaminergic pathways in the fetus. Alternatively, monoaminergic pathway abnormalities might reflect a direct effect of EtOH on the fetal brain. To distinguish between these possibilities, we measured their expressions in fetal brains and in fetal brain-derived exosomes (FB-Es) isolated from the mothers’ blood. We hypothesized that maternal use of EtOH and/or SSRIs during pregnancy would be associated with impaired fetal neural development, detectable as abnormal levels of monoaminergic and apoptotic biomarkers in FB-Es. Methods: Fetal brain tissues and maternal blood were collected at 9–23 weeks of pregnancy. EtOH groups were compared with unexposed controls matched for gestational age (GA). The expression of 84 genes associated with the DA and 5-HT pathways was analyzed by quantitative reverse transcription polymerase chain reaction (qRT-PCR) on microarrays. FB-Es also were assayed for serotonin transporter protein (SERT) and brain-derived neurotrophic factor (BDNF) by enzyme-linked immunosorbent assay (ELISA). Results: Six EtOH-exposed human fetal brain samples were compared to SSRI- or polydrug-exposed samples and to unexposed controls. EtOH exposure was associated with significant upregulation of DA receptor D3 and 5-HT receptor HTR2C, while HTR3A was downregulated. Monoamine oxidase A (MAOA), MAOB, the serine/threonine kinase AKT3, and caspase-3 were upregulated, while mitogen-activated protein kinase 1 (MAPK1) and AKT2 were downregulated. ETOH was associated with significant upregulation of the DA transporter gene, while SERT was downregulated. There were significant correlations between EtOH exposure and (a) caspase-3 activation, (b) reduced SERT protein levels, and (c) reduced BDNF levels. SSRI exposure independently increased caspase-3 activity and downregulated SERT and BDNF. Early exposure to EtOH and SSRI together was associated synergistically with a significant upregulation of caspase-3 and a significant downregulation of SERT and BDNF. Reduced SERT and BDNF levels were strongly correlated with a reduction in eye diameter, a somatic manifestation of FASD. Conclusions: Maternal use of EtOH and SSRI during pregnancy each was associated with changes in fetal brain monoamine pathways, consistent with potential mechanisms for the affective dysregulation associated with FASD. Full article
(This article belongs to the Special Issue Signaling Pathways in Pregnancy)
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20 pages, 6510 KiB  
Article
Cellular Functions of High-Temperature Requirement Factor A4 in Placenta
by Chang-Zhu Pei, Bum-Chae Choi, Jun-Hyeok Park, Hyo Young Park, Jinyoung Paek, Kyung-Ju Lee, Bo-Seong Yun, Young Ju Kim and Kwang-Hyun Baek
Cells 2023, 12(11), 1459; https://doi.org/10.3390/cells12111459 - 24 May 2023
Cited by 2 | Viewed by 1498
Abstract
The expression of High-temperature requirement factor A4 (HtrA4) mRNA is significantly lower in the chorionic villi of patients with recurrent pregnancy loss (RPL) than in the control group. We conducted an investigation into the cellular functions of HtrA4 using the CRISPR/Cas9 system and [...] Read more.
The expression of High-temperature requirement factor A4 (HtrA4) mRNA is significantly lower in the chorionic villi of patients with recurrent pregnancy loss (RPL) than in the control group. We conducted an investigation into the cellular functions of HtrA4 using the CRISPR/Cas9 system and shRNA-HtrA4 to create knockout BeWo cells and HtrA4 knockdown JEG3 cells. Our results indicated that the knockout BeWo cells exhibited reduced capacity for invasion and fusion, but increased levels of proliferation and migration, with a significantly shortened cell cycle compared to wild-type cells. Wild-type BeWo cells highly expressed cell invasion- and fusion-related factors, while knockout BeWo cells highly expressed migration-, proliferation-, and cell cycle-related factors. The shRNA-HtrA4 JEG3 cells showed a decreased capacity for invasion, but an increased capacity for migration, accompanied by a decrease in the expression of cell invasion-related factors and an increase in migration-related factors. Moreover, our ELISA results revealed that the serum HtrA4 level was lower in patients with RPL than in the controls. These findings suggest that HtrA4 depletion may be associated with placental dysfunction. Full article
(This article belongs to the Special Issue Signaling Pathways in Pregnancy)
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16 pages, 2941 KiB  
Article
Maternal and Intrauterine Influences on Feto-Placental Growth Are Accompanied by Sexually Dimorphic Changes in Placental Mitochondrial Respiration, and Metabolic Signalling Pathways
by Esteban Salazar-Petres, Daniela Pereira-Carvalho, Jorge Lopez-Tello and Amanda N. Sferruzzi-Perri
Cells 2023, 12(5), 797; https://doi.org/10.3390/cells12050797 - 03 Mar 2023
Cited by 2 | Viewed by 1892
Abstract
Adverse maternal environments such as small size, malnutrition, and metabolic conditions are known to influence fetal growth outcomes. Similarly, fetal growth and metabolic alterations may alter the intrauterine environment and affect all fetuses in multiple gestation/litter-bearing species. The placenta is the site of [...] Read more.
Adverse maternal environments such as small size, malnutrition, and metabolic conditions are known to influence fetal growth outcomes. Similarly, fetal growth and metabolic alterations may alter the intrauterine environment and affect all fetuses in multiple gestation/litter-bearing species. The placenta is the site of convergence between signals derived from the mother and the developing fetus/es. Its functions are fuelled by energy generated by mitochondrial oxidative phosphorylation (OXPHOS). The aim of this study was to delineate the role of an altered maternal and/or fetal/intrauterine environment in feto-placental growth and placental mitochondrial energetic capacity. To address this, in mice, we used disruptions of the gene encoding phosphoinositol 3-kinase (PI3K) p110α, a growth and metabolic regulator to perturb the maternal and/or fetal/intrauterine environment and study the impact on wildtype conceptuses. We found that feto-placental growth was modified by a perturbed maternal and intrauterine environment, and effects were most evident for wildtype males compared to females. However, placental mitochondrial complex I+II OXPHOS and total electron transport system (ETS) capacity were similarly reduced for both fetal sexes, yet reserve capacity was additionally decreased in males in response to the maternal and intrauterine perturbations. These were also sex-dependent differences in the placental abundance of mitochondrial-related proteins (e.g., citrate synthase and ETS complexes), and activity of growth/metabolic signalling pathways (AKT and MAPK) with maternal and intrauterine alterations. Our findings thus identify that the mother and the intrauterine environment provided by littermates modulate feto-placental growth, placental bioenergetics, and metabolic signalling in a manner dependent on fetal sex. This may have relevance for understanding the pathways leading to reduced fetal growth, particularly in the context of suboptimal maternal environments and multiple gestation/litter-bearing species. Full article
(This article belongs to the Special Issue Signaling Pathways in Pregnancy)
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9 pages, 1022 KiB  
Communication
Enoxaparin Increases D6 Receptor Expression and Restores Cytoskeleton Organization in Trophoblast Cells from Preeclampsia
by Chiara Tersigni, Giuseppe Maulucci, Roberta Castellani, Giada Bianchetti, Marianna Onori, Rita Franco, Greta Barbaro, Marco De Spirito, Antonio Lanzone, Giovanni Scambia and Nicoletta Di Simone
Cells 2022, 11(13), 2036; https://doi.org/10.3390/cells11132036 - 27 Jun 2022
Viewed by 1487
Abstract
D6 is a scavenger receptor for CC chemokines expressed in the human placenta. It prevents excessive leukocyte tissue infiltration by internalizing chemokines through cytoskeleton-dependent intracellular transport. In preeclampsia (PE), the D6 receptor is overexpressed in trophoblast cells, but functionally impaired, due to cytoskeleton [...] Read more.
D6 is a scavenger receptor for CC chemokines expressed in the human placenta. It prevents excessive leukocyte tissue infiltration by internalizing chemokines through cytoskeleton-dependent intracellular transport. In preeclampsia (PE), the D6 receptor is overexpressed in trophoblast cells, but functionally impaired, due to cytoskeleton destructuring. Low molecular weight heparin (LMWH) represents a potential treatment for PE based on its anti-thrombotic and anti-inflammatory properties. Here, we investigated the effect of enoxaparin on D6 expression, and cytoskeleton organization primary cytotrophoblast cell cultures were obtained from the placentae of women with PE (n = 9) or uncomplicated pregnancy (n = 9). We demonstrated that enoxaparin is able to (i) increase D6 expression, and (ii) improve cytoskeletal fiber alignment in trophoblast cells from PE patients. Full article
(This article belongs to the Special Issue Signaling Pathways in Pregnancy)
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11 pages, 1793 KiB  
Article
Lung Inflammation Is Associated with Preeclampsia Development in the Rat
by Katrina Curtis, Derek Clarke, Makayla Hanegan, Brendan Stapley, Ryan Wendt, Nathan Beckett, Cade Litchfield, Kennedy Campbell, Paul Reynolds and Juan Arroyo
Cells 2022, 11(12), 1884; https://doi.org/10.3390/cells11121884 - 10 Jun 2022
Viewed by 1896
Abstract
Preeclampsia (PE) is an obstetric complication associated with significant health implications for the fetus and mother. Studies have shown a correlation between lung disease development and PE. Gas6 protein is expressed in the lung and placenta, and binds to the AXL Tyrosine kinase [...] Read more.
Preeclampsia (PE) is an obstetric complication associated with significant health implications for the fetus and mother. Studies have shown a correlation between lung disease development and PE. Gas6 protein is expressed in the lung and placenta, and binds to the AXL Tyrosine kinase receptor. Recently, our laboratory utilized Gas6 to induce preeclamptic-like conditions in rats. Our objective was to determine the role of Gas6/AXL signaling in the maternal lung during PE development. Briefly, pregnant rats were divided into control, Gas6, or Gas6 + R428 (an AXL inhibitor). Immunofluorescence was performed to determine AXL expression. Bronchoalveolar lavage fluid (BALF) was procured for the assessment of inflammatory cell secretion. Western blot was performed to detect signaling molecules and ELISA determined inflammatory cytokines. We observed increased proteinuria and increased blood pressure in Gas6-treated animals. AXL was increased in the lungs of the treated animals and BALF fluid revealed elevated total protein abundance in Gas6 animals. Extracellular-signal regulated kinase (ERK) and protein kinase B (AKT) signaling in the lung appeared to be mediated by Gas6 as well as the secretion of inflammatory cytokines. We conclude that Gas6 signaling is capable of inducing PE and that this is associated with increased lung inflammation. Full article
(This article belongs to the Special Issue Signaling Pathways in Pregnancy)
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Review

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22 pages, 1446 KiB  
Review
The Role of the NLRP3 Inflammasome in the Molecular and Biochemical Mechanisms of Cervical Ripening: A Comprehensive Review
by Wojciech Flis and Maciej W. Socha
Cells 2024, 13(7), 600; https://doi.org/10.3390/cells13070600 - 29 Mar 2024
Viewed by 547
Abstract
The uterine cervix is one of the key factors involved in ensuring a proper track of gestation and labor. At the end of the gestational period, the cervix undergoes extensive changes, which can be summarized as a transformation from a non-favorable cervix to [...] Read more.
The uterine cervix is one of the key factors involved in ensuring a proper track of gestation and labor. At the end of the gestational period, the cervix undergoes extensive changes, which can be summarized as a transformation from a non-favorable cervix to one that is soft and prone to dilation. During a process called cervical ripening, fundamental remodeling of the cervical extracellular matrix (ECM) occurs. The cervical ripening process is a derivative of many interlocking and mutually driving biochemical and molecular pathways under the strict control of mediators such as inflammatory cytokines, nitric oxide, prostaglandins, and reactive oxygen species. A thorough understanding of all these pathways and learning about possible triggering factors will allow us to develop new, better treatment algorithms and therapeutic goals that could protect women from both dysfunctional childbirth and premature birth. This review aims to present the possible role of the NLRP3 inflammasome in the cervical ripening process, emphasizing possible mechanisms of action and regulatory factors. Full article
(This article belongs to the Special Issue Signaling Pathways in Pregnancy)
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19 pages, 1259 KiB  
Review
Modulation of NRF2/KEAP1 Signaling in Preeclampsia
by Giovanni Tossetta, Sonia Fantone, Federica Piani, Caterina Crescimanno, Andrea Ciavattini, Stefano Raffaele Giannubilo and Daniela Marzioni
Cells 2023, 12(11), 1545; https://doi.org/10.3390/cells12111545 - 04 Jun 2023
Cited by 23 | Viewed by 2242
Abstract
Placentation is a key and tightly regulated process that ensures the normal development of the placenta and fetal growth. Preeclampsia (PE) is a hypertensive pregnancy-related disorder involving about 5–8% of all pregnancies and clinically characterized by de novo maternal hypertension and proteinuria. In [...] Read more.
Placentation is a key and tightly regulated process that ensures the normal development of the placenta and fetal growth. Preeclampsia (PE) is a hypertensive pregnancy-related disorder involving about 5–8% of all pregnancies and clinically characterized by de novo maternal hypertension and proteinuria. In addition, PE pregnancies are also characterized by increased oxidative stress and inflammation. The NRF2/KEAP1 signaling pathway plays an important role in protecting cells against oxidative damage due to increased reactive oxygen species (ROS) levels. ROS activate NRF2, allowing its binding to the antioxidant response element (ARE) region present in the promoter of several antioxidant genes such as heme oxygenase, catalase, glutathione peroxidase and superoxide dismutase that neutralize ROS, protecting cells against oxidative stress damages. In this review, we analyze the current literature regarding the role of the NRF2/KEAP1 pathway in preeclamptic pregnancies, discussing the main cellular modulators of this pathway. Moreover, we also discuss the main natural and synthetic compounds that can regulate this pathway in in vivo and in vitro models. Full article
(This article belongs to the Special Issue Signaling Pathways in Pregnancy)
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16 pages, 1177 KiB  
Review
Cross-Generational Impact of Innate Immune Memory Following Pregnancy Complications
by Nakeisha A. Lodge-Tulloch, Alexa J. Toews, Aline Atallah, Tiziana Cotechini, Sylvie Girard and Charles H. Graham
Cells 2022, 11(23), 3935; https://doi.org/10.3390/cells11233935 - 06 Dec 2022
Cited by 5 | Viewed by 2231
Abstract
Pregnancy complications can have long-term negative effects on the health of the affected mothers and their children. In this review, we highlight the underlying inflammatory etiologies of common pregnancy complications and discuss how aberrant inflammation may lead to the acquisition of innate immune [...] Read more.
Pregnancy complications can have long-term negative effects on the health of the affected mothers and their children. In this review, we highlight the underlying inflammatory etiologies of common pregnancy complications and discuss how aberrant inflammation may lead to the acquisition of innate immune memory. The latter can be described as a functional epigenetic reprogramming of innate immune cells following an initial exposure to an inflammatory stimulus, ultimately resulting in an altered response following re-exposure to a similar inflammatory stimulus. We propose that aberrant maternal inflammation associated with complications of pregnancy increases the cross-generational risk of developing noncommunicable diseases (i.e., pregnancy complications, cardiovascular disease, and metabolic disease) through a process mediated by innate immune memory. Elucidating a role for innate immune memory in the cross-generational health consequences of pregnancy complications may lead to the development of novel strategies aimed at reducing the long-term risk of disease. Full article
(This article belongs to the Special Issue Signaling Pathways in Pregnancy)
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25 pages, 866 KiB  
Review
Signaling Pathways Regulating Human Cervical Ripening in Preterm and Term Delivery
by Maciej W. Socha, Wojciech Flis, Miłosz Pietrus, Mateusz Wartęga and Martyna Stankiewicz
Cells 2022, 11(22), 3690; https://doi.org/10.3390/cells11223690 - 21 Nov 2022
Cited by 5 | Viewed by 4858
Abstract
At the end of gestation, the cervical tissue changes profoundly. As a result of these changes, the uterine cervix becomes soft and vulnerable to dilation. The process occurring in the cervical tissue can be described as cervical ripening. The ripening is a process [...] Read more.
At the end of gestation, the cervical tissue changes profoundly. As a result of these changes, the uterine cervix becomes soft and vulnerable to dilation. The process occurring in the cervical tissue can be described as cervical ripening. The ripening is a process derivative of enzymatic breakdown and inflammatory response. Therefore, it is apparent that cervical remodeling is a derivative of the reactions mediated by multiple factors such as hormones, prostaglandins, nitric oxide, and inflammatory cytokines. However, despite the research carried out over the years, the cellular pathways responsible for regulating this process are still poorly understood. A comprehensive understanding of the entire process of cervical ripening seems crucial in the context of labor induction. Greater knowledge could provide us with the means to help women who suffer from dysfunctional labor. The overall objective of this review is to present the current understanding of cervical ripening in terms of molecular regulation and cell signaling. Full article
(This article belongs to the Special Issue Signaling Pathways in Pregnancy)
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