bims-placeb 2026-04-12 papers

bims-placeb

Biomed News

on Placental cell biology

Issue of 2026–04–12
fourteen papers selected by
Carlos M Guardia, National Institute of Environmental Health Sciences

Elucidating the roles of microRNA-103a-3p in trophoblast invasion and SOX4-mediated extravillous differentiation induced by activin A.
Hypoxia regulates epithelial to mesenchymal transition-associated genes in human trophoblast cells by modulating DNA methylation.
Impact of Maternal Supraphysiological Hypercholesterolemia on Lysosomal and Mitochondrial Function in Placental Trophoblast Cells.
Prokineticin 2 is upregulated in preeclampsia and impairs trophoblast function.
Placental vitamin D malnutrition induced by vitamin D deficiency during pregnancy causes placenta dysplasia by regulating GSK-3β/β-catenin and CD44 as well as interfering their feedback interaction in rats.
Fetoplacental Circadian Rhythms Develop and Then Synchronize to the Mother In Utero.
Placenta Biology, Future Cardiovascular Health, and Impact on the Maternal-Fetal Heart.
O-GlcNAc Modification Orchestrates HUWE1-Mediated Ubiquitination of TfR1 to Regulate Ferroptosis and Trophoblast Syncytialization in Preeclampsia.
The dynamic interplay between insulin resistance and autophagy: Exploring the coordinated regulation of multiple pathways in the pathogenesis of miscarriage.
Maternal nutrition as a key determinant of placental and developing blood-brain barrier xenobiotic protective functions.
Single-cell spatiotemporal dissection of the human maternal-fetal interface.
Endometrial microbiota in maternal-fetal tolerance: An in vitro study of extravillous trophoblasts and uNK cells.
Deletion of endothelial KLF4 as a model for preeclampsia.
A high-fat, high-sugar diet impairs maternal metabolism throughout pregnancy and lactation in mice.

Cell Death Dis. 2026 Apr 10.

Elucidating the roles of microRNA-103a-3p in trophoblast invasion and SOX4-mediated extravillous differentiation induced by activin A.

Jiamin Xie, Matthew J Shannon, Hua Zhu, Minyue Dong, Alexander G Beristain, Peter C K Leung.

The dysregulation of growth factors is associated with defective trophoblast invasion, which leads to uteroplacental malperfusion due to the inadequate remodeling of spiral arteries. Pregnancy disorders, including preeclampsia, particularly early-onset preeclampsia, are closely related to compromised placental function caused by aberrant trophoblast invasion. Activin A, a growth factor detectable in serum that belongs to the transforming growth factor-β (TGF-β) superfamily, has been implicated in the development of preeclampsia, as evidenced by its elevated serum levels and its role in regulating trophoblast invasion. However, the existing research on its regulatory mechanisms in trophoblast invasion has focused mainly on intracellular, nonsecretory epithelial-mesenchymal transition (EMT) markers in conventional trophoblast cell lines, which limits its translational relevance to clinical applications. In this study, we performed small RNA sequencing combined with cell biology studies in primary human trophoblast and 2D human trophoblast stem cell models and revealed that the upregulation of the SOX4 (SRY-box transcription factor 4) and miR-103a-3p induced by activin A contributes to trophoblast invasion and potential extravillous differentiation. The bioinformatic analysis of proteomic and microRNA profiles from public databases revealed increased expression of the activin A protein and exosomal miR-103a-3p in maternal blood during the second trimester of pregnancy complicated by preeclampsia. Overall, our integrated approach reveals the regulatory mechanism by which activin A, SOX4, and miR-103a-3p regulate human trophoblast invasion and EVT differentiation, highlighting their potential as early diagnostic biomarkers for preeclampsia.

DOI: https://doi.org/10.1038/s41419-026-08665-6
PLoS One. 2026 ;21(4): e0325053

Hypoxia regulates epithelial to mesenchymal transition-associated genes in human trophoblast cells by modulating DNA methylation.

Jaganmoy Choudhury, Bodhana Dhole, Kanika Aggarwal, Palak Singh, Moses Azaraiah Jala, Deepak Pandey, Pradeep Kumar Chaturvedi, Surabhi Gupta.

Successful pregnancy is dependent on an aptly developed and functional placenta. During placentation, epithelial cytotrophoblast cells (CTBs) transdifferentiate into migratory extravillous trophoblasts (EVTs) that invade the maternal endometrium. Improper differentiation can result in inadequate EVT invasion leading to placental malformation-related pathologies like preeclampsia. Acquisition of invasive phenotype by EVTs indicates the involvement of epithelial to mesenchymal transition (EMT). In the early-stage placenta, the trophoblast cells are exposed to a hypoxic environment. However, the regulation of EMT in trophoblasts by this hypoxic condition is unclear. Therefore, we analyzed the expression pattern of EMT-associated genes and their DNA methylation level in two different trophoblast cell lines grown under hypoxia. Exposure to hypoxia was confirmed by a significant increase in the expression of HIF1A target gene Carbonic Anhydrase 9. Modulated expression of some EMT-associated core genes indicated the induction of EMT in trophoblasts by hypoxia. Interestingly, a significant increase in the expression of MMP2 and MMP9 was observed in HTR8/SVneo cells but not in JEG-3 cells. In HTR8/SVneo cells, hypoxia-induced modulation in the methylation levels of promoters for E-Cadherin and MMP9 gene correlated well with alterations in their gene expression. The expression of TET1, a DNA demethylating enzyme, also increased after hypoxia exposure. Thus, we concluded that hypoxia changes expression and promoter methylation of some EMT-associated genes in trophoblast cells.

DOI: https://doi.org/10.1371/journal.pone.0325053
J Cell Physiol. 2026 Apr;241(4): e70165

Impact of Maternal Supraphysiological Hypercholesterolemia on Lysosomal and Mitochondrial Function in Placental Trophoblast Cells.

María José Yañez, Fabián Campos, Patricia Valdebenito, Viviana A Cavieres, María José Barrera, Cheril Tapia-Rojas, Patricia V Burgos, Lara J Monteiro, Silvana Zanlungo, Sebastián E Illanes, Andrea Leiva.

  Dyslipidemia, characterized by an excessive amount of lipids in the bloodstream, is a significant risk factor for metabolic disorders and cardiovascular diseases (CVDs). Maternal supraphysiological hypercholesterolemia (MSPH) is associated with increased maternal levels of total cholesterol (TC) and low-density lipoprotein (LDL). This condition has been linked to negative consequences on the fetoplacental vasculature, including increased atherosclerosis development in the fetal aorta and later in children and adolescents. This study aims to determine whether the high cholesterol levels associated with MSPH affect lysosomal and mitochondrial functions in the syncytiotrophoblast (STB), considering the increased free cholesterol levels previously reported in primary human trophoblast (PHT) cells from MSPH pregnancies. Total cholesterol levels were measured in placental tissues and BeWo cells. Lysosomal mass, size, and activity, as well as mitochondrial mass, function, and morphology, were assessed in BeWo cells and placentas. Our results revealed that placental tissues from MSPH pregnancies and BeWo cells treated with oxidized (ox-LDL) exhibited increased free cholesterol levels and higher expression of cholesterol transport proteins. Treatment of BeWo cells with ox-LDL also led to an increase in lysosomal mass and size, accompanied by a decrease in lysosomal activity. Conversely, ox-LDL treatment induced mitochondrial fragmentation in BeWo cells, together with reduced ATP production and diminished mitochondrial membrane potential. Similar alterations in lysosomes and mitochondria were observed in the placenta of patients with a history of MSPH. MSPH-related high cholesterol levels induced by ox-LDL impair lysosomal and mitochondrial functions in the STB, potentially contributing to cellular dysfunction observed in MSPH. This study highlights the importance of understanding the underlying mechanisms of MSPH to improve maternal and fetal health outcomes.

Keywords:  hypercholesterolemia; lysosome; mitochondria; placenta; syncytiotrophoblast

DOI:  https://doi.org/10.1002/jcp.70165
J Matern Fetal Neonatal Med. 2026 Dec;39(1): 2650239

Prokineticin 2 is upregulated in preeclampsia and impairs trophoblast function.

Ying Li, Ting Qin, Xi-Gui Long, Hai-Tang Wei, Yan Chi.

   OBJECTIVE: To investigate the role of prokineticin 2 (PK2) in the pathogenesis of preeclampsia (PE), a severe hypertensive disorder of pregnancy with incompletely understood placental mechanisms.
METHODS: The placental expression of PK2 and prokineticin receptor 2 (PKR2) was assessed by immunohistochemistry, and PK2 levels were quantified by enzyme-linked immunosorbent assay in samples from patients with PE and a PE mouse model, compared with normal controls. The functional impact of recombinant PK2 protein on proliferation and migration was assessed in the trophoblast cell line HTR-8/SVneo. Transcriptomic analysis was performed on PK2-treated cells to identify differentially expressed genes and enriched pathways.
RESULTS: PK2 and PKR2 were significantly upregulated in PE placentas. PK2 expression was significantly higher in the culture medium of primary trophoblast cells derived from PE patients and a PE mouse model than in that from normal controls. Recombinant PK2 markedly inhibited trophoblast proliferation and migration. Transcriptomic analysis revealed PK2-induced upregulation of a gene set (including EGR1, FOS, JUN, CCN1, and CCN2) with significant enrichment in stress-response and inflammatory pathways.
CONCLUSIONS: This study identifies PK2 as a key pathogenic factor in PE that impairs trophoblast function. The findings suggest that its mechanism may involve the induction of AP-1 components. Our work provides the first evidence positioning the PK2/PKR2 axis as a novel contributor to PE pathogenesis and a potential therapeutic target.

Keywords:  AP-1 signaling pathway; Prokineticin 2; preeclampsia; prokineticin receptor 2; trophoblast

DOI:  https://doi.org/10.1080/14767058.2026.2650239
J Nutr Biochem. 2026 Apr 02. pii: S0955-2863(26)00101-4. [Epub ahead of print] 110359

Placental vitamin D malnutrition induced by vitamin D deficiency during pregnancy causes placenta dysplasia by regulating GSK-3β/β-catenin and CD44 as well as interfering their feedback interaction in rats.

Yu Han, Xiaoxia Sun, Yu Qiao, Jiongnan Wang, Jia Wang, Shangyun Lu, Fubin Qiu.

  Vitamin D deficiency (VDD) is highly prevalent during pregnancy, which can lead to poor placental development and functional abnormalities, and may trigger a series of pregnancy-related diseases in severe cases. The Wnt/β-catenin signalling pathway and its downstream target gene, CD44, play key roles in regulating the proliferation, migration and invasion of placental trophoblast cells. In this study, we found that VDD before and during SD rats pregnancy can lead to maternal placental vitamin D malnutrition, placental dysplasia, and impaired placental invasion, migration, proliferation and nutrient transport capabilities of placenta in vivo and in vitro. Importantly, we clarified VDD impaired placental function via regulation of p-GSK-3β/β-catenin and CD44, and that there is a feedback regulation between p-GSK-3β/β-catenin and CD44 in regulating VDD induced placental dysfunction. This study once again emphasizes the importance of vitamin D for placental development and provides a theoretical basis for the prevention and treatment of placental dysplasia caused by VDD during pregnancy.

Keywords:  CD44 ;feedback regulation; GSK-3β/β-catenin; placenta dysplasia; vitamin D deficiency

DOI:  https://doi.org/10.1016/j.jnutbio.2026.110359
J Biol Rhythms. 2026 Apr 10. 7487304261435435

Fetoplacental Circadian Rhythms Develop and Then Synchronize to the Mother In Utero.

K L Nikhil, Keenan Bates, Elizabeth Sapiro, Jacob L Amme, Ron McCarthy, Sarah L Speck, Varun Vasireddy, Ethan Roberts, Carmel A Martin-Fairey, Miguel-E Domínguez-Romero, Sandra P Cárdenas-García, Sarah K England, Erik D Herzog.

  Circadian rhythms in gene expression and hormones are ubiquitous across species and differentiated cell types, yet their developmental origins remain poorly understood. This study aimed to determine if daily rhythms can be detected in utero and if they synchronize to the mother. We developed methods to longitudinally monitor PERIOD2 (PER2), a core circadian clock protein, from embryonic day (E)8.5 to E17.5 by restricting PER2::LUCIFERASE expression to the mouse fetoplacental unit (fetus and fetal-derived tissues). In utero fetoplacental bioluminescence imaging showed that PER2 levels increased during pregnancy, with variable daily peak times that stabilized to early night by E15.5. Interestingly, pregnancies that did not exhibit daily in utero PER2 variation were more likely to fail. Because maternal glucocorticoids have been implicated in fetal development and synchronizing other circadian tissues, we tested whether glucocorticoid injections could shift fetoplacental PER2 rhythms in utero. Daily subcutaneous corticosterone injections over 5 days of late pregnancy phase-dependently shifted the fetoplacental PER2 rhythms in utero. Blocking glucocorticoid signaling in vitro reduced synchrony between maternal and fetal placenta. We conclude that in utero daily rhythms gradually develop and synchronize with the mother prior to birth, potentially through glucocorticoid signaling.

Keywords:  circadian ontogeny; circadian synchrony; fetal rhythms; gestation; glucocorticoids; in utero imaging; maternal-fetal communication; pregnancy

DOI:  https://doi.org/10.1177/07487304261435435
Arterioscler Thromb Vasc Biol. 2026 Apr 09.

Placenta Biology, Future Cardiovascular Health, and Impact on the Maternal-Fetal Heart.

Meenakshi Rana, Una Rose Wilcox, Suchita Nadkarni.

  The placenta is a highly specialized organ that ensures the developing fetus gets adequate oxygen and nutrients from its mother. The placenta shares common development pathways with the fetal heart and releases factors that can influence the way the mother's heart functions. Thus, pregnancy complications, where the placenta fails to develop properly, can lead to the development of fetal heart defects and induce long-term maternal cardiac dysfunction. In this review, we focus on how the placenta shapes cardiac events during development and the subsequent long-term impact on the offspring's heart. We also touch upon the potential role the placenta plays in maternal heart function.

Keywords:  eclampsia; extravillous trophoblasts; fetal growth retardation; growth and development; hypertension, pregnancy-induced

DOI:  https://doi.org/10.1161/ATVBAHA.125.323221
Free Radic Biol Med. 2026 Apr 08. pii: S0891-5849(26)00302-3. [Epub ahead of print]

O-GlcNAc Modification Orchestrates HUWE1-Mediated Ubiquitination of TfR1 to Regulate Ferroptosis and Trophoblast Syncytialization in Preeclampsia.

Hongshuo Zhang, Mengyue Li, Juan Zhang, Qianyi Sun, Xiaohan Jin, Runyuan Liu, Xiaotong Li, Xinmei Chen, Ao Wang, Zhengqing Luo, Yuhong Shang, Ying Kong.

  Trophoblast stress may be one of the etiologies of the pathology of the placenta in preeclampsia (PE). During pregnancy, females experience a substantial increase in iron requirements. Paradoxically, excessive iron intake or elevated iron levels can pose risks to pregnancy and contribute to reproductive disorders. Labile iron, owing to its oxidative and toxic properties, triggers cellular oxidative stress and initiates ferroptosis. O-GlcNAc modification has been linked to ferroptosis in recent studies. However, its involvement in the pathophysiology of PE remains elusive. Our research identified abnormal ferroptosis in preeclamptic placentas, and was accompanied by reduced O-GlcNAc modification levels. Increasing O-GlcNAc modification rescued trophoblast syncytialization defects and oxidative stress damage induced by iron overload or ferroptosis. Through O-GlcNAc modification proteomics, we screened and validated the E3 ubiquitin ligase HUWE1 as a pivotal factor in trophoblast ferroptosis and syncytialization. Mechanistically, O-GlcNAc modification stabilizes HUWE1, facilitating the ubiquitination-mediated degradation of its substrate, transferrin receptor1 (TfR1). This process reduces iron uptake by trophoblasts, thereby inhibiting ferroptosis during syncytialization. Moreover, elevated O-GlcNAcylation ameliorates iron overload-induced preeclamptic phenotypes and mitigates adverse pregnancy outcomes. These findings highlight the unique role of O-GlcNAcylated HUWE1 in regulating TfR1 ubiquitination and suggest that targeting this pathway may offer a novel therapeutic strategy for PE.

Keywords:  Ferroptosis; HUWE1; O-GlcNAc; Preeclampsia; TfR1

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.04.018
Placenta. 2026 Mar 25. pii: S0143-4004(26)00100-1. [Epub ahead of print]

The dynamic interplay between insulin resistance and autophagy: Exploring the coordinated regulation of multiple pathways in the pathogenesis of miscarriage.

Jiayu Fang, Haixuan Lai, Zhaolan Zeng, Yuyuan Liu, Li Li, Shuang Qin.

  This narrative review summarizes recent advances in understanding the interrelationship among insulin resistance (IR), autophagy, and miscarriage. As a critical regulator of metabolic homeostasis, IR not only contributes to the development of various metabolic disorders but is also associated with an increased risk of miscarriage. IR elevates miscarriage risk through multiple mechanisms, including altering the intrauterine environment, modulating androgen levels, impairing mitochondrial function, enhancing oxidative stress, and activating inflammatory pathways via increased reactive oxygen species (ROS). Triggered by stressors like oxidative stress, autophagy regulates placental development and function through its effects on trophoblasts, macrophages, and decidualization, consequently, dysregulated autophagy can contribute to miscarriage. Furthermore, IR inhibits autophagic activity via activation of the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway (through the PI3K-AKT axis), which suppresses ULK1. Chronic IR leads to oxidative stress (increased ROS) and mitochondrial dysfunction, which in turn promotes autophagy by inhibiting mTORC1 through the 5' adenosine monophosphate-activated protein kinase (AMPK) pathway. Moderate autophagy improves insulin sensitivity by removing damaged mitochondria and alleviating endoplasmic reticulum stress. However, excessive autophagy, such as in pancreatic β-cells, can degrade insulin granules and reduce insulin secretion, thereby exacerbating IR. This review explores the interactions among IR, autophagy and miscarriage, aiming to provide new insights for the prevention and treatment of miscarriage.

Keywords:  Autophagy; Insulin resistance; Miscarriage; Oxidative stress

DOI:  https://doi.org/10.1016/j.placenta.2026.03.015
J Physiol. 2026 Apr 04.

Maternal nutrition as a key determinant of placental and developing blood-brain barrier xenobiotic protective functions.

Kristin L Connor, Nycolle I S Souza, Bruno G Anjos, Stephen G Matthews, Enrrico Bloise.

  The placenta and the developing blood-brain barrier (BBB) function as two complementary fetal protective interfaces ensuring nutrient delivery at the same time as limiting fetal brain xenobiotic overexposure. In this review, we integrate evidence from animal and human studies demonstrating that the spectrum of maternal malnutrition, from undernutrition/underweight to overnutrition/obesity, profoundly remodels placental morphology and compromises placental barrier efficiency. Maternal undernutrition reduces placental exchange surface area, impairs villous vascular development and alters syncytiotrophoblasts maturation, whereas maternal overnutrition/obesity promotes villous immaturity, inflammation and limits vascular exchange capacity, thus impairing fetal xenobiotic protection. These nutritional insults also consistently impair expression and activity of protective efflux transporters, P-glycoprotein (P-gp/ABCB1), breast cancer resistance protein (BCRP/ABCG2) and multidrug resistance protein 2 (MRP2/ABCC2), weakening xenobiotic defence. Concurrently, solute carrier transporters for glucose (GLUT1), amino acids (SNATs and LATs) and fatty acid (FATP/CD36) are dysregulated with malnutrition, further debilitating these barriers and increasing risk for adverse developmental programming. The developing BBB may be similarly sensitive, with maternal nutritional adversity linked to increased permeability, diminished efflux capacity and reduced tight junction integrity. Moreover, micronutrients, including copper, folate, iron, vitamin A, vitamin B12, vitamin D and zinc emerge as pivotal regulators of these protective systems, directly modulating BBB efflux transporter activity, and junctional stability. This evidence demonstrates that maternal nutrition imbalance impairs fetal protection, with consequences for neurodevelopment. Optimizing maternal diet before and during pregnancy represents a strategy to reinforce placental and developing BBB function, safeguard the fetal brain, and improve long-term offspring health.

Keywords:  blood–brain barrier (BBB); brain development; detoxifying enzymes; efflux transporters; nutrients; placenta; xenobiotics

DOI:  https://doi.org/10.1113/JP289627
Nature. 2026 Apr 08.

Single-cell spatiotemporal dissection of the human maternal-fetal interface.

Cheng Wang, Yan Zhou, Yuejun Wang, Tuhin Kumar Guha, Zhida Luo, Anxhela Mustafaraj, Tara I McIntyre, Marisa E Schwab, Brittany R Davidson, Gabriella C Reeder, Ronald J Wong, Sarah K England, Juan M Gonzalez, Robert Blelloch, Alexis J Combes, Linda C Giudice, Adrian Erlebacher, Tippi C MacKenzie, David K Stevenson, Gary M Shaw, Michael P Snyder, Xiaofei Sun, Virginia D Winn, Susan J Fisher, Jingjing Li.

The human maternal-fetal interface is characterized by mosaic intermingling of maternal and fetal cells1. Yet the underlying cellular, molecular and spatial programmes remain incompletely defined. Here we generate a comprehensive atlas of the human maternal-fetal interface across normal pregnancies from early gestation to term by integrating large-scale paired single-nucleus transcriptomic and chromatin accessibility profiling with submicrometre-resolution spatial transcriptomics and CODEX multiplex protein imaging2, substantially boosting the spatiotemporal resolution of prior research3. This framework delineates common and transient cell types, states and spatial niches across the fetal and maternal compartments, reconstructs transcriptional programmes that guide cytotrophoblast and decidual stromal cell differentiation, and resolves recurrent architecture structural units that build this interface. We identify previously unrecognized arterial endothelial state transitions during cytotrophoblast-mediated spiral artery remodelling and develop a machine learning model that predicts cytotrophoblast invasiveness from transcriptomic signatures. We further discover a decidual stromal cell subtype that suppresses cytotrophoblast invasion via endocannabinoid signalling at the human maternal-fetal interface. By integrating the atlas with genome-wide association data, we pinpoint maternal and fetal cells that are most vulnerable to pre-eclampsia, preterm birth or miscarriage. This resource provides a comprehensive spatially resolved single-cell multiomic reference of the human placenta and decidua and offers a framework for decoding their normal and disordered development.

DOI: https://doi.org/10.1038/s41586-026-10316-x
J Reprod Immunol. 2026 Apr 01. pii: S0165-0378(26)00053-7. [Epub ahead of print]175 104884

Endometrial microbiota in maternal-fetal tolerance: An in vitro study of extravillous trophoblasts and uNK cells.

Kazuhide Takada, Yoshinori Takeda, Jonghyun Bae, Quang Duy Trinh, Dong Wook Kim, Satoshi Hayakawa, Shihoko Komine-Aizawa.

  Accumulating clinical studies have reported the significance of endometrial microbiota during pregnancy, especially in assisted reproductive technology. Although there are discussions on the relationship between endometrial microbiota and immunological tolerance at the maternal-fetal interface, the data supporting these processes is still insufficient. We, therefore, investigated the effect of endometrial microbiota culture supernatants on maternal-fetal tolerance in vitro, focusing on extravillous trophoblasts (EVT) and uterine natural killer (uNK) cells, which constitute approximately 70% of lymphocytes in human uterine decidua in early pregnancy. The cells were treated with the culture supernatants of Lactobacillus crispatus, Lactobacillus iners, Gardnerella vaginalis, Klebsiella pneumoniae subsp. pneumoniae, and Enterobacter cloaca. Cell killing assay showed that the bacterial culture supernatant of L. crispatus significantly enhanced the cell killing ability of NK-92MI cells against Sw.71 cells., whereas that of K. pneumoniae decreased the cell killing rate. Western blotting showed that the L. crispatus supernatant significantly decreased the expression of leukocyte immunoglobulin-like receptor B1 (LILRB1) on NK-92MI cells. The culture supernatant of K. pneumoniae significantly increased human leukocyte antigen (HLA)-C, HLA-G, and programmed death-ligand 1 (PD-L1) expressions on Sw.71 cells, and promoted the secretion of sPD-L1 from the cells. The L. iners culture supernatant significantly decreased PD-L1 expression in Sw.71 cells. The present results suggest that endometrial microbiota may modulate EVT and uNK cell interaction and affect maternal-fetal tolerance during implantation and placentation. To improve infertility treatments and elucidate the pathophysiology of pregnancy complications, further clarification of the function of the endometrial microbiota during pregnancy is warranted.

Keywords:  Endometrial microbiota; Extravillous trophoblast; Klebsiella; Lactobacillus; Maternal–fetal tolerance; UNK cell

DOI:  https://doi.org/10.1016/j.jri.2026.104884
bioRxiv. 2026 Mar 31. pii: 2026.03.30.715448. [Epub ahead of print]

Deletion of endothelial KLF4 as a model for preeclampsia.

Emily Meredith, Andrew T Meredith, Arya Mani, Martin A Schwartz.

Preeclampsia (PE), or gestational hypertension, affects around 5% of pregnancies and leads to approximately 70,000 maternal and 500,000 fetal deaths per year worldwide, with increased cardiovascular and metabolic disease in survivors. PE is associated with elevated circulating levels of the alternative splice isoform of VEGF receptor 1 (sFlt1), defects in placental vasculature, kidney damage and, in severe disease, fetal growth restriction. Current mouse models induce PE via direct expression of sFlt1 or elevation of blood pressure, which bypass the natural risk factors for human disease, such as age, obesity, hypertension and diabetes. These risk factors have in common reduced expression of Krüppel-like factors 2 and 4 (KLF2/4), the endothelial transcription factors that protect against cardiovascular disease. We now report that inducible deletion of KLF4 in maternal endothelium ( KLF4 iECKO ) results in gestational hypertension, elevated sFlt1, defective placental vasculature, kidney damage and fetal growth restriction. KLF4 iECKO may thus serve as a mouse PE model suitable for mechanistic analysis and screening of treatments that address upstream risk factors.

DOI: https://doi.org/10.64898/2026.03.30.715448
J Physiol. 2026 Apr 04.

A high-fat, high-sugar diet impairs maternal metabolism throughout pregnancy and lactation in mice.

Stephanie E O'Hara, Kelly M Gembus, Georgia S Clarke, Amanda J Page, Kathryn L Gatford, Lisa M Nicholas.

  Prenatal exposure to maternal overweight and elevated glucose increases risk of cardiometabolic disease in offspring. Preclinical models such as the high-fat, high-sugar (HFHS) fed mouse allow mechanistic studies and testing of interventions, but it is first critical to understand the extent of exposures across early development. We therefore assessed the impacts of feeding a HFHS diet to C57Bl/6J mice for 11 weeks before mating and throughout pregnancy and lactation, on maternal weight, body composition, activity and energy expenditure, feeding behaviour, substrate utilisation and glucose metabolism. We also assessed the impacts of maternal diet on late gestation fetuses, neonates and early offspring growth. HFHS dams were fatter than controls with impaired glucose tolerance before mating and throughout pregnancy and lactation (P < 0.001). Dams also exhibited altered feeding behaviours, increased energy expenditure (light phase: P < 0.001, dark phase: P < 0.001) and a shift in fuel usage from carbohydrate to fat oxidation throughout pregnancy (lower respiratory exchange ratio: light phase: P = 0.002, dark phase: P < 0.001). Fetuses of HFHS dams were hyperglycaemic at gestational day 18 (P = 0.031). Altered patterns of offspring growth during lactation resulted in fatter pups at weaning. Consumption of a HFHS before and throughout pregnancy and lactation exposes offspring to changes in maternal metabolism in utero and throughout lactation. Since maternal impacts differ between studies, it is essential that these are characterised in each model to understand the critical factors that drive programming of offspring metabolism. KEY POINTS: Consumption of an obesogenic, high-fat, high-sugar (HFHS) diet impairs glucose tolerance during pregnancy, but how this impacts metabolic adaptations during pregnancy and lactation remains unclear. In the present study, consumption of a HFHS diet in mice increased adiposity and impaired glucose tolerance before mating and throughout pregnancy and lactation. HFHS consumption impacted metabolic adaptations to pregnancy, including failure to shift from fat to carbohydrate oxidation, reduced fat deposition and lower insulin secretion. These alterations in maternal metabolism during pregnancy resulted in fetal hyperglycaemia and altered patterns of offspring neonatal growth, resulting in offspring that were fatter at weaning. These findings have implications for metabolic health of both mothers and their offspring.

Keywords:  glucose; high‐fat; high‐sugar diet; insulin; lactation; metabolism; mouse; pregnancy

DOI:  https://doi.org/10.1113/JP289985