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Molecular Pathology of the Placenta in Pregnancy Complications
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Molecular Pathology of the Placenta in Pregnancy Complications

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: 20 May 2026 | Viewed by 3692

Special Issue Editors

Dr. Zoltan Kozinszky

E-Mail Website
Guest Editor
1. Capio Specialized Center for Gynecology, Postgången 53, 171 45 Solna, Sweden
2. Department of Obstetrics and Gynecology, University of Szeged, H-6725 Szeged, Hungary
Interests: molecular; ultrasound and clinical characterization of pregnancy complications; placental histology
Special Issues, Collections and Topics in MDPI journals
Dr. Andrea Suranyi

E-Mail Website
Guest Editor
Department of Obstetrics and Gynecology, University of Szeged, H-6725 Szeged, Hungary
Interests: perinatal ultrasound; serum markers for complications of pregnancy; histopathology of the placenta; neonatal pathological conditions
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Trophoblast invasion is essential in early pregnancy for remodeling maternal spiral arteries and ensuring adequate placental blood flow to support fetal development. This process involves three trophoblast subtypes: syncytiotrophoblast, responsible for nutrient exchange and hormone secretion; cytotrophoblast, which acts as a proliferative progenitor; and extravillous trophoblast, which invades maternal tissue and remodels vasculature. Dysregulated trophoblast invasion is linked to pregnancy complications such as preeclampsia, intrauterine growth restriction, gestational diabetes mellitus (GDM), and hypertensive disorders. Several maternal serum biomarkers reflect placental function, including placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1), pregnancy-associated plasma protein A (PAPP-A) and human chorionic gonadotropin (hCG), as well as endoglin and laeverin. Endoglin, a TGF-β co-receptor, is key in angiogenesis, while laeverin, expressed by extravillous trophoblasts, aids invasion. Despite this, many placental proteins and molecular factors—such as inflammatory cytokines (TNF-α, IL-6), angiogenic modulators (angiopoietins), extracellular matrix proteins, and oxidative stress markers—are underexplored in maternal serum. Environmental factors like hypoxia, metabolic status, immune interactions, epigenetic regulation, and signaling pathways (Notch, Wnt, TGF-β) also affect trophoblast function. The limited profiling of these molecules presents a research gap in early prediction of complications like GDM and hypertensive disorders. New insights addressing these gaps are awaited to enhance biomarker discovery, diagnosis, and therapeutic strategies for improved maternal-fetal outcomes. This Special Issue also focuses on new technical tools in this field: organoids/assembloids, spatial transcriptomics, spatial proteomics, single-cell epigenomics/transcriptomics and targeted delivery to the placenta.

We look forward to receiving your contributions.

Dr. Zoltan Kozinszky
Dr. Andrea Suranyi
Guest Editors

Manuscript Submission Information

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Keywords

  • pregnancy complications
  • placental histology
  • biomarker
  • trophoblast invasion
  • molecular diagnostics and therapeutics

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Published Papers (5 papers)

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Research

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16 pages, 697 KB  
Article
Angiogenic Imbalance in Preeclampsia: Profiling VEGF A, sFlt1, PlGF, and sFlt1/PlGF Ratios
by Alexandru-Dan Assani, Lidia Boldeanu, Marius Bogdan Novac, Mohamed-Zakaria Assani, Isabela Siloși, Mihail Virgil Boldeanu, Anda Lorena Dijmărescu, Maria-Magdalena Manolea, Venera Cristina Dinescu and Constantin-Cristian Văduva
Int. J. Mol. Sci. 2026, 27(5), 2438; https://doi.org/10.3390/ijms27052438 - 6 Mar 2026
Viewed by 124
Abstract
Preeclampsia involves an angiogenic imbalance, but circulating vascular endothelial growth factor A (VEGF A) remains inconsistently described, particularly in relation to maternal adiposity. We studied 90 second-trimester pregnancies, 30 uncomplicated and 60 with preeclampsia, recording maternal body mass index (BMI) and gestational age [...] Read more.
Preeclampsia involves an angiogenic imbalance, but circulating vascular endothelial growth factor A (VEGF A) remains inconsistently described, particularly in relation to maternal adiposity. We studied 90 second-trimester pregnancies, 30 uncomplicated and 60 with preeclampsia, recording maternal body mass index (BMI) and gestational age at sampling. Serum soluble fms-like tyrosine kinase 1 (sFlt1), placental growth factor (PlGF), and VEGF A were measured by enzyme-linked immunosorbent assay (ELISA), and the sFlt1-to-PlGF ratio was calculated. Preeclampsia was associated with higher pre-pregnancy and pregnancy BMI, lower PlGF, and an approximately threefold higher sFlt1-to-PlGF ratio, while sFlt1 alone was only borderline higher. VEGF A was elevated in preeclampsia and rose across higher sFlt1-to-PlGF ratio categories, supporting the interpretation of VEGF A within the integrated sFlt1,PlGF axis rather than as an isolated signal. Full article
(This article belongs to the Special Issue Molecular Pathology of the Placenta in Pregnancy Complications)
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14 pages, 1619 KB  
Article
Integrative Analysis of Placental Methylomes Identifies Epigenetically Regulated Genes Implicated in Fetal Growth Restriction
by Magdalena Bednarek-Jędrzejek, Olga Taryma-Leśniak, Małgorzata Poniatowska, Mateusz Cejko, Katarzyna Maksym, Sylwia Dzidek, Małgorzata Blatkiewicz, Ewa Kwiatkowska, Andrzej Torbé and Sebastian Kwiatkowski
Int. J. Mol. Sci. 2026, 27(3), 1448; https://doi.org/10.3390/ijms27031448 - 31 Jan 2026
Viewed by 532
Abstract
Fetal growth restriction (FGR) is a major contributor to perinatal morbidity and mortality, most commonly arising from placental dysfunction, with increasing evidence implicating aberrant DNA methylation in its pathogenesis. To identify robust epigenetic alterations associated with FGR, we analyzed placental chorionic villi from [...] Read more.
Fetal growth restriction (FGR) is a major contributor to perinatal morbidity and mortality, most commonly arising from placental dysfunction, with increasing evidence implicating aberrant DNA methylation in its pathogenesis. To identify robust epigenetic alterations associated with FGR, we analyzed placental chorionic villi from an in-house early-onset FGR cohort and compared them with a publicly available dataset (GSE100197). DNA methylation profiling was performed using Illumina EPIC (in-house) and 450K (public) arrays, processed with identical normalization and quality-control pipelines, including adjustment for gestational age and estimation of placental cell-type composition. Differentially methylated positions (DMPs) were identified using linear regression models, revealing 10,427 DMPs in the in-house cohort and 7467 in the public dataset, with 108 shared DMPs showing consistent direction of change across both cohorts. Promoter-associated DMPs were mapped to genes involved in angiogenesis, morphogenesis, immune regulation, and transcriptional control, including EPHA1, ANGPTL6, ITGAX, BCL11B, and CYP19A1, while additional novel candidates such as SLC39A12, YEATS4, and MIR515 family members were also identified. Functional annotation suggests that these methylation changes may influence pathways essential for placental vascular development and structural organization. Overall, this cross-cohort comparison highlights reproducible epigenetic signatures of FGR and underscores the need for standardized approaches to clarify the molecular mechanisms underlying placental insufficiency. Full article
(This article belongs to the Special Issue Molecular Pathology of the Placenta in Pregnancy Complications)
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17 pages, 4087 KB  
Article
Pandanus amaryllifolius and Tectona grandis Extracts Improve Fetal Outcomes in Streptozotocin-Induced Gestational Diabetes in Rats
by Sasitorn Kerdsuknirund, Pakanit Kupittayanant, Pattama Tongdee, Porntip Nimkuntod and Sajeera Kupittayanant
Int. J. Mol. Sci. 2026, 27(2), 857; https://doi.org/10.3390/ijms27020857 - 15 Jan 2026
Viewed by 304
Abstract
Gestational diabetes mellitus (GDM) causes adverse effects on both mothers and offspring. This study investigated the effects of a polyherbal formulation combining Pandanus amaryllifolius root and Tectona grandis leaf extracts on maternal and fetal outcomes in streptozotocin (STZ)-induced GDM rats, compared with metformin. [...] Read more.
Gestational diabetes mellitus (GDM) causes adverse effects on both mothers and offspring. This study investigated the effects of a polyherbal formulation combining Pandanus amaryllifolius root and Tectona grandis leaf extracts on maternal and fetal outcomes in streptozotocin (STZ)-induced GDM rats, compared with metformin. Pregnant rats were assigned to a non-diabetic reference group and diabetic groups, including an untreated diabetic group (negative control), a metformin-treated group (positive control), and diabetic groups treated with low, medium, or high doses of the pandan–teak formulation from gestation day 7 to 21. Medium and high doses significantly increased maternal body weight and pancreatic mass index (p < 0.05) without altering maternal glycemia or insulin levels. Fetal weight increased at medium and high doses, whereas crown–rump length increased only at the high dose. Placental index and fetal glucose levels decreased in a dose-dependent manner (p < 0.05), with no significant change in implantation loss. These findings suggest that the pandan–teak formulation may exert complementary actions that support placental–fetal glucose regulation and fetal growth while maintaining maternal glycemic stability, indicating its potential as a plant-based adjunct approach for gestational diabetes focused on fetal protection. Full article
(This article belongs to the Special Issue Molecular Pathology of the Placenta in Pregnancy Complications)
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13 pages, 1956 KB  
Article
Differential Immune Checkpoint Expression in CD4+ and CD4− NKT Cell Populations During Healthy Pregnancy
by Matyas Meggyes, Nagy U. David, Livia Mezosi, Fanni Vastag, Dora Kevey and Laszlo Szereday
Int. J. Mol. Sci. 2025, 26(16), 8022; https://doi.org/10.3390/ijms26168022 - 19 Aug 2025
Cited by 1 | Viewed by 941
Abstract
This study investigated the expression of immune checkpoint molecules on CD4+ and CD4− NKT cell subpopulations throughout healthy pregnancy trimesters and in non-pregnant condition to understand their role in maternal–fetal immunotolerance. Using flow cytometry, we found that CD4− NKT cells [...] Read more.
This study investigated the expression of immune checkpoint molecules on CD4+ and CD4− NKT cell subpopulations throughout healthy pregnancy trimesters and in non-pregnant condition to understand their role in maternal–fetal immunotolerance. Using flow cytometry, we found that CD4− NKT cells significantly outnumbered CD4+ NKT cells in all investigated groups. In the case of the immune checkpoint molecules, PD-1 receptor expression was significantly lower in CD4− NKT cells compared to CD4+ counterpart cells only in non-pregnant women, while the PD-L1 ligand expression on CD4+ NKT cells significantly decreased in the third trimester. In contrast, LAG-3 and Galectin-3 expressions remained stable across all subsets and trimesters. For the TIGIT/CD226 axis, CD226 expression was significantly higher in CD4+ NKT cells in the third trimester and in non-pregnant women. The two ligands CD112 and CD155 were consistently lower on CD4− NKT cells across all groups. The activating receptor NKG2D was significantly higher on CD4− NKT cells in all examined cohorts. These findings suggest that CD4+ NKT cells tend towards a more tolerogenic phenotype, while CD4− NKT cells maintain a balanced cytotoxic potential with reduced immunoregulation function. The dynamic regulation of immune checkpoints on NKT cell subsets, particularly the downregulation of PD-L1 and CD226 in late pregnancy, highlights their fine-tuned role in balancing maternal–fetal immune tolerance with readiness for parturition. Full article
(This article belongs to the Special Issue Molecular Pathology of the Placenta in Pregnancy Complications)
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Review

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14 pages, 313 KB  
Review
Trophoblast Function in Preeclampsia: Decoding the Mechanistic Roles of Coding and Non-Coding Genes
by Mihaela Oancea, Stefan Strilciuc, Oana Zanoaga, Cristina Ciocan, Andrei Malutan, Ingrid Păunescu, Dan Boitor, Cornelia Braicu and Dan Mihu
Int. J. Mol. Sci. 2025, 26(23), 11709; https://doi.org/10.3390/ijms262311709 - 3 Dec 2025
Cited by 1 | Viewed by 1216
Abstract
Preeclampsia (PE) is an obstetric disorder with significant risks to both maternal and fetal health, characterized by hypertension and multi-organ dysfunction. Central to its pathogenesis is the impaired differentiation and function of trophoblast cells, leading to abnormal placental development and defective uterine vascular [...] Read more.
Preeclampsia (PE) is an obstetric disorder with significant risks to both maternal and fetal health, characterized by hypertension and multi-organ dysfunction. Central to its pathogenesis is the impaired differentiation and function of trophoblast cells, leading to abnormal placental development and defective uterine vascular remodeling. This dysfunctional placentation triggers a cascade of oxidative stress, systemic inflammation, and immune dysregulation, collectively exacerbating disease severity. The trophoblast regulates maternal–fetal interactions through complex and tightly controlled gene expression networks, in which non-coding RNAs such as microRNAs (miRNAs) and circular RNAs (circRNAs) play essential regulatory roles. Here, we summarize current findings on transcriptomic alterations associated with trophoblast anomalies in PE and discuss their potential translational applications. Understanding these molecular mechanisms may enhance early diagnosis, improve clinical outcomes, and pave the way for precision medicine and individualized therapeutic strategies in PE. Full article
(This article belongs to the Special Issue Molecular Pathology of the Placenta in Pregnancy Complications)
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