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Placental Related Disorders of Pregnancy
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Placental Related Disorders of Pregnancy

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Immunology".

Deadline for manuscript submissions: closed (30 September 2021) | Viewed by 67496

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editors

Dr. Hiten D. Mistry

E-Mail Website
Guest Editor
Department of Women and Children’s Health, School of Life Course and Population Sciences, King’s College London, London SE1 1UL, UK
Interests: pathophysiology of the hypertensive diseases of pregnancy; nutrition in pregnancy; global women’s health research studies
Special Issues, Collections and Topics in MDPI journals
Dr. Eun Lee

E-Mail Website
Guest Editor
Department of Microbiology and Immunology, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA
Interests: determining the pathogenesis and genetic association of preeclampsia; preterm birth and spontaneous miscarriages; ERAP2 peptide processing and its immunological roles; targeting ERAP2 for immunotherap

Special Issue Information

Dear Colleagues,

The placenta is a unique organ, produced outside the embryo, connected by a cord of vessels and is formed as a result of various degrees of interactions between fetal and maternal tissues within the pregnant uterus. The placenta fulfils a variety of functions, which are completed by several different organs in adult life. Unlike the relatively stable mature adult organs, the placenta is programmed to complete very different functions during development. Thus, the placenta can be described as a constantly evolving organ. Its major role is the homeostasis of a protected environment for the undisturbed growth and development of the embryo/fetus.

Placental-related disorders of pregnancy are almost unique to the human species, which affect around a third of human pregnancies. Many of these disorders result in increased maternal and fetal mortality and morbidity and can have life-long health implications for both the mother and her child. Recent changes in human lifestyle, such as delayed childbirth and hypercaloric diets, may have increased the global incidence of placental-related disorders over the last decades.

This Special Issue will cover all aspects placentation, with a particular focus on those related placental function and to disorders of pregnancy. Manuscripts related to any aspect of placental physiology, biochemistry and molecular biology, will be considered for this Special Issue, which will hope will be an excellent collection.

Dr. Hiten D Mistry
Dr. Eun Lee
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • placentation
  • pregnancy complications
  • placental function
  • disorders of pregnancy
  • physiology and biochemistry

Related Special Issue

Published Papers (22 papers)

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Editorial

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2 pages, 160 KiB  
Editorial
Placental Related Disorders of Pregnancy
by Eun D. Lee and Hiten D. Mistry
Int. J. Mol. Sci. 2022, 23(7), 3519; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23073519 - 24 Mar 2022
Cited by 2 | Viewed by 1851
Abstract
We are pleased to present this Special Issue of International Journal of Molecular Sciences, entitled ‘Placental Related Disorders of Pregnancy’ [...] Full article
(This article belongs to the Special Issue Placental Related Disorders of Pregnancy)

Research

Jump to: Editorial, Review

15 pages, 2946 KiB  
Article
Divergent Regulation of Decidual Oxidative-Stress Response by NRF2 and KEAP1 in Preeclampsia with and without Fetal Growth Restriction
by Siv Boon Mundal, Johanne Johnsen Rakner, Gabriela Brettas Silva, Lobke Marijn Gierman, Marie Austdal, Purusotam Basnet, Mattijs Elschot, Siril Skaret Bakke, Jenny Ostrop, Liv Cecilie Vestrheim Thomsen, Eric Keith Moses, Ganesh Acharya, Line Bjørge and Ann-Charlotte Iversen
Int. J. Mol. Sci. 2022, 23(4), 1966; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23041966 - 10 Feb 2022
Cited by 13 | Viewed by 2827
Abstract
Utero-placental development in pregnancy depends on direct maternal–fetal interaction in the uterine wall decidua. Abnormal uterine vascular remodeling preceding placental oxidative stress and placental dysfunction are associated with preeclampsia and fetal growth restriction (FGR). Oxidative stress is counteracted by antioxidants and oxidative repair [...] Read more.
Utero-placental development in pregnancy depends on direct maternal–fetal interaction in the uterine wall decidua. Abnormal uterine vascular remodeling preceding placental oxidative stress and placental dysfunction are associated with preeclampsia and fetal growth restriction (FGR). Oxidative stress is counteracted by antioxidants and oxidative repair mechanisms regulated by the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2). We aimed to determine the decidual regulation of the oxidative-stress response by NRF2 and its negative regulator Kelch-like ECH-associated protein 1 (KEAP1) in normal pregnancies and preeclamptic pregnancies with and without FGR. Decidual tissue from 145 pregnancies at delivery was assessed for oxidative stress, non-enzymatic antioxidant capacity, cellular NRF2- and KEAP1-protein expression, and NRF2-regulated transcriptional activation. Preeclampsia combined with FGR was associated with an increased oxidative-stress level and NRF2-regulated gene expression in the decidua, while decidual NRF2- and KEAP1-protein expression was unaffected. Although preeclampsia with normal fetal growth also showed increased decidual oxidative stress, NRF2-regulated gene expression was reduced, and KEAP1-protein expression was increased in areas of high trophoblast density. The trophoblast-dependent KEAP1-protein expression in preeclampsia with normal fetal growth indicates control of decidual oxidative stress by maternal–fetal interaction and underscores the importance of discriminating between preeclampsia with and without FGR. Full article
(This article belongs to the Special Issue Placental Related Disorders of Pregnancy)
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20 pages, 2469 KiB  
Article
Mutations That Affect the Surface Expression of TRPV6 Are Associated with the Upregulation of Serine Proteases in the Placenta of an Infant
by Claudia Fecher-Trost, Karin Wolske, Christine Wesely, Heidi Löhr, Daniel S. Klawitter, Petra Weissgerber, Elise Gradhand, Christine P. Burren, Anna E. Mason, Manuel Winter and Ulrich Wissenbach
Int. J. Mol. Sci. 2021, 22(23), 12694; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222312694 - 24 Nov 2021
Cited by 2 | Viewed by 1489
Abstract
Recently, we reported a case of an infant with neonatal severe under-mineralizing skeletal dysplasia caused by mutations within both alleles of the TRPV6 gene. One mutation results in an in frame stop codon (R510stop) that leads to a truncated, nonfunctional TRPV6 [...] Read more.
Recently, we reported a case of an infant with neonatal severe under-mineralizing skeletal dysplasia caused by mutations within both alleles of the TRPV6 gene. One mutation results in an in frame stop codon (R510stop) that leads to a truncated, nonfunctional TRPV6 channel, and the second in a point mutation (G660R) that, surprisingly, does not affect the Ca2+ permeability of TRPV6. We mimicked the subunit composition of the unaffected heterozygous parent and child by coexpressing the TRPV6 G660R and R510stop mutants and combinations with wild type TRPV6. We show that both the G660R and R510stop mutant subunits are expressed and result in decreased calcium uptake, which is the result of the reduced abundancy of functional TRPV6 channels within the plasma membrane. We compared the proteomic profiles of a healthy placenta with that of the diseased infant and detected, exclusively in the latter two proteases, HTRA1 and cathepsin G. Our results implicate that the combination of the two mutant TRPV6 subunits, which are expressed in the placenta of the diseased child, is responsible for the decreased calcium uptake, which could explain the skeletal dysplasia. In addition, placental calcium deficiency also appears to be associated with an increase in the expression of proteases. Full article
(This article belongs to the Special Issue Placental Related Disorders of Pregnancy)
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13 pages, 2279 KiB  
Article
Irisin Protects the Human Placenta from Oxidative Stress and Apoptosis via Activation of the Akt Signaling Pathway
by Hamid-Reza Kohan-Ghadr, Brooke Armistead, Mikaela Berg and Sascha Drewlo
Int. J. Mol. Sci. 2021, 22(20), 11229; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222011229 - 18 Oct 2021
Cited by 7 | Viewed by 2131
Abstract
Irisin is a newly discovered exercise-mediated polypeptide hormone. Irisin levels increase during pregnancy however, women with preeclampsia (PE) have significantly lower levels of Irisin compared to women of healthy pregnancies. Even though many studies suggest a role of Irisin in pregnancy, its function [...] Read more.
Irisin is a newly discovered exercise-mediated polypeptide hormone. Irisin levels increase during pregnancy however, women with preeclampsia (PE) have significantly lower levels of Irisin compared to women of healthy pregnancies. Even though many studies suggest a role of Irisin in pregnancy, its function in the human placenta is unclear. In the current study, we aimed to understand key roles of Irisin through its ability to protect against apoptosis is the preeclamptic placenta and in ex vivo and in vitro models of hypoxia/re-oxygenation (H/R) injury. Our studies show that Irisin prevents cell death by reducing pro-apoptotic signaling cascades, reducing cleavage of PARP to induce DNA repair pathways and reducing activity of Caspase 3. Irisin caused an increase in the levels of anti-apoptotic BCL2 to pro-apoptotic BAX and reduced ROS levels in an in vitro model of placental ischemia. Furthermore, we show that Irisin treatment acts through the Akt signaling pathway to prevent apoptosis and enhance cell survival. Our findings provide a novel understanding for the anti-apoptotic and pro-survival properties of Irisin in the human placenta under pathological conditions. This work yields new insights into placental development and disease and points towards intervention strategies for placental insufficiencies, such as PE, by protecting and maintaining placental function through inhibiting hypoxic ischemia-induced apoptosis. Full article
(This article belongs to the Special Issue Placental Related Disorders of Pregnancy)
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19 pages, 3564 KiB  
Article
Differences in Glycolysis and Mitochondrial Respiration between Cytotrophoblast and Syncytiotrophoblast In-Vitro: Evidence for Sexual Dimorphism
by Matthew Bucher, Leena Kadam, Kylia Ahuna and Leslie Myatt
Int. J. Mol. Sci. 2021, 22(19), 10875; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms221910875 - 08 Oct 2021
Cited by 11 | Viewed by 4455
Abstract
In the placenta the proliferative cytotrophoblast cells fuse into the terminally differentiated syncytiotrophoblast layer which undertakes several energy-intensive functions including nutrient uptake and transfer and hormone synthesis. We used Seahorse glycolytic and mitochondrial stress tests on trophoblast cells isolated at term from women [...] Read more.
In the placenta the proliferative cytotrophoblast cells fuse into the terminally differentiated syncytiotrophoblast layer which undertakes several energy-intensive functions including nutrient uptake and transfer and hormone synthesis. We used Seahorse glycolytic and mitochondrial stress tests on trophoblast cells isolated at term from women of healthy weight to evaluate if cytotrophoblast (CT) and syncytiotrophoblast (ST) have different bioenergetic strategies, given their different functions. Whereas there are no differences in basal glycolysis, CT have significantly greater glycolytic capacity and reserve than ST. In contrast, ST have significantly higher basal, ATP-coupled and maximal mitochondrial respiration and spare capacity than CT. Consequently, under stress conditions CT can increase energy generation via its higher glycolytic capacity whereas ST can use its higher and more efficient mitochondrial respiration capacity. We have previously shown that with adverse in utero conditions of diabetes and obesity trophoblast respiration is sexually dimorphic. We found no differences in glycolytic parameters between sexes and no difference in mitochondrial respiration parameters other than increases seen upon syncytialization appear to be greater in females. There were differences in metabolic flexibility, i.e., the ability to use glucose, glutamine, or fatty acids, seen upon syncytialization between the sexes with increased flexibility in female trophoblast suggesting a better ability to adapt to changes in nutrient supply. Full article
(This article belongs to the Special Issue Placental Related Disorders of Pregnancy)
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12 pages, 885 KiB  
Communication
Placental Expression of Bile Acid Transporters in Intrahepatic Cholestasis of Pregnancy
by Edgar Ontsouka, Alessandra Epstein, Sampada Kallol, Jonas Zaugg, Marc Baumann, Henning Schneider and Christiane Albrecht
Int. J. Mol. Sci. 2021, 22(19), 10434; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms221910434 - 28 Sep 2021
Cited by 11 | Viewed by 2059
Abstract
Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-related condition characterized by increased maternal circulating bile acids (BAs) having adverse fetal effects. We investigated whether the human placenta expresses specific regulation patterns to prevent fetal exposition to harmful amounts of BAs during ICP. Using [...] Read more.
Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-related condition characterized by increased maternal circulating bile acids (BAs) having adverse fetal effects. We investigated whether the human placenta expresses specific regulation patterns to prevent fetal exposition to harmful amounts of BAs during ICP. Using real-time quantitative PCR, we screened placentae from healthy pregnancies (n = 12) and corresponding trophoblast cells (n = 3) for the expression of 21 solute carriers and ATP-binding cassette transporter proteins, all acknowledged as BA- and/or cholestasis-related genes. The placental gene expression pattern was compared between healthy women and ICP patients (n = 12 each). Placental SLCO3A1 (OATP3A1) gene expression was significantly altered in ICP compared with controls. The other 20 genes, including SLC10A2 (ASBT) and EPHX1 (EPOX, mEH) reported for the first time in trophoblasts, were comparably abundant in healthy and ICP placentae. ABCG5 was undetectable in all placentae. Placental SLC10A2 (ASBT), SLCO4A1 (OATP4A1), and ABCC2 mRNA levels were positively correlated with BA concentrations in ICP. Placental SLC10A2 (ASBT) mRNA was also correlated with maternal body mass index. We conclude that at the transcriptional level only a limited response of BA transport systems is found under ICP conditions. However, the extent of the transcriptional response may also depend on the severity of the ICP condition and the magnitude by which the maternal BA levels are increased. Full article
(This article belongs to the Special Issue Placental Related Disorders of Pregnancy)
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16 pages, 9473 KiB  
Article
Conditional Mutation of Hand1 in the Mouse Placenta Disrupts Placental Vascular Development Resulting in Fetal Loss in Both Early and Late Pregnancy
by Jennifer A. Courtney, Rebecca L. Wilson, James Cnota and Helen N. Jones
Int. J. Mol. Sci. 2021, 22(17), 9532; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22179532 - 02 Sep 2021
Cited by 9 | Viewed by 2889
Abstract
Congenital heart defects (CHD) affect approximately 1% of all live births, and often require complex surgeries at birth. We have previously demonstrated abnormal placental vascularization in human placentas from fetuses diagnosed with CHD. Hand1 has roles in both heart and placental development and [...] Read more.
Congenital heart defects (CHD) affect approximately 1% of all live births, and often require complex surgeries at birth. We have previously demonstrated abnormal placental vascularization in human placentas from fetuses diagnosed with CHD. Hand1 has roles in both heart and placental development and is implicated in CHD development. We utilized two conditionally activated Hand1A126fs/+ murine mutant models to investigate the importance of cell-specific Hand1 on placental development in early (Nkx2-5Cre) and late (Cdh5Cre) pregnancy. Embryonic lethality occurred in Nkx2-5Cre/Hand1A126fs/+ embryos with marked fetal demise occurring after E10.5 due to a failure in placental labyrinth formation and therefore the inability to switch to hemotrophic nutrition or maintain sufficient oxygen transfer to the fetus. Labyrinthine vessels failed to develop appropriately and vessel density was significantly lower by day E12.5. In late pregnancy, the occurrence of Cdh5Cre+;Hand1A126fs/+ fetuses was reduced from 29% at E12.5 to 20% at E18.5 and remaining fetuses exhibited reduced fetal and placental weights, labyrinth vessel density and placenta angiogenic factor mRNA expression. Our results demonstrate for the first time the necessity of Hand1 in both establishment and remodeling of the exchange area beyond early pregnancy and in patterning vascularization of the placental labyrinth crucial for maintaining pregnancy and successful fetal growth. Full article
(This article belongs to the Special Issue Placental Related Disorders of Pregnancy)
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13 pages, 2469 KiB  
Article
Overexpression of ERAP2N in Human Trophoblast Cells Promotes Cell Death
by Kristen Lospinoso, Mikhail Dozmorov, Nadine El Fawal, Rhea Raghu, Wook-Jin Chae and Eun D. Lee
Int. J. Mol. Sci. 2021, 22(16), 8585; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22168585 - 10 Aug 2021
Cited by 5 | Viewed by 2440
Abstract
The genes involved in implantation and placentation are tightly regulated to ensure a healthy pregnancy. The endoplasmic reticulum aminopeptidase 2 (ERAP2) gene is associated with preeclampsia (PE). Our studies have determined that an isoform of ERAP2-arginine (N), expressed in trophoblast cells (TC), significantly [...] Read more.
The genes involved in implantation and placentation are tightly regulated to ensure a healthy pregnancy. The endoplasmic reticulum aminopeptidase 2 (ERAP2) gene is associated with preeclampsia (PE). Our studies have determined that an isoform of ERAP2-arginine (N), expressed in trophoblast cells (TC), significantly activates immune cells, and ERAP2N-expressing TCs are preferentially killed by both cytotoxic T lymphocytes (CTLs) and Natural Killer cells (NKCs). To understand the cause of this phenomenon, we surveyed differentially expressed genes (DEGs) between ERAP2N expressing and non-expressing TCs. Our RNAseq data revealed 581 total DEGs between the two groups. 289 genes were up-regulated, and 292 genes were down-regulated. Interestingly, most of the down-regulated genes of significance were pro-survival genes that play a crucial role in cell survival (LDHA, EGLN1, HLA-C, ITGB5, WNT7A, FN1). However, the down-regulation of these genes in ERAP2N-expressing TCs translates into a propensity for cell death. The Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that 64 DEGs were significantly enriched in nine pathways, including “Protein processing in endoplasmic reticulum” and “Antigen processing and presentation”, suggesting that the genes may be associated with peptide processes involved in immune recognition during the reproductive cycle. Full article
(This article belongs to the Special Issue Placental Related Disorders of Pregnancy)
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18 pages, 1386 KiB  
Article
CSH RNA Interference Reduces Global Nutrient Uptake and Umbilical Blood Flow Resulting in Intrauterine Growth Restriction
by Amelia R. Tanner, Cameron S. Lynch, Victoria C. Kennedy, Asghar Ali, Quinton A. Winger, Paul J. Rozance and Russell V. Anthony
Int. J. Mol. Sci. 2021, 22(15), 8150; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22158150 - 29 Jul 2021
Cited by 9 | Viewed by 2155
Abstract
Deficiency of the placental hormone chorionic somatomammotropin (CSH) can lead to the development of intrauterine growth restriction (IUGR). To gain insight into the physiological consequences of CSH RNA interference (RNAi), the trophectoderm of hatched blastocysts (nine days of gestational age; dGA) was infected [...] Read more.
Deficiency of the placental hormone chorionic somatomammotropin (CSH) can lead to the development of intrauterine growth restriction (IUGR). To gain insight into the physiological consequences of CSH RNA interference (RNAi), the trophectoderm of hatched blastocysts (nine days of gestational age; dGA) was infected with a lentivirus expressing either a scrambled control or CSH-specific shRNA, prior to transfer into synchronized recipient sheep. At 90 dGA, umbilical hemodynamics and fetal measurements were assessed by Doppler ultrasonography. At 120 dGA, pregnancies were fitted with vascular catheters to undergo steady-state metabolic studies with the 3H2O transplacental diffusion technique at 130 dGA. Nutrient uptake rates were determined and tissues were subsequently harvested at necropsy. CSH RNAi reduced (p ≤ 0.05) both fetal and uterine weights as well as umbilical blood flow (mL/min). This ultimately resulted in reduced (p ≤ 0.01) umbilical IGF1 concentrations, as well as reduced umbilical nutrient uptakes (p ≤ 0.05) in CSH RNAi pregnancies. CSH RNAi also reduced (p ≤ 0.05) uterine nutrient uptakes as well as uteroplacental glucose utilization. These data suggest that CSH is necessary to facilitate adequate blood flow for the uptake of oxygen, oxidative substrates, and hormones essential to support fetal and uterine growth. Full article
(This article belongs to the Special Issue Placental Related Disorders of Pregnancy)
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16 pages, 1911 KiB  
Article
Reduced Placental CD24 in Preterm Preeclampsia Is an Indicator for a Failure of Immune Tolerance
by Marei Sammar, Monika Siwetz, Hamutal Meiri, Adi Sharabi-Nov, Peter Altevogt and Berthold Huppertz
Int. J. Mol. Sci. 2021, 22(15), 8045; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22158045 - 28 Jul 2021
Cited by 7 | Viewed by 2533
Abstract
Introduction: CD24 is a mucin-like glycoprotein expressed at the surface of hematopoietic and tumor cells and was recently shown to be expressed in the first trimester placenta. As it was postulated as an immune suppressor, CD24 may contribute to maternal immune tolerance to [...] Read more.
Introduction: CD24 is a mucin-like glycoprotein expressed at the surface of hematopoietic and tumor cells and was recently shown to be expressed in the first trimester placenta. As it was postulated as an immune suppressor, CD24 may contribute to maternal immune tolerance to the growing fetus. Preeclampsia (PE), a major pregnancy complication, is linked to reduced immune tolerance. Here, we explored the expression of CD24 in PE placenta in preterm and term cases. Methods: Placentas were derived from first and early second trimester social terminations (N = 43), and third trimester normal term delivery (N = 67), preterm PE (N = 18), and preterm delivery (PTD) (N = 6). CD24 expression was determined by quantitative polymerase chain reaction (qPCR) and Western blotting. A smaller cohort included 3–5 subjects each of term and early PE, and term and preterm delivery controls analyzed by immunohistochemistry. Results: A higher expression (2.27-fold) of CD24 mRNA was determined in the normal term delivery compared to first and early second trimester cases. The mRNA of preterm PE cases was only higher by 1.31-fold compared to first and early second trimester, while in the age-matched PTD group had a fold increase of 5.72, four times higher compared to preterm PE. The delta cycle threshold (ΔCt) of CD24 mRNA expression in the preterm PE group was inversely correlated with gestational age (r = 0.737) and fetal size (r = 0.623), while correlation of any other group with these parameters was negligible. Western blot analysis revealed that the presence of CD24 protein in placental lysate of preterm PE was significantly reduced compared to term delivery controls (p = 0.026). In immunohistochemistry, there was a reduction of CD24 staining in villous trophoblast in preterm PE cases compared to gestational age-matched PTD cases (p = 0.042). Staining of PE cases at term was approximately twice higher compared to preterm PE cases (p = 0.025) but not different from normal term delivery controls. Conclusion: While higher CD24 mRNA expression levels were determined for normal term delivery compared to earlier pregnancy stages, this expression level was found to be lower in preterm PE cases, and could be said to be linked to reduced immune tolerance in preeclampsia. Full article
(This article belongs to the Special Issue Placental Related Disorders of Pregnancy)
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25 pages, 2661 KiB  
Article
Human Placental Transcriptome Reveals Critical Alterations in Inflammation and Energy Metabolism with Fetal Sex Differences in Spontaneous Preterm Birth
by Yu-Chin Lien, Zhe Zhang, Yi Cheng, Erzsebet Polyak, Laura Sillers, Marni J. Falk, Harry Ischiropoulos, Samuel Parry and Rebecca A. Simmons
Int. J. Mol. Sci. 2021, 22(15), 7899; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22157899 - 23 Jul 2021
Cited by 25 | Viewed by 3290
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Placental Related Disorders of Pregnancy)
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19 pages, 2615 KiB  
Article
Placental Transcriptome Adaptations to Maternal Nutrient Restriction in Sheep
by Chelsie B. Steinhauser, Colleen A. Lambo, Katharine Askelson, Gregory W. Burns, Susanta K. Behura, Thomas E. Spencer, Fuller W. Bazer and Michael Carey Satterfield
Int. J. Mol. Sci. 2021, 22(14), 7654; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22147654 - 17 Jul 2021
Cited by 5 | Viewed by 2111
Abstract
Placental development is modified in response to maternal nutrient restriction (NR), resulting in a spectrum of fetal growth rates. Pregnant sheep carrying singleton fetuses and fed either 100% (n = 8) or 50% (NR; n = 28) of their National Research Council [...] Read more.
Placental development is modified in response to maternal nutrient restriction (NR), resulting in a spectrum of fetal growth rates. Pregnant sheep carrying singleton fetuses and fed either 100% (n = 8) or 50% (NR; n = 28) of their National Research Council (NRC) recommended intake from days 35–135 of pregnancy were used to elucidate placentome transcriptome alterations at both day 70 and day 135. NR fetuses were further designated into upper (NR NonSGA; n = 7) and lower quartiles (NR SGA; n = 7) based on day 135 fetal weight. At day 70 of pregnancy, there were 22 genes dysregulated between NR SGA and 100% NRC placentomes, 27 genes between NR NonSGA and 100% NRC placentomes, and 22 genes between NR SGA and NR NonSGA placentomes. These genes mediated molecular functions such as MHC class II protein binding, signaling receptor binding, and cytokine activity. Gene set enrichment analysis (GSEA) revealed significant overrepresentation of genes for natural-killer-cell-mediated cytotoxicity in NR SGA compared to 100% NRC placentomes, and alterations in nutrient utilization pathways between NR SGA and NR NonSGA placentomes at day 70. Results identify novel factors associated with impaired function in SGA placentomes and potential for placentomes from NR NonSGA pregnancies to adapt to nutritional hardship. Full article
(This article belongs to the Special Issue Placental Related Disorders of Pregnancy)
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13 pages, 2108 KiB  
Article
Elevated Circulating and Placental SPINT2 Is Associated with Placental Dysfunction
by Ciara N. Murphy, Susan P. Walker, Teresa M. MacDonald, Emerson Keenan, Natalie J. Hannan, Mary E. Wlodek, Jenny Myers, Jessica F. Briffa, Tania Romano, Alexandra Roddy Mitchell, Carole-Anne Whigham, Ping Cannon, Tuong-Vi Nguyen, Manju Kandel, Natasha Pritchard, Stephen Tong and Tu’uhevaha J. Kaitu’u-Lino
Int. J. Mol. Sci. 2021, 22(14), 7467; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22147467 - 12 Jul 2021
Cited by 9 | Viewed by 2204
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Placental Related Disorders of Pregnancy)
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16 pages, 4394 KiB  
Article
Placental Villous Explant Culture 2.0: Flow Culture Allows Studies Closer to the In Vivo Situation
by Nadja Kupper, Elisabeth Pritz, Monika Siwetz, Jacqueline Guettler and Berthold Huppertz
Int. J. Mol. Sci. 2021, 22(14), 7464; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22147464 - 12 Jul 2021
Cited by 19 | Viewed by 2990
Abstract
During pregnancy, freely floating placental villi are adapted to fluid shear stress due to placental perfusion with maternal plasma and blood. In vitro culture of placental villous explants is widely performed under static conditions, hoping the conditions may represent the in utero environment. [...] Read more.
During pregnancy, freely floating placental villi are adapted to fluid shear stress due to placental perfusion with maternal plasma and blood. In vitro culture of placental villous explants is widely performed under static conditions, hoping the conditions may represent the in utero environment. However, static placental villous explant culture dramatically differs from the in vivo situation. Thus, we established a flow culture system for placental villous explants and compared commonly used static cultured tissue to flow cultured tissue using transmission and scanning electron microscopy, immunohistochemistry, and lactate dehydrogenase (LDH) and human chorionic gonadotropin (hCG) measurements. The data revealed a better structural and biochemical integrity of flow cultured tissue compared to static cultured tissue. Thus, this new flow system can be used to simulate the blood flow from the mother to the placenta and back in the most native-like in vitro system so far and thus can enable novel study designs. Full article
(This article belongs to the Special Issue Placental Related Disorders of Pregnancy)
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12 pages, 1750 KiB  
Article
Symptoms of Prenatal Depression Associated with Shorter Telomeres in Female Placenta
by Isabel Garcia-Martin, Richard J. A. Penketh, Samantha M. Garay, Rhiannon E. Jones, Julia W. Grimstead, Duncan M. Baird and Rosalind M. John
Int. J. Mol. Sci. 2021, 22(14), 7458; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22147458 - 12 Jul 2021
Cited by 4 | Viewed by 2499
Abstract
Background. Depression is a common mood disorder during pregnancy impacting one in every seven women. Children exposed to prenatal depression are more likely to be born at a low birth weight and develop chronic diseases later in life. A proposed hypothesis for this [...] Read more.
Background. Depression is a common mood disorder during pregnancy impacting one in every seven women. Children exposed to prenatal depression are more likely to be born at a low birth weight and develop chronic diseases later in life. A proposed hypothesis for this relationship between early exposure to adversity and poor outcomes is accelerated aging. Telomere length has been used as a biomarker of cellular aging. We used high-resolution telomere length analysis to examine the relationship between placental telomere length distributions and maternal mood symptoms in pregnancy. Methods. This study utilised samples from the longitudinal Grown in Wales (GiW) study. Women participating in this study were recruited at their presurgical appointment prior to a term elective caesarean section (ELCS). Women completed the Edinburgh Postnatal Depression Scale (EPDS) and trait subscale of the State-Trait Anxiety Inventory (STAI). Telomere length distributions were generated using single telomere length analysis (STELA) in 109 term placenta (37–42 weeks). Multiple linear regression was performed to examine the relationship between maternally reported symptoms of depression and anxiety at term and mean placental telomere length. Results: Prenatal depression symptoms were significantly negatively associated with XpYp telomere length in female placenta (B = −0.098, p = 0.026, 95% CI −0.184, −0.012). There was no association between maternal depression symptoms and telomere length in male placenta (B = 0.022, p = 0.586, 95% CI −0.059, 0.103). There was no association with anxiety symptoms and telomere length for either sex. Conclusion: Maternal prenatal depression is associated with sex-specific differences in term placental telomeres. Telomere shortening in female placenta may indicate accelerated placental aging. Full article
(This article belongs to the Special Issue Placental Related Disorders of Pregnancy)
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13 pages, 3083 KiB  
Article
Megalin, Proton Pump Inhibitors and the Renin–Angiotensin System in Healthy and Pre-Eclamptic Placentas
by Yuan Sun, Lunbo Tan, Rugina I. Neuman, Michelle Broekhuizen, Sam Schoenmakers, Xifeng Lu and A. H. Jan Danser
Int. J. Mol. Sci. 2021, 22(14), 7407; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22147407 - 10 Jul 2021
Cited by 10 | Viewed by 2367
Abstract
Soluble Fms-like tyrosine kinase-1 (sFlt-1) is increased in pre-eclampsia. The proton pump inhibitor (PPI) lowers sFlt-1, while angiotensin increases it. To investigate whether PPIs lower sFlt-1 by suppressing placental renin–angiotensin system (RAS) activity, we studied gene expression and protein abundance of RAS components, [...] Read more.
Soluble Fms-like tyrosine kinase-1 (sFlt-1) is increased in pre-eclampsia. The proton pump inhibitor (PPI) lowers sFlt-1, while angiotensin increases it. To investigate whether PPIs lower sFlt-1 by suppressing placental renin–angiotensin system (RAS) activity, we studied gene expression and protein abundance of RAS components, including megalin, a novel endocytic receptor for prorenin and renin, in placental tissue obtained from healthy pregnant women and women with early-onset pre-eclampsia. Renin, ACE, ACE2, and the angiotensin receptors were expressed at identical levels in healthy and pre-eclamptic placentas, while both the (pro)renin receptor and megalin were increased in the latter. Placental prorenin levels were upregulated in pre-eclamptic pregnancies. Angiotensinogen protein, but not mRNA, was detectable in placental tissue, implying that it originates from maternal blood. Ex vivo placental perfusion revealed a complete washout of angiotensinogen, while prorenin release remained constant. The PPI esomeprazole dose-dependently reduced megalin/(pro)renin receptor-mediated renin uptake in Brown Norway yolk sac epithelial cells and decreased sFlt-1 secretion from placental villous explants. Megalin inhibition blocked angiotensinogen uptake in epithelial cells. In conclusion, our data suggest that placental RAS activity depends on angiotensinogen taken up from the maternal systemic circulation. PPIs might interfere with placental (pro)renin-AGT uptake/transport, thereby reducing angiotensin formation as well as angiotensin-induced sFlt-1 synthesis. Full article
(This article belongs to the Special Issue Placental Related Disorders of Pregnancy)
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13 pages, 5061 KiB  
Article
Increased Placental Cell Senescence and Oxidative Stress in Women with Pre-Eclampsia and Normotensive Post-Term Pregnancies
by Paula J. Scaife, Amy Simpson, Lesia O. Kurlak, Louise V. Briggs, David S. Gardner, Fiona Broughton Pipkin, Carolyn J. P. Jones and Hiten D. Mistry
Int. J. Mol. Sci. 2021, 22(14), 7295; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22147295 - 07 Jul 2021
Cited by 20 | Viewed by 3268
Abstract
Up to 11% of pregnancies extend to post-term with adverse obstetric events linked to pregnancies over 42 weeks. Oxidative stress and senescence (cells stop growing and dividing by irreversibly arresting their cell cycle and gradually ageing) can result in diminished cell function. There [...] Read more.
Up to 11% of pregnancies extend to post-term with adverse obstetric events linked to pregnancies over 42 weeks. Oxidative stress and senescence (cells stop growing and dividing by irreversibly arresting their cell cycle and gradually ageing) can result in diminished cell function. There are no detailed studies of placental cell senescence markers across a range of gestational ages, although increased levels have been linked to pre-eclampsia before full term. This study aimed to determine placental senescence and oxidative markers across a range of gestational ages in women with uncomplicated pregnancies and those with a diagnosis of pre-eclampsia. Placentae were obtained from 37 women with uncomplicated pregnancies of 37–42 weeks and from 13 cases of pre-eclampsia of 31+2–41+2 weeks. The expression of markers of senescence, oxidative stress, and antioxidant defence (tumour suppressor protein p16INK4a, kinase inhibitor p21, interleukin-6 (IL-6), NADPH oxidase 4 (NOX4), glutathione peroxidases 1, 3, and 4 (GPx1, GPx3, and GPx4), placental growth factor (PlGF), and soluble fms-like tyrosine kinase-1 (sFlt-1)) genes was measured (quantitative real-time PCR). Protein abundance of p16INK4a, IL-6, NOX4, 8-hydroxy-2′-deoxy-guanosine (8-OHdG), and PlGF was assessed by immunocytochemistry. Placental NOX4 protein was higher in post-term than term deliveries and further increased by pre-eclampsia (p < 0.05 for all). P21 expression was higher in post-term placentae (p = 0.012) and in pre-eclampsia (p = 0.04), compared to term. Placental P16INK4a protein expression was increased post-term, compared to term (p = 0.01). In normotensive women, gestational age at delivery was negatively associated with GPx4 and PlGF (mRNA and protein) (p < 0.05 for all), whereas a positive correlation was seen with placental P21, NOX4, and P16INK4a (p < 0.05 for all) expression. Markers of placental oxidative stress and senescence appear to increase as gestational age increases, with antioxidant defences diminishing concomitantly. These observations increase our understanding of placental health and may contribute to assessment of the optimal gestational age for delivery. Full article
(This article belongs to the Special Issue Placental Related Disorders of Pregnancy)
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16 pages, 17737 KiB  
Article
YB-1 Is Altered in Pregnancy-Associated Disorders and Affects Trophoblast in Vitro Properties via Alternation of Multiple Molecular Traits
by Violeta Stojanovska, Aneri Shah, Katja Woidacki, Florence Fischer, Mario Bauer, Jonathan A. Lindquist, Peter R. Mertens and Ana C. Zenclussen
Int. J. Mol. Sci. 2021, 22(13), 7226; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22137226 - 05 Jul 2021
Cited by 5 | Viewed by 3395
Abstract
Cold shock Y-box binding protein-1 (YB-1) coordinates several molecular processes between the nucleus and the cytoplasm and plays a crucial role in cell function. Moreover, it is involved in cancer progression, invasion, and metastasis. As trophoblast cells share similar characteristics with cancer cells, [...] Read more.
Cold shock Y-box binding protein-1 (YB-1) coordinates several molecular processes between the nucleus and the cytoplasm and plays a crucial role in cell function. Moreover, it is involved in cancer progression, invasion, and metastasis. As trophoblast cells share similar characteristics with cancer cells, we hypothesized that YB-1 might also be necessary for trophoblast functionality. In samples of patients with intrauterine growth restriction, YB-1 mRNA levels were decreased, while they were increased in preeclampsia and unchanged in spontaneous abortions when compared to normal pregnant controls. Studies with overexpression and downregulation of YB-1 were performed to assess the key trophoblast processes in two trophoblast cell lines HTR8/SVneo and JEG3. Overexpression of YB-1 or exposure of trophoblast cells to recombinant YB-1 caused enhanced proliferation, while knockdown of YB-1 lead to proliferative disadvantage in JEG3 or HTR8/SVneo cells. The invasion and migration properties were affected at different degrees among the trophoblast cell lines. Trophoblast expression of genes mediating migration, invasion, apoptosis, and inflammation was altered upon YB-1 downregulation. Moreover, IL-6 secretion was excessively increased in HTR8/SVneo. Ultimately, YB-1 directly binds to NF-κB enhancer mark in HTR8/SVneo cells. Our data show that YB-1 protein is important for trophoblast cell functioning and, when downregulated, leads to trophoblast disadvantage that at least in part is mediated by NF-κB. Full article
(This article belongs to the Special Issue Placental Related Disorders of Pregnancy)
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Review

Jump to: Editorial, Research

14 pages, 5772 KiB  
Review
Interleukin-15 in Outcomes of Pregnancy
by Scott M. Gordon
Int. J. Mol. Sci. 2021, 22(20), 11094; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222011094 - 14 Oct 2021
Cited by 13 | Viewed by 3909
Abstract
Interleukin-15 (IL-15) is a pleiotropic cytokine that classically acts to support the development, maintenance, and function of killer lymphocytes. IL-15 is abundant in the uterus prior to and during pregnancy, but it is subject to tight spatial and temporal regulation. Both mouse models [...] Read more.
Interleukin-15 (IL-15) is a pleiotropic cytokine that classically acts to support the development, maintenance, and function of killer lymphocytes. IL-15 is abundant in the uterus prior to and during pregnancy, but it is subject to tight spatial and temporal regulation. Both mouse models and human studies suggest that homeostasis of IL-15 is essential for healthy pregnancy. Dysregulation of IL-15 is associated with adverse outcomes of pregnancy. Herein, we review producers of IL-15 and responders to IL-15, including non-traditional responders in the maternal uterus and fetal placenta. We also review regulation of IL-15 at the maternal–fetal interface and propose mechanisms of action of IL-15 to facilitate additional study of this critical cytokine in the context of pregnancy. Full article
(This article belongs to the Special Issue Placental Related Disorders of Pregnancy)
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15 pages, 2034 KiB  
Review
Unique Aspects of Human Placentation
by Anthony M. Carter
Int. J. Mol. Sci. 2021, 22(15), 8099; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22158099 - 28 Jul 2021
Cited by 20 | Viewed by 3669
Abstract
Human placentation differs from that of other mammals. A suite of characteristics is shared with haplorrhine primates, including early development of the embryonic membranes and placental hormones such as chorionic gonadotrophin and placental lactogen. A comparable architecture of the intervillous space is found [...] Read more.
Human placentation differs from that of other mammals. A suite of characteristics is shared with haplorrhine primates, including early development of the embryonic membranes and placental hormones such as chorionic gonadotrophin and placental lactogen. A comparable architecture of the intervillous space is found only in Old World monkeys and apes. The routes of trophoblast invasion and the precise role of extravillous trophoblast in uterine artery transformation is similar in chimpanzee and gorilla. Extended parental care is shared with the great apes, and though human babies are rather helpless at birth, they are well developed (precocial) in other respects. Primates and rodents last shared a common ancestor in the Cretaceous period, and their placentation has evolved independently for some 80 million years. This is reflected in many aspects of their placentation. Some apparent resemblances such as interstitial implantation and placental lactogens are the result of convergent evolution. For rodent models such as the mouse, the differences are compounded by short gestations leading to the delivery of poorly developed (altricial) young. Full article
(This article belongs to the Special Issue Placental Related Disorders of Pregnancy)
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33 pages, 2472 KiB  
Review
Immunoendocrine Dysregulation during Gestational Diabetes Mellitus: The Central Role of the Placenta
by Andrea Olmos-Ortiz, Pilar Flores-Espinosa, Lorenza Díaz, Pilar Velázquez, Carlos Ramírez-Isarraraz and Verónica Zaga-Clavellina
Int. J. Mol. Sci. 2021, 22(15), 8087; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22158087 - 28 Jul 2021
Cited by 32 | Viewed by 4705
Abstract
Gestational Diabetes Mellitus (GDM) is a transitory metabolic condition caused by dysregulation triggered by intolerance to carbohydrates, dysfunction of beta-pancreatic and endothelial cells, and insulin resistance during pregnancy. However, this disease includes not only changes related to metabolic distress but also placental immunoendocrine [...] Read more.
Gestational Diabetes Mellitus (GDM) is a transitory metabolic condition caused by dysregulation triggered by intolerance to carbohydrates, dysfunction of beta-pancreatic and endothelial cells, and insulin resistance during pregnancy. However, this disease includes not only changes related to metabolic distress but also placental immunoendocrine adaptations, resulting in harmful effects to the mother and fetus. In this review, we focus on the placenta as an immuno-endocrine organ that can recognize and respond to the hyperglycemic environment. It synthesizes diverse chemicals that play a role in inflammation, innate defense, endocrine response, oxidative stress, and angiogenesis, all associated with different perinatal outcomes. Full article
(This article belongs to the Special Issue Placental Related Disorders of Pregnancy)
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22 pages, 4803 KiB  
Review
The Road to Low-Dose Aspirin Therapy for the Prevention of Preeclampsia Began with the Placenta
by Scott W. Walsh and Jerome F. Strauss III
Int. J. Mol. Sci. 2021, 22(13), 6985; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22136985 - 29 Jun 2021
Cited by 22 | Viewed by 5159
Abstract
The road to low-dose aspirin therapy for the prevention of preeclampsia began in the 1980s with the discovery that there was increased thromboxane and decreased prostacyclin production in placentas of preeclamptic women. At the time, low-dose aspirin therapy was being used to prevent [...] Read more.
The road to low-dose aspirin therapy for the prevention of preeclampsia began in the 1980s with the discovery that there was increased thromboxane and decreased prostacyclin production in placentas of preeclamptic women. At the time, low-dose aspirin therapy was being used to prevent recurrent myocardial infarction and other thrombotic events based on its ability to selectively inhibit thromboxane synthesis without affecting prostacyclin synthesis. With the discovery that thromboxane was increased in preeclamptic women, it was reasonable to evaluate whether low-dose aspirin would be effective for preeclampsia prevention. The first clinical trials were very promising, but then two large multi-center trials dampened enthusiasm until meta-analysis studies showed aspirin was effective, but with caveats. Low-dose aspirin was most effective when started <16 weeks of gestation and at doses >100 mg/day. It was effective in reducing preterm preeclampsia, but not term preeclampsia, and patient compliance and patient weight were important variables. Despite the effectiveness of low-dose aspirin therapy in correcting the placental imbalance between thromboxane and prostacyclin and reducing oxidative stress, some aspirin-treated women still develop preeclampsia. Alterations in placental sphingolipids and hydroxyeicosatetraenoic acids not affected by aspirin, but with biologic actions that could cause preeclampsia, may explain treatment failures. Consideration should be given to aspirin’s effect on neutrophils and pregnancy-specific expression of protease-activated receptor 1, as well as additional mechanisms of action to prevent preeclampsia. Full article
(This article belongs to the Special Issue Placental Related Disorders of Pregnancy)
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