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Pathogenesis of Pregnancy-Related Complications

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (29 February 2020) | Viewed by 68049

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Prof. Dr. Ilona Hromadnikova

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Head, Department of Molecular Biology and Cell Pathology, Third Faculty of Medicine, Charles University, Prague, Czech Republic
Interests: pregnancy-related complications; pathogenesis; diagnosis/prognosis biomarkers; epigenetics; extracellular nucleic acids in maternal circulation; postpartum/postnatal short-term and long-term consequences
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Dear Colleagues,

Preeclampsia, HELLP syndrome, fetal growth restriction, gestational diabetes mellitus, preterm birth (preterm prelabor rupture of membranes and spontaneous preterm labor) and invasive placenta are major complications responsible for maternal and perinatal morbidity and mortality. Elucidation of the molecular mechanisms related to the initiation and onset of severe pregnancy-related complications enables the identification of potential biomarkers for early stratification of at-risk patients. Additionally, pregnancy-related complications induce long-term metabolic and vascular abnormalities that might increase the overall risk of metabolic, cardiovascular, cerebrovascular, kidney, and other diseases later in life in mothers and their offspring. This Special Issue aims to provide an overview of the latest research on the molecular and cellular mechanisms associated with pregnancy-related complications, as well as the contribution of pregnancy-related complications to the later development of various diseases. This will include underlying mechanisms, diagnostics/prognostics and treatment strategies associated with pregnancy-related complications, and will be of interest to scientists and clinicians working in this fastly expanding area.

Prof. Dr. Ilona Hromadnikova
Guest Editor

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Keywords

gestational hypertension
preeclampsia
HELLP syndrome
fetal growth restriction
gestational diabetes mellitus
preterm birth
invasive placenta

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Related Special Issue

Pathogenesis of Pregnancy-Related Complication (5th Edition) in International Journal of Molecular Sciences (3 articles)

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10 pages, 17053 KiB

Open AccessArticle

Increased Angiogenesis and Lymphangiogenesis in the Placental Villi of Women with Chronic Venous Disease during Pregnancy

by Miguel A Ortega, Miguel A Saez, Oscar Fraile-Martínez, Ángel Asúnsolo, Leonel Pekarek, Coral Bravo, Santiago Coca, Felipe Sainz, Melchor Álvarez- Mon, Julia Buján and Natalio García-Honduvilla

Int. J. Mol. Sci. 2020, 21(7), 2487; https://doi.org/10.3390/ijms21072487 - 3 Apr 2020

Cited by 28 | Viewed by 3228

Abstract

Pregnancy is a period in a woman’s life associated with an increased risk of developing lower extremity chronic venous disease (CVD). Pregnancy-associated CVD is associated with changes in placental villi. We investigated angiogenesis and lymphangiogenesis in the placental villi of women with CVD during pregnancy compared with healthy controls with no history of CVD (HC). An observational, analytical, and prospective cohort study was conducted on 114 women in their third trimester of pregnancy (32 weeks). Sixty-two participants were clinically diagnosed with CVD. In parallel, 52 controls with no history of CVD (HC) were studied. Gene and protein expression of CD31, podoplanin (D2-40), Flt-1, and placental growth factor (PIGF) was analysed by real-time polymerase chain reaction (RT-qPCR) and immunohistochemistry. CD31 and D2-40 gene expression was significantly greater in the placental villi of women with CVD, as were the numbers of vessels positive for CD31 and D2-40. Significantly higher gene and protein expression of Flt-1 and PIGF was observed in the placental villi of women with CVD. Histological analysis showed more placental villi with periodic acid of Schiff (PAS)-positive material in women with CVD. Our results show a connection between pregnancy-associated CVD and leading to higher proangiogenic and lymphangiogenic activity in placental villi. Full article

(This article belongs to the Special Issue Pathogenesis of Pregnancy-Related Complications)

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46 pages, 21669 KiB

Open AccessArticle

Diabetes Mellitus and Cardiovascular Risk Assessment in Mothers with a History of Gestational Diabetes Mellitus Based on Postpartal Expression Profile of MicroRNAs Associated with Diabetes Mellitus and Cardiovascular and Cerebrovascular Diseases

by Ilona Hromadnikova, Katerina Kotlabova, Lenka Dvorakova and Ladislav Krofta

Int. J. Mol. Sci. 2020, 21(7), 2437; https://doi.org/10.3390/ijms21072437 - 31 Mar 2020

Cited by 40 | Viewed by 5153

Abstract

Mothers with a history of gestational diabetes mellitus (GDM) have an increased risk of developing diabetes in the future and a lifelong cardiovascular risk. Postpartal expression profile of cardiovascular/cerebrovascular disease associated microRNAs was assessed 3–11 years after the delivery in whole peripheral blood of young and middle-aged mothers with a prior exposure to GDM with the aim to identify a high-risk group of mothers at risk of later development of diabetes mellitus and cardiovascular/cerebrovascular diseases who would benefit from implementation of early primary prevention strategies and long-term follow-up. The hypothesis of the assessment of cardiovascular risk in women was based on the knowledge that a series of microRNAs play a role in the pathogenesis of diabetes mellitus and cardiovascular/cerebrovascular diseases. Abnormal expression profile of multiple microRNAs was found in women with a prior exposure to GDM (miR-1-3p, miR-16-5p, miR-17-5p, miR-20a-5p, miR-20b-5p, miR-21-5p, miR-23a-3p, miR-24-3p, miR-26a-5p, miR-29a-3p, miR-100-5p, miR-103a-3p, miR-125b-5p, miR-126-3p, miR-130b-3p, miR-133a-3p, miR-143-3p, miR-145-5p, miR-146a-5p, miR-181a-5p, miR-195-5p, miR-199a-5p, miR-221-3p, miR-342-3p, miR-499a-5p, and-miR-574-3p). Postpartal combined screening of miR-1-3p, miR-16-5p, miR-17-5p, miR-20b-5p, miR-21-5p, miR-23a-3p, miR-26a-5p, miR-29a-3p, miR-103a-3p, miR-133a-3p, miR-146a-5p, miR-181a-5p, miR-195-5p, miR-199a-5p, miR-221-3p, and miR-499a-5p showed the highest accuracy for the identification of mothers with a prior exposure to GDM at a higher risk of later development of cardiovascular/cerebrovascular diseases (AUC 0.900, p < 0.001, sensitivity 77.48%, specificity 93.26%, cut off >0.611270413). It was able to identify 77.48% mothers with an increased cardiovascular risk at 10.0% FPR. Any of changes in epigenome (upregulation of miR-16-5p, miR-17-5p, miR-29a-3p, and miR-195-5p) that were induced by GDM-complicated pregnancy are long-acting and may predispose mothers affected with GDM to later development of diabetes mellitus and cardiovascular/cerebrovascular diseases. In addition, novel epigenetic changes (upregulation of serious of microRNAs) appeared in a proportion of women that were exposed to GDM throughout the postpartal life. Likewise, a previous occurrence of either GH, PE, and/or FGR, as well as a previous occurrence of GDM, is associated with the upregulation of miR-1-3p, miR-17-5p, miR-20a-5p, miR-20b-5p, miR-29a-3p, miR-100-5p, miR-125b-5p, miR-126-3p, miR-130b-3p, miR-133a-3p, miR-143-3p, miR-145-5p, miR-146a-5p, miR-181a-5p, miR-199a-5p, miR-221-3p, and miR-499a-5p. On the other hand, upregulation of miR-16-5p, miR-21-5p, miR-23a-3p, miR-24-3p, miR-26a-5p, miR-103a-3p, miR-195-5p, miR-342-3p, and miR-574-3p represents a unique feature of aberrant expression profile of women with a prior exposure to GDM. Screening of particular microRNAs may stratify a high-risk group of mothers with a history of GDM who might benefit from implementation of early primary prevention strategies. Full article

(This article belongs to the Special Issue Pathogenesis of Pregnancy-Related Complications)

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15 pages, 4014 KiB

Open AccessArticle

SERPINA1 Peptides in Urine as A Potential Marker of Preeclampsia Severity

by Natalia Starodubtseva, Natalia Nizyaeva, Oleg Baev, Anna Bugrova, Masara Gapaeva, Kamilla Muminova, Alexey Kononikhin, Vladimir Frankevich, Eugene Nikolaev and Gennady Sukhikh

Int. J. Mol. Sci. 2020, 21(3), 914; https://doi.org/10.3390/ijms21030914 - 30 Jan 2020

Cited by 22 | Viewed by 4099

Abstract

Preeclampsia (PE) is a multisystem disorder associated with pregnancy and its frequency varies from 5 to 20 percent of pregnancies. Although a number of preeclampsia studies have been carried out, there is no consensus about disease etiology and pathogenesis so far. Peptides of SERPINA1 (α1-antitrypsin) in urine remain one of the most promising peptide markers of PE. In this study the diagnostic potential of urinary α1-antitrypsin peptides in PE was evaluated. The urinary peptidome composition of 79 pregnant women with preeclampsia (PE), chronic arterial hypertension (CAH), and a control group was investigated. Mann–Whitney U-test (p < 0.05) revealed seven PE specific SERPINA1 peptides demonstrating 52% sensitivity and 100% specificity. SERPINA1 in urine has been associated with the most severe forms of preeclampsia (p = 0.014), in terms of systolic hypertension (p = 0.01) and proteinuria (p = 0.006). According to Spearman correlation analysis, the normalized intensity of SERPINA1 urinary peptides has a similar diagnostic pattern with known diagnostic PE markers, such as sFLT/PLGF. SERPINA1 peptides were not urinary excreted in superimposed PE (PE with CAH), which is a milder form of PE. An increase in expression of SERPINA1 in the structural elements of the placenta during preeclampsia reflects a protective mechanism against hypoxia. Increased synthesis of SERPINA1 in the trophoblast leads to protein accumulation in fibrinoid deposits. It may block syncytial knots and placenta villi, decreasing trophoblast invasion. Excretion of PE specific SERPINA1 peptides is associated with syncytiotrophoblast membrane destruction degradation and increased SERPINA1 staining. It confirms that the placenta could be the origin of SERPINA1 peptides in urine. Significant correlation (p < 0.05) of SERPINA1 expression in syncytiotrophoblast membrane and cytoplasm with the main clinical parameters of severe PE proves the role of SERPINA1 in PE pathogenesis. Estimation of SERPINA1 peptides in urine can be used as a diagnostic test of the severity of the condition to determine further treatment, particularly the need for urgent surgical delivery. Full article

(This article belongs to the Special Issue Pathogenesis of Pregnancy-Related Complications)

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27 pages, 24353 KiB

Open AccessArticle

Placenta-Specific Genes, Their Regulation During Villous Trophoblast Differentiation and Dysregulation in Preterm Preeclampsia

by Andras Szilagyi, Zsolt Gelencser, Roberto Romero, Yi Xu, Peter Kiraly, Amanda Demeter, Janos Palhalmi, Balazs A. Gyorffy, Kata Juhasz, Petronella Hupuczi, Katalin Adrienna Kekesi, Gudrun Meinhardt, Zoltan Papp, Sorin Draghici, Offer Erez, Adi Laurentiu Tarca, Martin Knöfler and Nandor Gabor Than

Int. J. Mol. Sci. 2020, 21(2), 628; https://doi.org/10.3390/ijms21020628 - 17 Jan 2020

Cited by 31 | Viewed by 6152

Abstract

The human placenta maintains pregnancy and supports the developing fetus by providing nutrition, gas-waste exchange, hormonal regulation, and an immunological barrier from the maternal immune system. The villous syncytiotrophoblast carries most of these functions and provides the interface between the maternal and fetal circulatory systems. The syncytiotrophoblast is generated by the biochemical and morphological differentiation of underlying cytotrophoblast progenitor cells. The dysfunction of the villous trophoblast development is implicated in placenta-mediated pregnancy complications. Herein, we describe gene modules and clusters involved in the dynamic differentiation of villous cytotrophoblasts into the syncytiotrophoblast. During this process, the immune defense functions are first established, followed by structural and metabolic changes, and then by peptide hormone synthesis. We describe key transcription regulatory molecules that regulate gene modules involved in placental functions. Based on transcriptomic evidence, we infer how villous trophoblast differentiation and functions are dysregulated in preterm preeclampsia, a life-threatening placenta-mediated obstetrical syndrome for the mother and fetus. In the conclusion, we uncover the blueprint for villous trophoblast development and its impairment in preterm preeclampsia, which may aid in the future development of non-invasive biomarkers for placental functions and early identification of women at risk for preterm preeclampsia as well as other placenta-mediated pregnancy complications. Full article

(This article belongs to the Special Issue Pathogenesis of Pregnancy-Related Complications)

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37 pages, 3582 KiB

Open AccessArticle

Evaluation of Vascular Endothelial Function in Young and Middle-Aged Women with Respect to a History of Pregnancy, Pregnancy-Related Complications, Classical Cardiovascular Risk Factors, and Epigenetics

by Ilona Hromadnikova, Katerina Kotlabova, Lenka Dvorakova and Ladislav Krofta

Int. J. Mol. Sci. 2020, 21(2), 430; https://doi.org/10.3390/ijms21020430 - 9 Jan 2020

Cited by 24 | Viewed by 4798

Abstract

The aim of the study was to examine the effect of previous pregnancies and classical cardiovascular risk factors on vascular endothelial function in a group of 264 young and middle-aged women 3 to 11 years postpartum. We examined microvascular functions by peripheral arterial tonometry and EndoPAT 2000 device with respect to a history of gestational hypertension, preeclampsia, fetal growth restriction, the severity of the disease with regard to the degree of clinical signs and delivery date. Besides, we compared Reactive Hyperemia Index (RHI) values and the prevalence of vascular endothelial dysfunction among the groups of women with normal and abnormal values of BMI, waist circumference, systolic and diastolic blood pressures, heart rate, total serum cholesterol levels, serum high-density lipoprotein cholesterol levels, serum low-density lipoprotein cholesterol levels, serum triglycerides levels, serum lipoprotein A levels, serum C-reactive protein levels, serum uric acid levels, and plasma homocysteine levels. Furthermore, we determined the effect of total number of pregnancies and total parity per woman, infertility and blood pressure treatment, presence of trombophilic gene mutations, current smoking of cigarettes, and current hormonal contraceptive use on the vascular endothelial function. We also examined the association between the vascular endothelial function and postpartum whole peripheral blood expression of microRNAs involved in pathogenesis of cardiovascular/cerebrovascular diseases (miR-1-3p, miR-16-5p, miR-17-5p, miR-20a-5p, miR-20b-5p, miR-21-5p, miR-23a-3p, miR-24-3p, miR-26a-5p, miR-29a-3p, miR-92a-3p, miR-100-5p, miR-103a-3p, miR-125b-5p, miR-126-3p, miR-130b-3p, miR-133a-3p, miR-143-3p, miR-145-5p, miR-146a-5p, miR-155-5p, miR-181a-5p, miR-195-5p, miR-199a-5p, miR-210-3p, miR-221-3p, miR-342-3p, miR-499a-5p, and miR-574-3p). A proportion of overweight women (17.94% and 20.59%) and women with central obesity (18.64% and 21.19%) had significantly lower RHI values at 10.0% false positive rate (FPR) both before and after adjustment of the data for the age of patients. At 10.0% FPR, a proportion of women with vascular endothelial dysfunction (RHI ≤ 1.67) was identified to have up-regulated expression profile of miR-1-3p (11.76%), miR-23a-3p (17.65%), and miR-499a-5p (18.82%) in whole peripheral blood. RHI values also negatively correlated with expression of miR-1-3p, miR-23a-3p, and miR-499a-5p in whole peripheral blood. Otherwise, no significant impact of other studied factors on vascular endothelial function was found. We suppose that screening of these particular microRNAs associated with vascular endothelial dysfunction may help to stratify a highly risky group of young and middle-aged women that would benefit from early implementation of primary prevention strategies. Nevertheless, it is obvious, that vascular endothelial dysfunction is just one out of multiple cardiovascular risk factors which has only a partial impact on abnormal expression of cardiovascular and cerebrovascular disease associated microRNAs in whole peripheral blood of young and middle-aged women. Full article

(This article belongs to the Special Issue Pathogenesis of Pregnancy-Related Complications)

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21 pages, 727 KiB

Open AccessReview

Gestational Diabetes Mellitus: A Harbinger of the Vicious Cycle of Diabetes

by Emilyn U. Alejandro, Therriz P. Mamerto, Grace Chung, Adrian Villavieja, Nawirah Lumna Gaus, Elizabeth Morgan and Maria Ruth B. Pineda-Cortel

Int. J. Mol. Sci. 2020, 21(14), 5003; https://doi.org/10.3390/ijms21145003 - 15 Jul 2020

Cited by 155 | Viewed by 27988

Abstract

Gestational diabetes mellitus (GDM), characterized by a transitory form of diabetes induced by insulin resistance and pancreatic β-cell dysfunction during pregnancy, has been identified as one of the major obstacles in achieving improved maternal and child health. Approximately 9–25% of pregnancies worldwide are impacted by the acute, long-term, and transgenerational health complications of this disease. Here, we discuss how GDM affects longstanding maternal and neonatal outcomes, as well as health risks that likely persist into future generations. In addition to the current challenges in the management and diagnosis of and the complications associated with GDM, we discuss current preclinical models of GDM to better understand the underlying pathophysiology of the disease and the timely need to increase our scientific toolbox to identify strategies to prevent and treat GDM, thereby advancing clinical care. Full article

(This article belongs to the Special Issue Pathogenesis of Pregnancy-Related Complications)

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23 pages, 895 KiB

Open AccessReview

Can Endothelial Glycocalyx Be a Major Morphological Substrate in Pre-Eclampsia?

by Marina M. Ziganshina, Ekaterina L. Yarotskaya, Nicolai V. Bovin, Stanislav V. Pavlovich and Gennady T. Sukhikh

Int. J. Mol. Sci. 2020, 21(9), 3048; https://doi.org/10.3390/ijms21093048 - 26 Apr 2020

Cited by 23 | Viewed by 3975

Abstract

Today pre-eclampsia (PE) is considered as a disease of various theories; still all of them agree that endothelial dysfunction is the leading pathogenic factor. Endothelial dysfunction is a sequence of permanent immune activation, resulting in the change of both the phenotype and the functions of an endothelial cell and of the extracellular layer associated with the cell membrane—endothelial glycocalyx (eGC). Numerous studies demonstrate that eGC mediates and regulates the key functions of endothelial cells including regulation of vascular tone and thromboresistance; and these functions are disrupted during PE. Taking into account that eGC and its components undergo alterations under pathological conditions leading to endothelial activation, it is supposed that eGC plays a certain role in pathogenesis of PE. Envisaging the eGC damage as a key factor of PE, might be a new approach to prevention, treatment, and rehabilitation of patients with PE. This approach could include the development of drugs protecting eGC and promoting regeneration of this structure. Since the issue of PE is far from being solved, any effort in this direction might be valuable. Full article

(This article belongs to the Special Issue Pathogenesis of Pregnancy-Related Complications)

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18 pages, 1824 KiB

Open AccessReview

Protein Misfolding during Pregnancy: New Approaches to Preeclampsia Diagnostics

by Elizaveta M. Gerasimova, Sergey A. Fedotov, Daniel V. Kachkin, Elena S. Vashukova, Andrey S. Glotov, Yury O. Chernoff and Aleksandr A. Rubel

Int. J. Mol. Sci. 2019, 20(24), 6183; https://doi.org/10.3390/ijms20246183 - 7 Dec 2019

Cited by 33 | Viewed by 11463

Abstract

Preeclampsia (PE) is a multisystem heterogeneous complication of pregnancy remaining a leading cause of maternal and perinatal morbidity and mortality over the world. PE has a large spectrum of clinical features and symptoms, which make diagnosis challenging. Despite a long period of studying, PE etiology is still unclear and there are no reliable rapid tests for early diagnosis of this disease. During the last decade, it was shown that proteins misfolding and aggregation are associated with PE. Several proteins, including amyloid beta peptide, transthyretin, alpha-1 antitrypsin, albumin, IgG k-free light chains, and ceruloplasmin are dysregulated in PE, resulting in toxic deposition of amyloid-like aggregates in the placenta and body fluids. It is also possible that aggregated proteins induce defective trophoblast invasion, placental ischemia, ER stress, and promote PE manifestation. The fact that protein aggregation is an emerging biomarker of PE provides an opportunity to develop new diagnostic approaches based on amyloids special features, such as Congo red (CR) staining and thioflavin T (ThT) enhanced fluorescence. Full article

(This article belongs to the Special Issue Pathogenesis of Pregnancy-Related Complications)

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