Cells

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20 pages, 1939 KiB

Open AccessArticle

Primary Human Trophoblasts Mimic the Preeclampsia Phenotype after Acute Hypoxia–Reoxygenation Insult

by Barbara Fuenzalida, Sampada Kallol, Jonas Zaugg, Martin Mueller, Hiten D. Mistry, Jaime Gutierrez, Andrea Leiva and Christiane Albrecht

Cells 2022, 11(12), 1898; https://doi.org/10.3390/cells11121898 - 11 Jun 2022

Cited by 9 | Viewed by 2604

Abstract

Preeclampsia (PE) is a pregnancy-specific disorder that affects 3 to 5% of pregnancies worldwide and is one of the leading causes of maternal and fetal morbidity and mortality. Nevertheless, how these events occur remains unclear. We hypothesized that the induction of hypoxic conditions [...] Read more.

Preeclampsia (PE) is a pregnancy-specific disorder that affects 3 to 5% of pregnancies worldwide and is one of the leading causes of maternal and fetal morbidity and mortality. Nevertheless, how these events occur remains unclear. We hypothesized that the induction of hypoxic conditions in vitro in primary human trophoblast cells would mimic several characteristics of PE found in vivo. We applied and characterized a model of primary cytotrophoblasts isolated from healthy pregnancies that were placed under different oxygen concentrations: ambient O₂ (5% pCO₂, 21%pO₂, 24 h, termed “normoxia”), low O₂ concentration (5% pCO₂, 1.5% pO₂, 24 h, termed “hypoxia”), or “hypoxia/reoxygenation” (H/R: 6 h intervals of normoxia and hypoxia for 24 h). Various established preeclamptic markers were assessed in this cell model and compared to placental tissues obtained from PE pregnancies. Seventeen PE markers were analyzed by qPCR, and the protein secretion of soluble fms-like tyrosine kinase 1 (sFlT-1) and the placenta growth factor (PlGF) was determined by ELISA. Thirteen of seventeen genes associated with angiogenesis, the renin–angiotensin system, oxidative stress, endoplasmic reticulum stress, and the inflammasome complex were susceptible to H/R and hypoxia, mimicking the expression pattern of PE tissue. In cell culture supernatants, the secretion of sFlT-1 was increased in hypoxia, while PlGF release was significantly reduced in H/R and hypoxia. In the supernatants of our cell models, the sFlT-1/PlGF ratio in hypoxia and H/R was higher than 38, which is a strong indicator for PE in clinical practice. These results suggest that our cellular models reflect important pathological processes occurring in PE and are therefore suitable as PE in vitro models. Full article

(This article belongs to the Special Issue The Pathophysiology of Preeclampsia and Eclampsia)

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4 pages, 356 KiB

Open AccessCommunication

Nebivolol Increases Nitric Oxide Synthase via β₃ Adrenergic Receptor in Endothelial Cells Following Exposure to Plasma from Preeclamptic Patients

by Thaina Omia Bueno-Pereira, Priscila Rezeck Nunes, Mariana Bertozzi Matheus, Ananda Lini Vieira da Rocha and Valeria Cristina Sandrim

Cells 2022, 11(5), 883; https://doi.org/10.3390/cells11050883 - 4 Mar 2022

Cited by 5 | Viewed by 2020

Abstract

Background: Low bioavailability of nitric oxide (NO) is related to the pathophysiology of preeclampsia (PE). In the present study, we investigated the effect of nebivolol (NEB), a β₃-receptor agonist with vasodilator properties, on the NO synthesis in endothelial cells incubated with [...] Read more.

Background: Low bioavailability of nitric oxide (NO) is related to the pathophysiology of preeclampsia (PE). In the present study, we investigated the effect of nebivolol (NEB), a β₃-receptor agonist with vasodilator properties, on the NO synthesis in endothelial cells incubated with plasma from preeclamptic patients. Methods and results: Human umbilical vein endothelial cells (HUVECs) were incubated with plasma from healthy pregnant (HP) and PE women; NO quantification was assessed by a fluorescence compound. We found that endothelial cells incubated with plasma from women with PE show lower NO levels compared with the HP group (p < 0.0001). However, NEB treatment increases NO levels, partially, mediated by β₃ adrenergic receptors (p < 0.0001) and through eNOS activation (p < 0.0001). Conclusions: Our results suggest that NEB acts in NO synthesis through eNOS activation and β₃ adrenergic receptors in the endothelium. However, further studies will be needed to understand this molecule. Full article

(This article belongs to the Special Issue The Pathophysiology of Preeclampsia and Eclampsia)

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14 pages, 1600 KiB

Open AccessArticle

Cerebral Biomarkers and Blood-Brain Barrier Integrity in Preeclampsia

by Therese Friis, Anna-Karin Wikström, Jesenia Acurio, José León, Henrik Zetterberg, Kaj Blennow, Maria Nelander, Helena Åkerud, Helena Kaihola, Catherine Cluver, Felipe Troncoso, Pablo Torres-Vergara, Carlos Escudero and Lina Bergman

Cells 2022, 11(5), 789; https://doi.org/10.3390/cells11050789 - 24 Feb 2022

Cited by 10 | Viewed by 4096

Abstract

Cerebral complications in preeclampsia contribute substantially to maternal mortality and morbidity. There is a lack of reliable and accessible predictors for preeclampsia-related cerebral complications. In this study, plasma from women with preeclampsia (n = 28), women with normal pregnancies (n = 28) and [...] Read more.

Cerebral complications in preeclampsia contribute substantially to maternal mortality and morbidity. There is a lack of reliable and accessible predictors for preeclampsia-related cerebral complications. In this study, plasma from women with preeclampsia (n = 28), women with normal pregnancies (n = 28) and non-pregnant women (n = 16) was analyzed for concentrations of the cerebral biomarkers neurofilament light (NfL), tau, neuron-specific enolase (NSE) and S100B. Then, an in vitro blood–brain barrier (BBB) model, based on the human cerebral microvascular endothelial cell line (hCMEC/D3), was employed to assess the effect of plasma from the three study groups. Transendothelial electrical resistance (TEER) was used as an estimation of BBB integrity. NfL and tau are proteins expressed in axons, NSE in neurons and S100B in glial cells and are used as biomarkers for neurological injury in other diseases such as dementia, traumatic brain injury and hypoxic brain injury. Plasma concentrations of NfL, tau, NSE and S100B were all higher in women with preeclampsia compared with women with normal pregnancies (8.85 vs. 5.25 ng/L, p < 0.001; 2.90 vs. 2.40 ng/L, p < 0.05; 3.50 vs. 2.37 µg/L, p < 0.001 and 0.08 vs. 0.05 µg/L, p < 0.01, respectively). Plasma concentrations of NfL were also higher in women with preeclampsia compared with non-pregnant women (p < 0.001). Higher plasma concentrations of the cerebral biomarker NfL were associated with decreased TEER (p = 0.002) in an in vitro model of the BBB, a finding which indicates that NfL could be a promising biomarker for BBB alterations in preeclampsia. Full article

(This article belongs to the Special Issue The Pathophysiology of Preeclampsia and Eclampsia)

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11 pages, 2874 KiB

Open AccessArticle

G-Protein Coupled Receptor Dysregulation May Play Roles in Severe Preeclampsia—A Weighted Gene Correlation Network Analysis of Placental Gene Expression Profile

by Manuel S. Vidal, Jr., Christian Deo T. Deguit, Gracia Fe B. Yu and Melissa D. Amosco

Cells 2022, 11(5), 763; https://doi.org/10.3390/cells11050763 - 22 Feb 2022

Cited by 6 | Viewed by 2324

Abstract

Preeclampsia is one of the major hypertensive diseases of pregnancy. Genetic factors contribute to abnormal placentation. The inadequate transformation of cytotrophoblasts causes failure of maternal spiral arteries’ remodeling and results in narrow, atherotic-prone vessels, leading to relative placental ischemia. This study aims to [...] Read more.

Preeclampsia is one of the major hypertensive diseases of pregnancy. Genetic factors contribute to abnormal placentation. The inadequate transformation of cytotrophoblasts causes failure of maternal spiral arteries’ remodeling and results in narrow, atherotic-prone vessels, leading to relative placental ischemia. This study aims to explore the possibility of identifying dysregulated gene networks that may offer a potential target in the possible prevention of preeclampsia. We performed a weighted gene correlated network analysis (WGCNA) on a subset of gene expression profiles of placental tissues from severe preeclamptic pregnancies. We identified a gene module (number of genes = 402, GS = 0.35, p = 0.02) enriched for several G-protein-coupled receptor (GPCR)-related genes with significant protein–protein molecular interaction (number of genes = 38, FDR = 0.0007) that may play key roles in preeclampsia. Some genes are noted to play key roles in preeclampsia, including LPAR4/5, CRLR, NPY, TACR1/2, and SFRP4/5, whose functions generally relate to angiogenesis and vasodilation or vasoconstriction. Other upregulated genes, including olfactory and orexigenic genes, serve limited functions in the disease pathogenesis. Altogether, this study shows the utility of WGCNA in exploring possible new gene targets, and additionally reinforces the feasibility of targeting GPCRs that may offer intervention against development and disease progression among severe preeclampsia patients. Full article

(This article belongs to the Special Issue The Pathophysiology of Preeclampsia and Eclampsia)

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14 pages, 1741 KiB

Open AccessArticle

Sustained Elevated Circulating Activin A Impairs Global Longitudinal Strain in Pregnant Rats: A Potential Mechanism for Preeclampsia-Related Cardiac Dysfunction

by Bhavisha A. Bakrania, Ana C. Palei, Umesh Bhattarai, Yingjie Chen, Joey P. Granger and Sajid Shahul

Cells 2022, 11(4), 742; https://doi.org/10.3390/cells11040742 - 21 Feb 2022

Cited by 1 | Viewed by 2730

Abstract

Mediators of cardiac injury in preeclampsia are not well understood. Preeclamptic women have decreased cardiac global longitudinal strain (GLS), a sensitive measure of systolic function that indicates fibrosis and tissue injury. GLS is worse in preeclampsia compared to gestational hypertension, despite comparable blood [...] Read more.

Mediators of cardiac injury in preeclampsia are not well understood. Preeclamptic women have decreased cardiac global longitudinal strain (GLS), a sensitive measure of systolic function that indicates fibrosis and tissue injury. GLS is worse in preeclampsia compared to gestational hypertension, despite comparable blood pressure, suggesting that placental factors may be involved. We previously showed that Activin A, a pro-fibrotic factor produced in excess by the placenta in preeclampsia, predicts impaired GLS postpartum. Here, we hypothesized that chronic excess levels of Activin A during pregnancy induces cardiac dysfunction. Rats were assigned to sham or activin A infusion (1.25–6 µg/day) on a gestational day (GD) 14 (n = 6–10/group). All animals underwent blood pressure measurement and comprehensive echocardiography followed by euthanasia and the collection of tissue samples on GD 19. Increased circulating activin A (sham: 0.59 ± 0.05 ng/mL, 6 µg/day: 2.8 ± 0.41 ng/mL, p < 0.01) was associated with impaired GLS (Sham: −22.1 ± 0.8%, 6 µg/day: −14.7 ± 1.14%, p < 0.01). Activin A infusion (6 µg/day) increased beta-myosin heavy chain expression in heart tissue, indicating cardiac injury. In summary, our findings indicate that increasing levels of activin A during pregnancy induces cardiac dysfunction and supports the concept that activin A may serve as a possible mediator of PE-induced cardiac dysfunction. Full article

(This article belongs to the Special Issue The Pathophysiology of Preeclampsia and Eclampsia)

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8 pages, 1139 KiB

Open AccessArticle

Glucose Transporter 9 (GLUT9) Plays an Important Role in the Placental Uric Acid Transport System

by Benjamin P. Lüscher, Christiane Albrecht, Bruno Stieger, Daniel V. Surbek and Marc U. Baumann

Cells 2022, 11(4), 633; https://doi.org/10.3390/cells11040633 - 11 Feb 2022

Cited by 8 | Viewed by 2550

Abstract

Background: Hyperuricemia is a common laboratory finding in pregnant women compromised by preeclampsia. A growing body of evidence suggests that uric acid is involved in the pathogenesis of preeclampsia. Glucose transporter 9 (GLUT9) is a high-capacity uric acid transporter. The aim of this [...] Read more.

Background: Hyperuricemia is a common laboratory finding in pregnant women compromised by preeclampsia. A growing body of evidence suggests that uric acid is involved in the pathogenesis of preeclampsia. Glucose transporter 9 (GLUT9) is a high-capacity uric acid transporter. The aim of this study was to investigate the placental uric acid transport system, and to identify the (sub-) cellular localization of GLUT9. Methods: Specific antibodies against GLUT9a and GLUT9b isoforms were raised, and human villous (placental) tissue was immunohistochemically stained. A systemic GLUT9 knockout (G9KO) mouse model was used to assess the placental uric acid transport capacity by measurements of uric acid serum levels in the fetal and maternal circulation. Results: GLUT9a and GLUT9b co-localized with the villous (apical) membrane, but not with the basal membrane, of the syncytiotrophoblast. Fetal and maternal uric acid serum levels were closely correlated. G9KO fetuses showed substantially higher uric acid serum concentrations than their mothers. Conclusions: These findings demonstrate that the placenta efficiently maintains uric acid homeostasis, and that GLUT9 plays a key role in the placental uric acid transport system, at least in this murine model. Further studies investigating the role of the placental uric acid transport system in preeclampsia are eagerly needed. Full article

(This article belongs to the Special Issue The Pathophysiology of Preeclampsia and Eclampsia)

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11 pages, 2267 KiB

Open AccessArticle

Evidence of Neuroinflammation and Blood–Brain Barrier Disruption in Women with Preeclampsia and Eclampsia

by Lina Bergman, Roxanne Hastie, Henrik Zetterberg, Kaj Blennow, Sonja Schell, Eduard Langenegger, Ashley Moodley, Susan Walker, Stephen Tong and Catherine Cluver

Cells 2021, 10(11), 3045; https://doi.org/10.3390/cells10113045 - 5 Nov 2021

Cited by 14 | Viewed by 3555

Abstract

Cerebral complications in preeclampsia are leading causes of maternal mortality. Animal models suggest that an injured blood–brain barrier and neuroinflammation may be important but there is paucity of data from human studies. Therefore, we aimed to evaluate this in women with preeclampsia and [...] Read more.

Cerebral complications in preeclampsia are leading causes of maternal mortality. Animal models suggest that an injured blood–brain barrier and neuroinflammation may be important but there is paucity of data from human studies. Therefore, we aimed to evaluate this in women with preeclampsia and eclampsia. We included women recruited to the South African Preeclampsia Obstetric Adverse Events (PROVE) biobank. Blood and cerebrospinal fluid (CSF) were collected around delivery. CSF was analyzed for neuroinflammatory markers interleukin 1β, interleukin 6, interleukin-8 and tumor necrosis factor alpha (TNF-alpha). The CSF to plasma albumin ratio was measured to assess blood–brain barrier function. Women with eclampsia (n = 4) showed increased CSF concentrations of all pro-inflammatory cytokines and TNF-alpha compared to women with normotensive pregnancies (n = 7) and also for interleukin-6 and TNF-alpha compared to women with preeclampsia (n = 4). Women with preeclampsia also showed increases in pro-inflammatory cytokines IL-6 and IL-8 but not TNF-alpha in the CSF compared to women with normotensive pregnancies. In particular, women with eclampsia but also women with preeclampsia showed an increase in the CSF to plasma albumin ratio compared to normotensive women. In conclusion, women with preeclampsia and eclampsia show evidence of neuroinflammation and an injured blood–brain barrier. These findings are seen in particular among women with eclampsia. Full article

(This article belongs to the Special Issue The Pathophysiology of Preeclampsia and Eclampsia)

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10 pages, 2551 KiB

Open AccessArticle

Progesterone Induced Blocking Factor Reduces Hypertension and Placental Mitochondrial Dysfunction in Response to sFlt-1 during Pregnancy

by Evangeline Deer, Jalisa Jones, Denise C. Cornelius, Kyleigh Comley, Owen Herrock, Nathan Campbell, Sarah Fitzgerald, Tarek Ibrahim, Babbette LaMarca and Lorena M. Amaral

Cells 2021, 10(11), 2817; https://doi.org/10.3390/cells10112817 - 20 Oct 2021

Cited by 12 | Viewed by 2688

Abstract

Preeclampsia (PE) is characterized by new onset hypertension in association with placental ischemia, reduced fetal weight, elevated soluble fms-like tyrosine kinase-1 (sFlt-1), and placental mitochondrial (mt) dysfunction and oxidative stress (ROS). Progesterone induced blocking factor (PIBF) is a product of progesterone signaling that [...] Read more.

Preeclampsia (PE) is characterized by new onset hypertension in association with placental ischemia, reduced fetal weight, elevated soluble fms-like tyrosine kinase-1 (sFlt-1), and placental mitochondrial (mt) dysfunction and oxidative stress (ROS). Progesterone induced blocking factor (PIBF) is a product of progesterone signaling that blocks inflammatory processes and we have previously shown PIBF to lower mean arterial blood pressure (MAP) and sFlt-1 in a rat model of PE. Infusion of sFlt-1 causes hypertension and many characteristics of PE in pregnant rodents, however, its role in causing mt dysfunction is unknown. Therefore, we hypothesize that PIBF will improve mt function and MAP in response to elevated sFlt-1 during pregnancy. We tested our hypothesis by infusing sFlt-1 via miniosmotic pumps in normal pregnant (NP) Sprague-Dawley rats (3.7 μg·kg⁻¹·day⁻¹) on gestation days (GD) 13–19 in the presence or absence of PIBF (2.0 µg/mL) injected intraperitoneally on GD 15 and examined mean arterial blood pressure (MAP) and placental mt ROS on GD 19. sFlt-1 increased MAP to 112 + 2 (n = 11) compared to NP rats (98 + 2 mmHg, n = 15, p < 0.05), which was lowered in the presence of sFlt-1 (100 + 1 mmHg, n = 5, p < 0.05). Placental mtATP was reduced in sFlt-1 infused rats versus NP controls, but was improved with PIBF. Placental mtROS was elevated with sFlt-1 compared to NP controls, but was reduced with PIBF. Sera from NP + sFlt-1 increased endothelial cell mtROS, which was attenuated with PIBF. These data demonstrate sFlt-1 induced HTN during pregnancy reduces placental mt function. Importantly, PIBF improved placental mt function and HTN, indicating the efficacy of improved progesterone signaling as potential therapeutics for PE. Full article

(This article belongs to the Special Issue The Pathophysiology of Preeclampsia and Eclampsia)

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13 pages, 1584 KiB

Open AccessArticle

Low Dose of IL-2 Normalizes Hypertension and Mitochondrial Function in the RUPP Rat Model of Placental Ischemia

by Evangeline Deer, Lorena M. Amaral, Nathan Campbell, Sarah Fitzgerald, Owen Herrock, Tarek Ibrahim and Babbette LaMarca

Cells 2021, 10(10), 2797; https://doi.org/10.3390/cells10102797 - 19 Oct 2021

Cited by 6 | Viewed by 2468

Abstract

IL-2 is a cytokine released from CD4+T cells with dual actions and can either potentiate the inflammatory response or quell a chronic inflammatory response depending on its circulating concentration. IL-2 is elevated in many chronic inflammatory conditions and is increased during preeclampsia (PE). [...] Read more.

IL-2 is a cytokine released from CD4+T cells with dual actions and can either potentiate the inflammatory response or quell a chronic inflammatory response depending on its circulating concentration. IL-2 is elevated in many chronic inflammatory conditions and is increased during preeclampsia (PE). PE is characterized by new-onset hypertension during pregnancy and organ dysfunction and increasing evidence indicates that proinflammatory cytokines cause hypertension and mitochondrial (mt) dysfunction during pregnancy. The reduced uterine perfusion pressure (RUPP) model of placental ischemia is a rat model of PE that we commonly use in our laboratory and we have previously shown that low doses of recombinant IL-2 can decrease blood pressure in RUPP rats. The objective of this study was to determine the effects of a low dose of recombinant IL-2 on multi-organ mt dysfunction in the RUPP rat model of PE. We tested our hypothesis by infusing recombinant IL-2 (0.05 ng/mL) into RUPP rats on GD14 and examined mean arterial pressure (MAP), renal, placental and endothelial cell mt function compared to control RUPP. MAP was elevated in RUPP rats (n = 6) compared to controls (n = 5) (122 ± 5 vs. 102 ± 3 mmHg, p < 0.05), but was reduced by administration of LD recombinant IL-2 (107 ± 1 vs. 122 ± 5 mmHg, n = 9, p < 0.05). Renal, placental and endothelial mt ROS were significantly increased in RUPP rats compared to RUPP+ IL-2 and controls. Placental and renal respiration rates were reduced in RUPP rats compared to control rats but were normalized with IL-2 administration to RUPPs. These data indicate that low-dose IL-2 normalized multi-organ mt function and hypertension in response to placental ischemia. Full article

(This article belongs to the Special Issue The Pathophysiology of Preeclampsia and Eclampsia)

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14 pages, 1334 KiB

Open AccessArticle

Peripartum Investigation of Red Blood Cell Properties in Women Diagnosed with Early-Onset Preeclampsia

by Beata Csiszar, Gergely Galos, Simone Funke, Dora Kinga Kevey, Matyas Meggyes, Laszlo Szereday, Peter Kenyeres, Kalman Toth and Barbara Sandor

Cells 2021, 10(10), 2714; https://doi.org/10.3390/cells10102714 - 10 Oct 2021

Cited by 10 | Viewed by 2786

Abstract

We investigated peripartum maternal red blood cell (RBC) properties in early-onset preeclampsia (PE). Repeated blood samples were taken prospectively for hemorheological measurements at PE diagnosis (n = 13) or during 26–34 weeks of gestation in healthy pregnancies (n = 24), then at delivery, [...] Read more.

We investigated peripartum maternal red blood cell (RBC) properties in early-onset preeclampsia (PE). Repeated blood samples were taken prospectively for hemorheological measurements at PE diagnosis (n = 13) or during 26–34 weeks of gestation in healthy pregnancies (n = 24), then at delivery, and 72 h postpartum. RBC aggregation was characterized by M index (infrared light transmission between the aggregated RBCs in stasis) and aggregation index (AI—laser backscattering from the RBC aggregates). We observed significantly elevated RBC aggregation (M index = 9.8 vs. 8.5; AI = 72.9% vs. 67.5%; p < 0.001) and reduced RBC deformability in PE (p < 0.05). A positive linear relationship was observed between AI and gestational age at birth in PE by regression analysis (R² = 0.554; p = 0.006). ROC analysis of AI showed an AUC of 0.84 (0.68–0.99) (p = 0.001) for PE and indicated a cutoff of 69.4% (sensitivity = 83.3%; specificity = 62.5%), while M values showed an AUC of 0.75 (0.58–0.92) (p = 0.019) and indicated a cutoff of 8.39 (sensitivity = 90.9% and specificity = 50%). The predicted probabilities from the combination of AI and M variables showed increased AUC = 0.90 (0.79–1.00) (p < 0.001). Our results established impaired microcirculation in early-onset PE manifesting as deteriorated maternal RBC properties. The longer the pathologic pregnancy persists, the more pronounced the maternal erythrocyte aggregation. AI and M index could help in the prognostication of early-onset PE, but further investigations are warranted to confirm the prognostic role before the onset of symptoms. Full article

(This article belongs to the Special Issue The Pathophysiology of Preeclampsia and Eclampsia)

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25 pages, 6096 KiB

Open AccessArticle

Functional Analysis of p21^Cip1/CDKN1A and Its Family Members in Trophoblastic Cells of the Placenta and Its Roles in Preeclampsia

by Nina-Naomi Kreis, Alexandra Friemel, Lukas Jennewein, Samira Catharina Hoock, Anna Elisabeth Hentrich, Thorsten Nowak, Frank Louwen and Juping Yuan

Cells 2021, 10(9), 2214; https://doi.org/10.3390/cells10092214 - 27 Aug 2021

Cited by 8 | Viewed by 3568

Abstract

Preeclampsia (PE), a gestational hypertensive disease originating from the placenta, is characterized by an imbalance of various cellular processes. The cell cycle regulator p21^Cip1/CDKN1A (p21) and its family members p27 and p57 regulate signaling pathways fundamental to placental development. The aim [...] Read more.

Preeclampsia (PE), a gestational hypertensive disease originating from the placenta, is characterized by an imbalance of various cellular processes. The cell cycle regulator p21^Cip1/CDKN1A (p21) and its family members p27 and p57 regulate signaling pathways fundamental to placental development. The aim of the present study was to enlighten the individual roles of these cell cycle regulators in placental development and their molecular involvement in the pathogenesis of PE. The expression and localization of p21, phospho-p21 (Thr-145), p27, and p57 was immunohistochemically analyzed in placental tissues from patients with early-onset PE, early-onset PE complicated by the HELLP (hemolysis, elevated liver enzymes and low platelet count) syndrome as well as late-onset PE compared to their corresponding control tissues from well-matched women undergoing caesarean sections. The gene level was evaluated using real-time quantitative PCR. We demonstrate that the delivery mode strongly influenced placental gene expression, especially for CDKN1A (p21) and CDKN1B (p27), which were significantly upregulated in response to labor. Cell cycle regulators were highly expressed in first trimester placentas and impacted by hypoxic conditions. In support of these observations, p21 protein was abundant in trophoblast organoids and hypoxia reduced its gene expression. Microarray analysis of the trophoblastic BeWo cell line depleted of p21 revealed various interesting candidate genes and signaling pathways for the fusion process. The level of p21 was reduced in fusing cytotrophoblasts in early-onset PE placentas and depletion of p21 led to reduced expression of fusion-related genes such as syncytin-2 and human chorionic gonadotropin (β-hCG), which adversely affected the fusion capability of trophoblastic cells. These data highlight that cell cycle regulators are important for the development of the placenta. Interfering with p21 influences multiple pathways related to the pathogenesis of PE. Full article

(This article belongs to the Special Issue The Pathophysiology of Preeclampsia and Eclampsia)

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12 pages, 1834 KiB

Open AccessArticle

Melatonin, a Potential Therapeutic Agent for Preeclampsia, Reduces the Extrusion of Toxic Extracellular Vesicles from Preeclamptic Placentae

by Yunhui Tang, Katie Groom, Larry Chamley and Qi Chen

Cells 2021, 10(8), 1904; https://doi.org/10.3390/cells10081904 - 27 Jul 2021

Cited by 13 | Viewed by 2641

Abstract

Preeclampsia, characterised by maternal endothelial cell activation, is triggered by toxic factors, such as placental extracellular vesicles (EVs) from a dysfunctional placenta. The increased oxidative stress seen in the preeclamptic placenta links to endoplasmic reticulum (ER) stress. The ER regulates protein folding and [...] Read more.

Preeclampsia, characterised by maternal endothelial cell activation, is triggered by toxic factors, such as placental extracellular vesicles (EVs) from a dysfunctional placenta. The increased oxidative stress seen in the preeclamptic placenta links to endoplasmic reticulum (ER) stress. The ER regulates protein folding and trafficking. When the ER is stressed, proteins are misfolded, and misfolded proteins are toxic. Misfolded proteins can be exported from cells, via EVs which target to other cells where the misfolded proteins may also be toxic. Melatonin is a hormone and antioxidant produced by the pineal gland and placenta. Levels of melatonin are reduced in preeclampsia. In this study we investigated whether melatonin treatment can change the nature of placental EVs that are released from a preeclamptic placenta. EVs were collected from preeclamptic (n = 6) and normotensive (n = 6) placental explants cultured in the presence or absence of melatonin for 18 h. Misfolded proteins were measured using a fluorescent compound, Thioflavin-T (ThT). Endothelial cells were exposed to placental EVs overnight. Endothelial cell activation was measured by the quantification of cell-surface ICAM-1 using a cell-based ELISA. EVs from preeclamptic placentae carried significantly (p < 0.001) more misfolded proteins than normotensive controls. Incubating preeclamptic placental explants in the presence of melatonin (1 µM and 10 µM) significantly (p < 0.001) reduced the misfolded proteins carried by EVs. Culturing endothelial cells in the presence of preeclamptic EVs significantly increased the expression of ICAM-1. This increased ICAM-1 expression was significantly reduced when the endothelial cells were exposed to preeclamptic EVs cultured in the presence of melatonin. This study demonstrates that melatonin reduces the amount of misfolded proteins carried by EVs from preeclamptic placentae and reduces the ability of these EVs to activate endothelial cells. Our study provides further preclinical support for the use of melatonin as a treatment for preeclampsia. Full article

(This article belongs to the Special Issue The Pathophysiology of Preeclampsia and Eclampsia)

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13 pages, 1418 KiB

Open AccessArticle

Acid Sensing Ion Channel 2a Is Reduced in the Reduced Uterine Perfusion Pressure Mouse Model and Increases Seizure Susceptibility in Pregnant Mice

by Maria Jones-Muhammad, Qingmei Shao, Loretta Cain-Shields, James P. Shaffery and Junie P. Warrington

Cells 2021, 10(5), 1135; https://doi.org/10.3390/cells10051135 - 8 May 2021

Cited by 7 | Viewed by 2948

Abstract

Eclampsia is diagnosed in pregnant women who develop novel seizures. Our laboratory showed that the reduced uterine perfusion pressure (RUPP) rat model of preeclampsia displays reduced latency to drug-induced seizures. While acid sensing ion channels (ASIC1a and 3) are important for reducing seizure [...] Read more.

Eclampsia is diagnosed in pregnant women who develop novel seizures. Our laboratory showed that the reduced uterine perfusion pressure (RUPP) rat model of preeclampsia displays reduced latency to drug-induced seizures. While acid sensing ion channels (ASIC1a and 3) are important for reducing seizure longevity and severity, the role of ASIC2a in mediating seizure sensitivity in pregnancy has not been investigated. We hypothesized that 1) RUPP reduces hippocampal ASIC2a, and 2) pregnant mice with reduced ASIC2a (ASIC2a+/−) have increased seizure sensitivity. On gestational day 18.5, hippocampi from sham and RUPP C57BL/6 mice were harvested, and ASIC2a was assessed using Western blot. Pregnant wild-type and ASIC2a+/− mice received 40 mg/kg of pentylenetetrazol (i.p.) and were video recorded for 30 min. Behaviors were scored using a modified Racine scale (0–7: 0 = no seizure; 7 = respiratory arrest/death). Seizure severity was classified as mild (score = 1–3) or severe (score = 4–7). RUPP mice had reduced hippocampal and placental ASIC2a protein. ASIC2a+/− mice had reduced latency to seizures, increased seizure duration, increased severe seizure duration, and higher maximum seizure scores. Reduced hippocampal ASIC2a in RUPP mice and increased seizure activity in pregnant ASIC2a+/− mice support the hypothesis that reduced ASIC2a increases seizure sensitivity associated with the RUPP. Full article

(This article belongs to the Special Issue The Pathophysiology of Preeclampsia and Eclampsia)

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Review

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24 pages, 683 KiB

Open AccessReview

The Relationship between Obesity and Pre-Eclampsia: Incidental Risks and Identification of Potential Biomarkers for Pre-Eclampsia

by Talitha Abraham and Andrea M. P. Romani

Cells 2022, 11(9), 1548; https://doi.org/10.3390/cells11091548 - 5 May 2022

Cited by 23 | Viewed by 7056

Abstract

Obesity has been steadily increasing over the past decade in the US and worldwide. Since 1975, the prevalence of obesity has increased by 2% per decade, unabated despite new and more stringent guidelines set by WHO, CDC, and other public health organizations. Likewise, [...] Read more.

Obesity has been steadily increasing over the past decade in the US and worldwide. Since 1975, the prevalence of obesity has increased by 2% per decade, unabated despite new and more stringent guidelines set by WHO, CDC, and other public health organizations. Likewise, maternal obesity has also increased worldwide over the past several years. In the United States, pre-pregnancy rates have increased proportionally across all racial groups. Obesity during pregnancy has been directly linked to obstetric complications including gestational diabetes, HTN, hematomas, pre-eclampsia, and congenital defects. In the particular case of pre-eclampsia, the incidence rate across the globe is 2.16%, but the condition accounts for 30% of maternal deaths, and a robust body of evidence underscored the relationship between obesity and pre-eclampsia. More recently, attention has focused on the identification of reliable biomarkers predictive of an elevated risk for pre-eclampsia. The aim of this literature review is to elucidate the relationship between obesity and these predictive biomarkers for future prediction and prevention of pre-eclampsia condition in women at risk. Full article

(This article belongs to the Special Issue The Pathophysiology of Preeclampsia and Eclampsia)

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14 pages, 1097 KiB

Open AccessReview

Tocotrienol in Pre-Eclampsia Prevention: A Mechanistic Analysis in Relation to the Pathophysiological Framework

by Zaleha Abdullah Mahdy, Kok-Yong Chin, Nik Lah Nik-Ahmad-Zuky, Aida Kalok and Rahana Abdul Rahman

Cells 2022, 11(4), 614; https://doi.org/10.3390/cells11040614 - 10 Feb 2022

Cited by 2 | Viewed by 3559

Abstract

The pathophysiology of pre-eclampsia involves two major pathways, namely systemic oxidative stress and subsequent generalised inflammatory response, which eventually culminates in endothelial cell injury and the syndrome of pre-eclampsia with multi-organ dysfunction. Aspirin has been used to reduce the risk of pre-eclampsia, but [...] Read more.

The pathophysiology of pre-eclampsia involves two major pathways, namely systemic oxidative stress and subsequent generalised inflammatory response, which eventually culminates in endothelial cell injury and the syndrome of pre-eclampsia with multi-organ dysfunction. Aspirin has been used to reduce the risk of pre-eclampsia, but it only possesses anti-inflammatory properties without any antioxidant effect. Hence, it can only partially alleviate the problem. Tocotrienols are a unique form of vitamin E with strong antioxidant and anti-inflammatory properties that can be exploited as a preventive agent for pre-eclampsia. Many preclinical models showed that tocotrienol can also prevent hypertension and ischaemic/reperfusion injury, which are the two main features in pre-eclampsia. This review explores the mechanism of action of tocotrienol in relation to the pathophysiology of pre-eclampsia. In conclusion, the study provides sufficient justification for the establishment of a large clinical trial to thoroughly assess the capability of tocotrienol in preventing pre-eclampsia. Full article

(This article belongs to the Special Issue The Pathophysiology of Preeclampsia and Eclampsia)

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32 pages, 1827 KiB

Open AccessReview

The Pivotal Role of the Placenta in Normal and Pathological Pregnancies: A Focus on Preeclampsia, Fetal Growth Restriction, and Maternal Chronic Venous Disease

by Miguel A. Ortega, Oscar Fraile-Martínez, Cielo García-Montero, Miguel A. Sáez, Miguel Angel Álvarez-Mon, Diego Torres-Carranza, Melchor Álvarez-Mon, Julia Bujan, Natalio García-Honduvilla, Coral Bravo, Luis G. Guijarro and Juan A. De León-Luis

Cells 2022, 11(3), 568; https://doi.org/10.3390/cells11030568 - 6 Feb 2022

Cited by 58 | Viewed by 10097

Abstract

The placenta is a central structure in pregnancy and has pleiotropic functions. This organ grows incredibly rapidly during this period, acting as a mastermind behind different fetal and maternal processes. The relevance of the placenta extends far beyond the pregnancy, being crucial for [...] Read more.

The placenta is a central structure in pregnancy and has pleiotropic functions. This organ grows incredibly rapidly during this period, acting as a mastermind behind different fetal and maternal processes. The relevance of the placenta extends far beyond the pregnancy, being crucial for fetal programming before birth. Having integrative knowledge of this maternofetal structure helps significantly in understanding the development of pregnancy either in a proper or pathophysiological context. Thus, the aim of this review is to summarize the main features of the placenta, with a special focus on its early development, cytoarchitecture, immunology, and functions in non-pathological conditions. In contraposition, the role of the placenta is examined in preeclampsia, a worrisome hypertensive disorder of pregnancy, in order to describe the pathophysiological implications of the placenta in this disease. Likewise, dysfunction of the placenta in fetal growth restriction, a major consequence of preeclampsia, is also discussed, emphasizing the potential clinical strategies derived. Finally, the emerging role of the placenta in maternal chronic venous disease either as a causative agent or as a consequence of the disease is equally treated. Full article

(This article belongs to the Special Issue The Pathophysiology of Preeclampsia and Eclampsia)

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26 pages, 2090 KiB

Open AccessReview

Vascular Dysfunction in Preeclampsia

by Megan A. Opichka, Matthew W. Rappelt, David D. Gutterman, Justin L. Grobe and Jennifer J. McIntosh

Cells 2021, 10(11), 3055; https://doi.org/10.3390/cells10113055 - 6 Nov 2021

Cited by 111 | Viewed by 9104

Abstract

Preeclampsia is a life-threatening pregnancy-associated cardiovascular disorder characterized by hypertension and proteinuria at 20 weeks of gestation. Though its exact underlying cause is not precisely defined and likely heterogenous, a plethora of research indicates that in some women with preeclampsia, both maternal and [...] Read more.

Preeclampsia is a life-threatening pregnancy-associated cardiovascular disorder characterized by hypertension and proteinuria at 20 weeks of gestation. Though its exact underlying cause is not precisely defined and likely heterogenous, a plethora of research indicates that in some women with preeclampsia, both maternal and placental vascular dysfunction plays a role in the pathogenesis and can persist into the postpartum period. Potential abnormalities include impaired placentation, incomplete spiral artery remodeling, and endothelial damage, which are further propagated by immune factors, mitochondrial stress, and an imbalance of pro- and antiangiogenic substances. While the field has progressed, current gaps in knowledge include detailed initial molecular mechanisms and effective treatment options. Newfound evidence indicates that vasopressin is an early mediator and biomarker of the disorder, and promising future therapeutic avenues include mitigating mitochondrial dysfunction, excess oxidative stress, and the resulting inflammatory state. In this review, we provide a detailed overview of vascular defects present during preeclampsia and connect well-established notions to newer discoveries at the molecular, cellular, and whole-organism levels. Full article

(This article belongs to the Special Issue The Pathophysiology of Preeclampsia and Eclampsia)

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14 pages, 1161 KiB

Open AccessReview

NLRP3 Activation and Its Relationship to Endothelial Dysfunction and Oxidative Stress: Implications for Preeclampsia and Pharmacological Interventions

by Priscila Rezeck Nunes, Sarah Viana Mattioli and Valeria Cristina Sandrim

Cells 2021, 10(11), 2828; https://doi.org/10.3390/cells10112828 - 21 Oct 2021

Cited by 32 | Viewed by 4698

Abstract

Preeclampsia (PE) is a specific syndrome of human pregnancy, being one of the main causes of maternal death. Persistent inflammation in the endothelium stimulates the secretion of several inflammatory mediators, activating different signaling patterns. One of these mechanisms is related to NLRP3 activation, [...] Read more.

Preeclampsia (PE) is a specific syndrome of human pregnancy, being one of the main causes of maternal death. Persistent inflammation in the endothelium stimulates the secretion of several inflammatory mediators, activating different signaling patterns. One of these mechanisms is related to NLRP3 activation, initiated by high levels of danger signals such as cholesterol, urate, and glucose, producing IL-1, IL-18, and cell death by pyroptosis. Furthermore, reactive oxygen species (ROS), act as an intermediate to activate NLRP3, contributing to subsequent inflammatory cascades and cell damage. Moreover, increased production of ROS may elevate nitric oxide (NO) catabolism and consequently decrease NO bioavailability. NO has many roles in immune responses, including the regulation of signaling cascades. At the site of inflammation, vascular endothelium is crucial in the regulation of systemic inflammation with important implications for homeostasis. In this review, we present the important role of NLRP3 activation in exacerbating oxidative stress and endothelial dysfunction. Considering that the causes related to these processes and inflammation in PE remain a challenge for clinical practice, the use of drugs related to inhibition of the NLRP3 may be a good option for future solutions for this disease. Full article

(This article belongs to the Special Issue The Pathophysiology of Preeclampsia and Eclampsia)

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23 pages, 13127 KiB

Open AccessReview

Pathological AT1R-B2R Protein Aggregation and Preeclampsia

by Ursula Quitterer and Said AbdAlla

Cells 2021, 10(10), 2609; https://doi.org/10.3390/cells10102609 - 1 Oct 2021

Cited by 6 | Viewed by 4168

Abstract

Preeclampsia is one of the most frequent and severe complications of pregnancy. Symptoms of preeclampsia usually occur after 20 weeks of pregnancy and include hypertension and kidney dysfunction with proteinuria. Up to now, delivery of the infant has been the most effective and [...] Read more.

Preeclampsia is one of the most frequent and severe complications of pregnancy. Symptoms of preeclampsia usually occur after 20 weeks of pregnancy and include hypertension and kidney dysfunction with proteinuria. Up to now, delivery of the infant has been the most effective and life-saving treatment to alleviate symptoms of preeclampsia because a causative treatment does not exist, which could prolong a pregnancy complicated with preeclampsia. Preeclampsia is a complex medical condition, which is attributed to a variety of different risk factors and causes. Risk factors account for insufficient placentation and impaired vasculogenesis and finally culminate in this life-threatening condition of pregnancy. Despite progress, many pathomechanisms and causes of preeclampsia are still incompletely understood. In recent years, it was found that excessive protein complex formation between G-protein-coupled receptors is a common sign of preeclampsia. Specifically, the aberrant heteromerization of two vasoactive G-protein-coupled receptors (GPCRs), the angiotensin II AT1 receptor and the bradykinin B2 receptor, is a causative factor of preeclampsia symptoms. Based on this knowledge, inhibition of abnormal GPCR protein complex formation is an experimental treatment approach of preeclampsia. This review summarizes the impact of pathological GPCR protein aggregation on symptoms of preeclampsia and delineates potential new therapeutic targets. Full article

(This article belongs to the Special Issue The Pathophysiology of Preeclampsia and Eclampsia)

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12 pages, 724 KiB

Open AccessStudy Protocol

PROVE—Pre-Eclampsia Obstetric Adverse Events: Establishment of a Biobank and Database for Pre-Eclampsia

by Lina Bergman, Karl Bergman, Eduard Langenegger, Ashley Moodley, Stephanie Griffith-Richards, Johan Wikström, David Hall, Lloyd Joubert, Philip Herbst, Sonja Schell, Teelkien van Veen, Michael Belfort, Stephen Y. C. Tong, Susan Walker, Roxanne Hastie and Catherine Cluver

Cells 2021, 10(4), 959; https://doi.org/10.3390/cells10040959 - 20 Apr 2021

Cited by 13 | Viewed by 4956

Abstract

Pre-eclampsia is a leading cause of maternal and perinatal morbidity and mortality. The burden of disease lies mainly in low-middle income countries. The aim of this project is to establish a pre-eclampsia biobank in South Africa to facilitate research in the field of [...] Read more.

Pre-eclampsia is a leading cause of maternal and perinatal morbidity and mortality. The burden of disease lies mainly in low-middle income countries. The aim of this project is to establish a pre-eclampsia biobank in South Africa to facilitate research in the field of pre-eclampsia with a focus on phenotyping severe disease.The approach of our biobank is to collect biological specimens, detailed clinical data, tests, and biophysical examinations, including magnetic resonance imaging (MRI) of the brain, MRI of the heart, transcranial Doppler, echocardiography, and cognitive function tests.Women diagnosed with pre-eclampsia and normotensive controls are enrolled in the biobank at admission to Tygerberg University Hospital (Cape Town, South Africa). Biological samples and clinical data are collected at inclusion/delivery and during the hospital stay. Special investigations as per above are performed in a subset of women. After two months, women are followed up by telephonic interviews. This project aims to establish a biobank and database for severe organ complications of pre-eclampsia in a low-middle income country where the incidence of pre-eclampsia with organ complications is high. The study integrates different methods to investigate pre-eclampsia, focusing on improved understanding of pathophysiology, prediction of organ complications, and potentially future drug evaluation and discovery. Full article

(This article belongs to the Special Issue The Pathophysiology of Preeclampsia and Eclampsia)

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