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Molecular Mechanisms of Pregnancy-Related Vascular Remodeling and Pregnancy 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 (30 April 2022) | Viewed by 52473

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Special Issue Editors

Prof. Dr. Nihar Ranjan Nayak

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Guest Editor

Department of Obstetrics and Gynecology, UMKC School of Medicine, Kansas City, MO 64108, USA
Interests: pregnancy; pregnancy disorders placenta; vascular remodeling; vascular development; preeclampsia
Special Issues, Collections and Topics in MDPI journals

Prof. David K. Stevenson

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Guest Editor

Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine, Stanford, CA, USA
Interests: neonatology; placenta; pregnancy; neonatal jaundice; maternal–fetal interaction; vascular complications in pregnancy

Special Issue Information

Dear Colleagues,

Complications of pregnancy, including preeclampsia, HELLP syndrome, placental abruption, preterm birth, and intrauterine growth restriction, have enormous impacts on the lifelong health of mothers and the babies born to the mothers with these conditions. Normal pregnancy involves dramatic maternal and placental vascular remodeling and adaptations throughout pregnancy, and failure of these vascular changes contributes to the development of most pregnancy complications. Although defects in trophoblast function and placentation and the resulting vascular dysfunction have been implicated in the pathophysiology of pregnancy complications, the molecular underpinnings of such defects are poorly understood. The goal of this Special Issue is to publish high-quality manuscripts with particular emphasis on molecular understanding of the pathophysiology of pregnancy-related vascular adaptations and complications. We welcome reviews, new methods, short communications, and original articles covering all aspects of uterine and placental vascular development and remodeling, maternal vascular adaptations and dysfunctions (both during pregnancy and in the postpartum period), fetal and neonatal diseases associated with vascular complications of pregnancy, and clinical studies and experimental models addressing pregnancy-related vascular complications.

Prof. Nihar Ranjan Nayak
Prof. David K. Stevenson
Guest Editors

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Keywords

Vascular remodeling
Angiogenesis
Angiogenic factors
Spiral artery
Placenta
Decidua
Pregnancy disorders
Trophoblast invasion
Maternal–fetal interaction
Vascular complications in pregnancy
Fetal and neonatal disorders
Developmental origins of health and disease

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Published Papers (10 papers)

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Editorial

Jump to: Research, Review

3 pages, 171 KiB

Open AccessEditorial

Molecular Mechanisms of Pregnancy-Related Vascular Remodeling and Pregnancy Complications

by David K. Stevenson, Ronald J. Wong and Nihar R. Nayak

Int. J. Mol. Sci. 2023, 24(4), 3712; https://doi.org/10.3390/ijms24043712 - 13 Feb 2023

Cited by 1 | Viewed by 1498

Abstract

The purpose of this editorial is to highlight the various observations made in this Special Issue in the International Journal of Molecular Sciences [...] Full article

(This article belongs to the Special Issue Molecular Mechanisms of Pregnancy-Related Vascular Remodeling and Pregnancy Complications)

Research

Jump to: Editorial, Review

22 pages, 4454 KiB

Open AccessArticle

Maternal Neutrophil Depletion Fails to Avert Systemic Lipopolysaccharide-Induced Early Pregnancy Defects in Mice

by Sourav Panja, John T. Benjamin and Bibhash C. Paria

Int. J. Mol. Sci. 2021, 22(15), 7932; https://doi.org/10.3390/ijms22157932 - 25 Jul 2021

Cited by 1 | Viewed by 3031

Abstract

Maternal infection-induced early pregnancy complications arise from perturbation of the immune environment at the uterine early blastocyst implantation site (EBIS), yet the underlying mechanisms remain unclear. Here, we demonstrated in a mouse model that the progression of normal pregnancy from days 4 to 6 induced steady migration of leukocytes away from the uterine decidual stromal zone (DSZ) that surrounds the implanted blastocyst. Uterine macrophages were found to be CD206⁺ M2-polarized. While monocytes were nearly absent in the DSZ, DSZ cells were found to express monocyte marker protein Ly6C. Systemic endotoxic lipopolysaccharide (LPS) exposure on day 5 of pregnancy led to: (1) rapid (at 2 h) induction of neutrophil chemoattractants that promoted huge neutrophil infiltrations at the EBISs by 24 h; (2) rapid (at 2 h) elevation of mRNA levels of MyD88, but not Trif, modulated cytokines at the EBISs; and (3) dose-dependent EBIS defects by day 7 of pregnancy. Yet, elimination of maternal neutrophils using anti-Ly6G antibody prior to LPS exposure failed to avert LPS-induced EBIS defects allowing us to suggest that activation of Tlr4-MyD88 dependent inflammatory pathway is involved in LPS-induced defects at EBISs. Thus, blocking the activation of the Tlr4-MyD88 signaling pathway may be an interesting approach to prevent infection-induced pathology at EBISs. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Pregnancy-Related Vascular Remodeling and Pregnancy Complications)

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12 pages, 4323 KiB

Open AccessArticle

Alpha-1 Antitrypsin-Induced Endoplasmic Reticulum Stress Promotes Invasion by Extravillous Trophoblasts

by Kanoko Yoshida, Kazuya Kusama, Yuta Fukushima, Takako Ohmaru-Nakanishi, Kiyoko Kato and Kazuhiro Tamura

Int. J. Mol. Sci. 2021, 22(7), 3683; https://doi.org/10.3390/ijms22073683 - 1 Apr 2021

Cited by 17 | Viewed by 2952

Abstract

Alpha-1 antitrypsin (A1AT) is a glycoprotein that has been shown to protect tissues from proteolytic damage under various inflammatory conditions. Several studies show that A1AT may be associated with pre-eclampsia. However, the role of A1AT expression in placental physiology is not fully understood. In the present study, we aim to characterize the expression and function of placental A1AT. A1AT knockdown is found to reduce the expression of the serine protease HTRA1 in a trophoblast cell line. In addition, A1AT overexpression (A1AT-OE) increases the expression of HTRA1, IL6, CXCL8, and several markers of endoplasmic reticulum (ER) stress. Treatment with tunicamycin or thapsigargin, which induces ER stress, increases HTRA1 expression. Furthermore, immunohistochemistry reveals that HTRA1 is expressed in trophoblasts and the endometrial decidual cells of human placentas. An invasion assay shows that A1AT and HTRA1 stimulate cell invasion, but treatment with the ER stress inhibitors reduces the expression of HTRA1 and ER stress markers and prevents cell invasion in A1AT-OE trophoblasts. These results suggest that endogenous A1AT regulates inflammatory cytokine expression and HTRA1-induced trophoblast invasion via the induction of ER stress. It is concluded that an imbalance in the functional link between A1AT and ER stress at the maternal–fetal interface might cause abnormal placental development. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Pregnancy-Related Vascular Remodeling and Pregnancy Complications)

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Review

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21 pages, 3143 KiB

Open AccessReview

Modeling Trophoblast Cell-Guided Uterine Spiral Artery Transformation in the Rat

by Vinay Shukla and Michael J. Soares

Int. J. Mol. Sci. 2022, 23(6), 2947; https://doi.org/10.3390/ijms23062947 - 9 Mar 2022

Cited by 20 | Viewed by 5973

Abstract

The rat possesses hemochorial placentation with deep intrauterine trophoblast cell invasion and trophoblast-guided uterine spiral artery remodeling, which resembles human placentation. Uterine spiral arteries are extensively remodeled to deliver sufficient supply of maternal blood and nutrients to the developing fetus. Inadequacies in these key processes negatively impact fetal growth and development. Recent innovations in genome editing combined with effective phenotyping strategies have provided new insights into placental development. Application of these research approaches has highlighted both conserved and species-specific features of hemochorial placentation. The review provides foundational information on rat hemochorial placental development and function during physiological and pathological states, especially as related to the invasive trophoblast cell-guided transformation of uterine spiral arteries. Our goal is to showcase the utility of the rat as a model for in vivo mechanistic investigations targeting regulatory events within the uterine-placental interface. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Pregnancy-Related Vascular Remodeling and Pregnancy Complications)

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19 pages, 1120 KiB

Open AccessReview

Defective Uteroplacental Vascular Remodeling in Preeclampsia: Key Molecular Factors Leading to Long Term Cardiovascular Disease

by Kirim Hong, Soo Hyun Kim, Dong Hyun Cha and Hee Jin Park

Int. J. Mol. Sci. 2021, 22(20), 11202; https://doi.org/10.3390/ijms222011202 - 18 Oct 2021

Cited by 33 | Viewed by 6251

Abstract

Preeclampsia is a complex hypertensive disorder in pregnancy which can be lethal and is responsible for more than 70,000 maternal deaths worldwide every year. Besides the higher risk of unfavorable obstetric outcomes in women with preeclampsia, another crucial aspect that needs to be considered is the association between preeclampsia and the postpartum cardiovascular health of the mother. Currently, preeclampsia is classified as one of the major risk factors of cardiovascular disease (CVD) in women, which doubles the risk of venous thromboembolic events, stroke, and ischemic heart disease. In order to comprehend the pathophysiology behind the linkage between preeclampsia and the development of postpartum CVD, a thorough understanding of the abnormal uteroplacental vascular remodeling in preeclampsia is essential. Therefore, this review aims to summarize the current knowledge of the defective process of spiral artery remodeling in preeclampsia and how the resulting placental damage leads to excessive angiogenic imbalance and systemic inflammation in long term CVD. Key molecular factors in the pathway—including novel findings of microRNAs—will be discussed with suggestions of future management strategies of preventing CVD in women with a history of preeclampsia. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Pregnancy-Related Vascular Remodeling and Pregnancy Complications)

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18 pages, 778 KiB

Open AccessReview

Non-Coding RNAs in Preeclampsia—Molecular Mechanisms and Diagnostic Potential

by Jelena Munjas, Miron Sopić, Aleksandra Stefanović, Rok Košir, Ana Ninić, Ivana Joksić, Tamara Antonić, Vesna Spasojević-Kalimanovska and Uršula Prosenc Zmrzljak

Int. J. Mol. Sci. 2021, 22(19), 10652; https://doi.org/10.3390/ijms221910652 - 30 Sep 2021

Cited by 33 | Viewed by 5480

Abstract

Preeclampsia (PE) is a leading cause of maternal and neonatal morbidity and mortality worldwide. Defects in trophoblast invasion, differentiation of extravillous trophoblasts and spiral artery remodeling are key factors in PE development. Currently there are no predictive biomarkers clinically available for PE. Recent technological advancements empowered transcriptome exploration and led to the discovery of numerous non-coding RNA species of which microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) are the most investigated. They are implicated in the regulation of numerous cellular functions, and as such are being extensively explored as potential biomarkers for various diseases. Altered expression of numerous lncRNAs and miRNAs in placenta has been related to pathophysiological processes that occur in preeclampsia. In the following text we offer summary of the latest knowledge of the molecular mechanism by which lnRNAs and miRNAs (focusing on the chromosome 19 miRNA cluster (C19MC)) contribute to pathophysiology of PE development and their potential utility as biomarkers of PE, with special focus on sample selection and techniques for the quantification of lncRNAs and miRNAs in maternal circulation. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Pregnancy-Related Vascular Remodeling and Pregnancy Complications)

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25 pages, 16608 KiB

Open AccessReview

Roles of Two Small Leucine-Rich Proteoglycans Decorin and Biglycan in Pregnancy and Pregnancy-Associated Diseases

by Chidambra D. Halari, Michael Zheng and Peeyush K. Lala

Int. J. Mol. Sci. 2021, 22(19), 10584; https://doi.org/10.3390/ijms221910584 - 30 Sep 2021

Cited by 8 | Viewed by 4087

Abstract

Two small leucine-rich proteoglycans (SLRP), decorin and biglycan, play important roles in structural–functional integrity of the placenta and fetal membranes, and their alterations can result in several pregnancy-associated diseases. In this review, we briefly discuss normal placental structure and functions, define and classify SLRPs, and then focus on two SLRPs, decorin (DCN) and biglycan (BGN). We discuss the consequences of deletions/mutations of DCN and BGN. We then summarize DCN and BGN expression in the pregnant uterus, myometrium, decidua, placenta, and fetal membranes. Actions of these SLRPs as ligands are then discussed in the context of multiple binding partners in the extracellular matrix and cell surface (receptors), as well as their alterations in pathological pregnancies, such as preeclampsia, fetal growth restriction, and preterm premature rupture of membranes. Lastly, we raise some unanswered questions as food for thought. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Pregnancy-Related Vascular Remodeling and Pregnancy Complications)

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21 pages, 2591 KiB

Open AccessReview

The Impact of Hypoxia in Early Pregnancy on Placental Cells

by Hui Zhao, Ronald J. Wong and David K. Stevenson

Int. J. Mol. Sci. 2021, 22(18), 9675; https://doi.org/10.3390/ijms22189675 - 7 Sep 2021

Cited by 76 | Viewed by 10257

Abstract

Oxygen levels in the placental microenvironment throughout gestation are not constant, with severe hypoxic conditions present during the first trimester. This hypoxic phase overlaps with the most critical stages of placental development, i.e., blastocyst implantation, cytotrophoblast invasion, and spiral artery remodeling initiation. Dysregulation of any of these steps in early gestation can result in pregnancy loss and/or adverse pregnancy outcomes. Hypoxia has been shown to regulate not only the self-renewal, proliferation, and differentiation of trophoblast stem cells and progenitor cells, but also the recruitment, phenotype, and function of maternal immune cells. In this review, we will summarize how oxygen levels in early placental development determine the survival, fate, and function of several important cell types, e.g., trophoblast stem cells, extravillous trophoblasts, syncytiotrophoblasts, uterine natural killer cells, Hofbauer cells, and decidual macrophages. We will also discuss the cellular mechanisms used to cope with low oxygen tensions, such as the induction of hypoxia-inducible factor (HIF) or mammalian target of rapamycin (mTOR) signals, regulation of the metabolic pathway, and adaptation to autophagy. Understanding the beneficial roles of hypoxia in early placental development will provide insights into the root cause(s) of some pregnancy disorders, such as spontaneous abortion, preeclampsia, and intrauterine growth restriction. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Pregnancy-Related Vascular Remodeling and Pregnancy Complications)

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16 pages, 2662 KiB

Open AccessReview

HIV Associated Preeclampsia: A Multifactorial Appraisal

by Thajasvarie Naicker, Nalini Govender, Tashlen Abel, Nitalia Naidoo, Merantha Moodley, Yazira Pillay, Shoohana Singh, Olive Pearl Khaliq and Jagidesa Moodley

Int. J. Mol. Sci. 2021, 22(17), 9157; https://doi.org/10.3390/ijms22179157 - 25 Aug 2021

Cited by 9 | Viewed by 4962

Abstract

Introduction: This review explores angiogenesis, vascular dysfunction, the complement system, RAAS, apoptosis and NETosis as potential pathways that are dysregulated during preeclampsia, HIV infection and ART usage. Results: HIV-1 accessory and matrix proteins are protagonists for the elevation of oxidative stress, apoptosis, angiogenesis, and elevation of adhesion markers. Despite the immunodeficiency during HIV-1 infection, HIV-1 exploits our cellular defence arsenal by escaping cell-mediated lysis, yet HIV-1 infectivity is enhanced via C5a release of TNF-α and IL-6. This review demonstrates that PE is an oxidatively stressed microenvironment associated with increased apoptosis and NETosis, but with a decline in angiogenesis. Immune reconstitution in the duality of HIV-1 and PE by protease inhibitors, HAART and nucleoside reverse transcriptase, affect similar cellular pathways that eventuate in loss of endothelial cell integrity and, hence, its dysfunction. Conclusions: HIV-1 infection, preeclampsia and ARTs differentially affect endothelial cell function. In the synergy of both conditions, endothelial dysfunction predominates. This knowledge will help us to understand the effect of HIV infection and ART on immune reconstitution in preeclampsia. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Pregnancy-Related Vascular Remodeling and Pregnancy Complications)

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24 pages, 1034 KiB

Open AccessReview

Uteroplacental Circulation in Normal Pregnancy and Preeclampsia: Functional Adaptation and Maladaptation

by Xiangqun Hu and Lubo Zhang

Int. J. Mol. Sci. 2021, 22(16), 8622; https://doi.org/10.3390/ijms22168622 - 11 Aug 2021

Cited by 29 | Viewed by 6175

Abstract

Uteroplacental blood flow increases as pregnancy advances. Adequate supply of nutrients and oxygen carried by uteroplacental blood flow is essential for the well-being of the mother and growth/development of the fetus. The uteroplacental hemodynamic change is accomplished primarily through uterine vascular adaptation, involving hormonal regulation of myogenic tone, vasoreactivity, release of vasoactive factors and others, in addition to the remodeling of spiral arteries. In preeclampsia, hormonal and angiogenic imbalance, proinflammatory cytokines and autoantibodies cause dysfunction of both endothelium and vascular smooth muscle cells of the uteroplacental vasculature. Consequently, the vascular dysfunction leads to increased vascular resistance and reduced blood flow in the uteroplacental circulation. In this article, the (mal)adaptation of uteroplacental vascular function in normal pregnancy and preeclampsia and underlying mechanisms are reviewed. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Pregnancy-Related Vascular Remodeling and Pregnancy Complications)

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