bims-placeb 2025-09-28 papers

bims-placeb

Biomed News

on Placental cell biology

Issue of 2025–09–28
twelve papers selected by
Carlos M Guardia, National Institute of Environmental Health Sciences

Human placental trophoblast cells express and secrete basigin via a regulated process of extracellular vesicle release.
Fetal and maternal immune cells exhibit tandem maturation across gestation and dysregulation in preterm birth.
Human trophoblast stem cell-differentiated syncytiotrophoblasts as a model for hypoxia-enhanced secretion of the anti-angiogenic factor sFLT1.
Advanced maternal age induced altered FoxO1 activation and cellular senescence in early placenta development in rats.
Transposable elements as key regulators of placental development.
Three-dimensional microarchitecture of the human placental villous tree in health and disease.
Primitive Means First, Not Worst: Critical Roles for Primitive Endoderm in Embryos and Embryo Models.
A mouse model of HIV in pregnancy: the EcoHIV+ pregnancy model.
Individual and mixture associations of placental per- and polyfluoroalkyl substance with neurodevelopment at 12 and 24 months of age.
Prenatal air pollution exposure and placental vasculature development among participants of the UPSIDE cohort study.
MicroRNAs Secreted by the Embryo in Spent Culture Medium Can Regulate mRNAs Involved in Endometrial Receptivity, Embryo Attachment, and Invasion.
Single cell analysis of uterine artery endothelial cells reveals cytokine induced emergence of specific immunomodulatory subtypes: implications for preeclampsia.

Reproduction. 2025 Nov 01. pii: e250045. [Epub ahead of print]170(5):

Human placental trophoblast cells express and secrete basigin via a regulated process of extracellular vesicle release.

Muhammad Ashir Nabeel, Victoriya Ermilova, Kailiang Li, Richard Leach, Romana A Nowak.

   In brief: The release of basigin protein by human placental trophoblast cells via extracellular vesicle release is a regulated process. This study shows interactions of trophoblast cells with uterine cells during early placental development.
Abstract: Successful pregnancy relies on the regulated invasion of trophoblast cells into the maternal endometrium and subsequent remodeling of spiral arteries. Various factors are involved in regulating these processes, including matrix metalloproteinases (MMPs), cytokines such as interleukins (IL) and transforming growth factor β (TGFβ), and hypoxic conditions. Basigin (BSG), a glycosylated protein, plays an important role in MMP induction and inflammation. The role of BSG during early stages of placental development is not yet clear, nor is the process by which BSG is secreted by trophoblast cells. This study investigated the mechanism of BSG secretion from trophoblast cells in extracellular vesicles (EVs), and whether BSG release in EVs is a regulated process. RT-PCR was used to identify BSG isoforms 2, 3, and 4 in the trophoblast-like cell lines JAR, JEG-3, and HTR-8/SVneo. BSG protein expression was confirmed in trophoblast cell lines and conditioned medium by immunoblotting. We confirmed that BSG is released from HTR-8/SVneo cells via EVs. Treatment of HTR-8/SVneo cells with the protein kinase C activator PMA increased release of BSG-containing EVs, whereas the protein kinase C inhibitor Bis reduced release. Hypoxia/reoxygenation increased BSG protein in released EVs. IL-1β enhanced, while TGF-β1 reduced BSG in released EVs. This effect occurred at the post-transcriptional level, as the quantity of EVs released and levels of BSG mRNA expression in HTR-8/SVneo cells were not altered. Our findings support that BSG, released via EVs, may play an important role in facilitating interactions between trophoblast cells and uterine cells during early stages of placental development.

Keywords:  basigin; early placental development; extracellular vesicles; trophoblast

DOI:  https://doi.org/10.1530/REP-25-0045
bioRxiv. 2025 Sep 21. pii: 2025.09.20.677440. [Epub ahead of print]

Fetal and maternal immune cells exhibit tandem maturation across gestation and dysregulation in preterm birth.

Tyler A Rice, Yi Cao, Leon Bichmann, Taylor S Snisky, Serrena Singh, Weihong Gu, Dean Yimlamai, Jonathan S D Radda, Siyuan Wang, John S Tsang, Christina Megli, Liza Konnikova.

Immune cells are crucially important for the development and function of many organ systems including the maternal-fetal interface during pregnancy: the placenta and fetal membranes. While maternal uterine NK cells have been studied in pre-eclampsia, and fetal Hofbauer cells in early gestation, much less is known about fetal-derived adaptive immune cells in the placenta and their contributions to healthy gestation versus complications of pregnancy including preterm birth. In this study, we enriched immune cells from 32 term and preterm placentas (chorionic villi, decidua basalis, and cord blood) and conducted single cell transcriptomics to evaluate the state and putative function of innate and adaptive immunity accompanying fetal trophoblast cells. Gestational age was a major driver of pro-labor pro-inflammatory cytokines IL1B and TNF that in some cases were elevated too early by preterm complications. Similarly, term placentas exhibited notable expansion of TCR clones, which were gestational age-dependent except in pathologies like chorioamnionitis and vasa previa. We used genome-wide SNP calling to deconvolute the origin of fetal cells and maternal cells, finding that both mother and fetus contribute substantially to all major immune cell lineages within the placental villi. Comparing these cells to one another, we report novel candidate markers specific to fetal-derived T cells and strong expression of IL1RL1 by fetal mesenchymal cells from preterm birth cases. This work adds to our knowledge of fetal immune development and seeks to identify what immunological steps go awry in preterm birth, paving the way towards risk evaluation in pregnant mothers and ultimately preventive care.

DOI: https://doi.org/10.1101/2025.09.20.677440
Exp Cell Res. 2025 Sep 24. pii: S0014-4827(25)00373-8. [Epub ahead of print] 114773

Human trophoblast stem cell-differentiated syncytiotrophoblasts as a model for hypoxia-enhanced secretion of the anti-angiogenic factor sFLT1.

Tadashi Sasagawa, Masabumi Shibuya.

  Preeclampsia (PE) is a major disease in the field of obstetrics. Onset and progression of PE are associated with abnormally high serum levels of soluble fms-like tyrosine kinase-1 (sFLT1), an anti-angiogenic factor primarily secreted by syncytiotrophoblasts (STBs) present in the placenta. Although a cell-based assay using primary human trophoblasts has been developed to identify compounds that inhibit sFLT1 secretion, routine application of this assay is limited owing to the complexity of isolating these cells from the placenta and their inability to be passaged. Recently, human trophoblast stem cell (hTSC) lines that can differentiate into STBs and extravillous trophoblasts have been established. Their high proliferative ability allows for obtaining sufficient STBs for drug screening. In the present study, we investigated whether hTSC-differentiated STBs (dSTBs) exhibit enhanced secretion of sFLT1 under hypoxic conditions, similar to primary trophoblasts. Hypoxic stimulation significantly increased sFLT1 secretion by the dSTBs. This response was markedly inhibited by small interfering RNAs targeting the hypoxia-inducible factor (HIF)-2α and HIF-1β, as well as by the HIF-2α inhibitor, belzutifan. These findings suggest that the dSTBs described above are a practical and scalable alternative to primary trophoblasts for drug screening in PE treatment.

Keywords:  HIF-2α; human trophoblast stem cells; hypoxia; preeclampsia; sFLT1; syncytiotrophoblasts

DOI:  https://doi.org/10.1016/j.yexcr.2025.114773
Mol Cell Endocrinol. 2025 Sep 19. pii: S0303-7207(25)00213-8. [Epub ahead of print]610 112662

Advanced maternal age induced altered FoxO1 activation and cellular senescence in early placenta development in rats.

María Laura Leonardi, Alejandro Ranieri, Cintia Romina Gatti, Evangelina Capobianco, Alicia Jawerbaum, Romina Higa.

   INTRODUCTION: Advanced maternal age (AMA) is associated with increased risks of adverse pregnancy outcomes partly due to placental dysfunction; however, the underlying mechanisms remain poorly understood. This study aimed to investigate early placental development in AMA pregnancies, focusing on FoxO1 activation and its role in cellular senescence and oxidative stress.
METHODS: Three-month-old (Control) and 10-month-old (AMA) Wistar rats were mated with young males. On day 12 of pregnancy, FOXO1 activity and the expression of its target genes, oxidative status and morphometry were evaluated in the decidua and developing placenta.
RESULTS: AMA rats exhibited a reduced number of implantation sites, fewer viable embryos, and decreased embryonic crown-rump length, indicating restricted growth. Markers of oxidative stress were increased in the decidua. At the molecular level, FOXO1 phosphorylation was reduced in the decidua, suggesting increased FOXO1 activation, whereas in the developing placenta, FOXO1 phosphorylation was elevated, indicating its inactivation. SGK1, a kinase that regulates FOXO1 phosphorylation, showed decreased phosphorylation in the decidua of AMA rats. Moreover, the senescence markers Cdkn1a (P21) and Cdkn2a (P16), known FOXO1 target genes, were upregulated in the decidua and downregulated in the developing placenta. These changes were associated with impaired cell proliferation in the decidua and a reduced syncitiotrophoblast layer in the developing placenta.
CONCLUSION: These findings highlight the differential regulation of FOXO1 in the decidua and placenta during AMA pregnancies. Increased FOXO1 activity in the decidua, likely driven by oxidative stress, and reduced SGK1 phosphorylation, may impair decidual function and contribute to altered placenta development with reduced FOXO1 activity.

Keywords:  Advanced maternal age; Decidua; FoxO1; Placenta

DOI:  https://doi.org/10.1016/j.mce.2025.112662
Vavilovskii Zhurnal Genet Selektsii. 2025 Sep;29(5): 666-675

Transposable elements as key regulators of placental development.

M A Zhilkina, E N Tolmacheva, S A Vasilyev.

  Transposable elements (TEs), comprising over one-third of the human genome, play a crucial role in its evolution, serving as a significant source of regulatory sequences. Under normal circumstances, their activity is tightly controlled by DNA methylation mechanisms; however, the effectiveness of this suppression varies substantially across tissues. The placenta, characterized by global hypomethylation, represents a unique environment where retroviruses and retrotransposons, typically silenced in somatic cells, gain the opportunity for activation. This distinct epigenetic landscape of the placenta allows transposons to participate in the regulation of genomic activity, influencing processes ranging from early embryogenesis to postnatal development. DNA hypomethylation in the placenta not only promotes TE mobilization, but also opens the possibility of using their components as independent genes and regulatory elements - promoters, enhancers, and other functional modules. These elements are involved in key aspects of placental development, including syncytiotrophoblast formation, extravillous trophoblast invasion, spiral artery remodeling, and endometrial decidualization. Importantly, TEs can serve as sources of alternative promoters for neighboring genes, and ancient mammalian transposons contain multiple transcription factor binding sites, enabling coordinated regulation of genes sharing a common function. Despite the growing interest in the role of transposable elements in placental development and function, many questions remain unanswered. In particular, the mechanisms of non-long terminal repeat (non-LTR) retrotransposon function during pregnancy remain poorly understood. A deep understanding of these processes is necessary to elucidate regulatory disorders in the placenta associated with major obstetric syndromes. This review examines the contribution of transposable elements to the functioning of the human genome, particularly their impact on gene expression, in the context of pregnancy and placental development.

Keywords:  placenta development; retrotransposons; retroviruses; transposable elements

DOI:  https://doi.org/10.18699/vjgb-25-73
Front Cell Dev Biol. 2025 ;13 1639740

Three-dimensional microarchitecture of the human placental villous tree in health and disease.

Nirav Barapatre, Hans-Georg Frank.

   Background: Placental dysfunction plays a central role in pregnancy complications such as fetal growth restriction (FGR), preeclampsia (PE), and gestational diabetes mellitus (GDM). Recent advances in 3D microscopy and stereological analysis have revealed microanatomical changes not detectable by conventional histology.
Objective: To summarise key morphological and cellular alterations in the human placenta across FGR, PE, and GDM, with a focus on architecture of the villous tree, proliferative trophoblast dynamics, and sex-specific adaptations.
Methods: A synthesis of quantitative 3D histological studies was undertaken, focusing on villous compartment volumes, trophoblast proliferation markers (PCNA), nuclear distribution patterns, and branching indices in placentas from affected and control pregnancies.
Results: FGR placentas exhibit central loss of contractile villi (C-villi), increased syncytial nuclear density, and abolished sexual dimorphism. In PE, peripheral villous volume (NC-villi) is reduced, with marked increased proliferation of trophoblast in female placentas and disrupted nuclear spacing. GDM placentas show a global reduction in villous branching and altered proliferative dynamics of villous trophoblast, particularly in females, already in the absence of placental macrosomia.
Conclusion: Despite distinct clinical profiles, FGR, PE, and GDM exhibit specific yet partially overlapping placental microstructural pathologies, characterised by trophoblast dysregulation and sex-specific adaptations. These findings underscore the significance of fetal sex and quantitative three-dimensional morphometry in advancing our understanding of placental disease mechanisms.

Keywords:  3D microscopic imaging; FGR; GDM; placenta; preeclampisa; stereological analyses; trophoblast; villous tree

DOI:  https://doi.org/10.3389/fcell.2025.1639740
Dev Biol. 2025 Sep 20. pii: S0012-1606(25)00266-0. [Epub ahead of print]

Primitive Means First, Not Worst: Critical Roles for Primitive Endoderm in Embryos and Embryo Models.

Marcelio A Shammami, Alyssa Virola-Iarussi, Ian McCrary, Amy Ralston.

  In mammals, extraembryonic tissues, such as the placenta and yolk sac, are the first cell types to be specified during development because they enable the embryo to take residence and thrive in the uterine environment. Among extraembryonic tissue types, primitive endoderm (PrE), which will eventually contribute to the yolk sac, is especially fascinating. The PrE itself is named for functioning like the embryo's original gut-like tissue. For many years, our understanding of the PrE was limited by the intrinsically challenging nature of accessing and observing this tissue. However, pioneering studies in mouse have gradually revealed that the PrE is more than just nutritive in function. In fact, the PrE lineage gives rise to signaling centers that oversee developmental processes within the fetus - through processes that are very likely conserved between rodents and primates. Thus, understanding the stages between PrE and yolk sac promises clinically relevant models, including stem cell embryo models, which could lead to enhanced success for in vitro fertilization (IVF). Here, we examine the functions of PrE in the context of embryos, stem cells, and embryo models.

Keywords:  amnion; blastocyst; extraembryonic; naïve; pluripotency; postimplantation; potency; preimplantation; primed; primitive endoderm; stem cells; trophoblast; yolk sac

DOI:  https://doi.org/10.1016/j.ydbio.2025.09.008
EBioMedicine. 2025 Sep 23. pii: S2352-3964(25)00387-1. [Epub ahead of print]120 105943

A mouse model of HIV in pregnancy: the EcoHIV+ pregnancy model.

Michelle Ranjbar, Ingrid Hsieh, Maud Collomb, Lena Serghides.

   BACKGROUND: HIV infection during pregnancy poses risks to maternal and foetal health. Identifying underlying mechanisms can be challenging in humans. While humanised mouse models exist, they are unsuitable for pregnancy research, highlighting the need for alternative models. Here we introduce a mouse pregnancy model using infection with EcoHIV, a chimeric ecotropic HIV virus.
METHODS: Female C57BL/6J mice were infected with 2.5 × 106 pg/mL EcoHIV, or mock infected, either 7 days prior to mating, or on gestational day (GD) 11.5. Dam weight gain was monitored. Pregnant dams were euthanised on GD14.5 or GD18.5. Foetal and placenta weights, foetal viability, litter size and resorptions were recorded. Placenta efficiency (foetal to placental weight ratio) was calculated. Infection was assessed using HIV Gag expression quantified by qPCR in RNA isolated from maternal blood, spleen, and foetal body.
FINDINGS: EcoHIV infection was detectable in 90% of dams infected prior to pregnancy and 100% of dams infected during pregnancy. Maternal weight gain was lower in EcoHIV infected mice, with the greatest reduction seen in those infected during pregnancy. EcoHIV infection was associated with significantly lower foetal weight, higher placenta weight, and lower placenta efficiency compared to controls at GD18.5. Perinatal EcoHIV transmission occurred in a portion of foetuses, with litter average transmission rates ranging from 3.1% with infection during pregnancy to 17.9% with infection prior to pregnancy.
INTERPRETATION: The EcoHIV pregnancy model mimics clinical aspects and can be a valuable tool to understand HIV infection in pregnancy and its consequences on maternal and foetal health.
FUNDING: This project has been funded by the Canadian Institutes of Health Research (CIHR) (award # PJT-180630, PJH-192202, HAL-157984). MR received salary support from NSERC/CIHR Canada Graduate Scholarship, Institute of Medical Science Fellowship Award, and Emerging & Pandemic Infections Consortium (EPIC) Doctoral Award. LS holds a Tier 1 Canada Research Chair in Maternal-Child Health and HIV.

Keywords:  EcoHIV; Foetal growth restriction; HIV pregnancy model; HIV transmission; Mouse model; Placenta function; Viraemia

DOI:  https://doi.org/10.1016/j.ebiom.2025.105943
Environ Adv. 2025 Oct;pii: 100650. [Epub ahead of print]21

Individual and mixture associations of placental per- and polyfluoroalkyl substance with neurodevelopment at 12 and 24 months of age.

Neha Sehgal, Stephanie M Eick, Kartik Shankar, Dana Boyd Barr, Jayne B Bellando, Ginger McCorkle, Clark R Sims, Parinya Panuwet, Volha Yakimavets, Donald Turner, Lauren A Havens, Andrew J Morris, Kevin J Pearson, Aline Andres, Todd M Everson.

  Maternal serum per- and polyfluoroalkyl substances (PFAS) are linked to infant neurodevelopment vulnerabilities. However, the impact of placental PFAS exposure, a more proximal in utero exposure estimate, remains unknown. We hypothesize that elevated placental PFAS levels are associated with delayed neurodevelopment at 12 and 24 months. Mother-infant dyads (n = 151) were enrolled in a prospective cohort in Arkansas, US. PFOA, PFOS, PFHxS, PFNA, and PFDA were detected in >65 % of placentas. The Bayley Scales of Infant and Toddler Development (BSID)-III was administered at 12 and 24 months. Individual associations of each placental PFAS on BSID-III scores were examined using linear regressions. Mixture effects were assessed using quantile g-computation and Bayesian Kernel Machine Regression. Placental PFAS were jointly associated with lower cognitive (Ψ = -2.6; 95 % CI = -6.0, 0.9) and motor (Ψ = -2.9; 95 % CI = -6.6, 0.9) scores at 12 months and higher social-emotional scores (Ψ = 3.3; 95 % CI = -1.9, 8.5) at 24 months among males. Among females, higher PFAS mixture levels were associated with higher language (Ψ = 3.3; 95 % CI = -1.2, 7.7) and social-emotional (Ψ = 3.7; 95 % CI = -3.3, 10.6) scores at 24 months. Linear regressions showed PFHxS and PFOS were associated with lower cognitive scores at 12 months and PFDA was associated with lower motor scores at 12 months among males, while PFOS and PFNA were associated with higher social-emotional scores at 24 months among females, although confidence intervals included the null. In a matched subset with maternal serum, cord serum and placental PFAS (n = 98), we observed mostly null associations consistently across biomatrices and noted few associations, such as a negative relation of cord PFOA and PFHxS with language scores at 12 months among females. Overall, placental PFAS levels were modestly associated with performance on neurodevelopmental assessments in early childhood and these relationships were sex- and compound-specific, and most confidence intervals cross the null.

Keywords:  BSID-III; Mixtures analysis; Neurodevelopment; PFAS; Placenta

DOI:  https://doi.org/10.1016/j.envadv.2025.100650
Environ Res. 2025 Sep 20. pii: S0013-9351(25)02132-2. [Epub ahead of print] 122880

Prenatal air pollution exposure and placental vasculature development among participants of the UPSIDE cohort study.

Shivram Kumar, Carolyn M Salafia, Ruchit Shah, Theresa Girardi, Richard K Miller, Sally W Thurston, Philip K Hopke, David Skrill, Jessica Brunner, Donald Harrington, Yihui Ge, Yan Lin, Catherine Yount, Emily Barrett, Thomas G O'Connor, Junfeng Jim Zhang, David Q Rich.

   BACKGROUND: Air pollution exposure during pregnancy has been associated with reduced fetal growth and birth weight, but mechanisms mediating this association are not well understood.
OBJECTIVES: We examined whether pregnancy air pollution exposures were associated with altered placental vascularization.
METHODS: We studied pregnant women (N=163) from the UPSIDE cohort study, part of the Environmental Influences on Child Health Outcomes (ECHO) Study. Using placenta photographs taken at birth (gestational weeks 37-42), we derived seventeen chorionic plate surface vessel outcomes in 7 groups: arterial area, arterial branches, arterial arc length, arterial endpoint distance to perimeter, arterial branch angle, arterial tortuosity, and artery-vein distances. Distributed lag nonlinear models were used to determine if/when gestational week mean PM2.5 and NO2 concentrations were associated with the seventeen chorionic plate surface vessel outcomes.
RESULTS: Placental measures were more strongly associated with weekly NO2 than PM2.5. Higher early-pregnancy NO2 concentrations were associated with lower measures of the arterial area and arterial endpoint distance to perimeter groups, and greater measures of the arterial tortuosity group (e.g., each 9-ppb increase in NO2 concentration in gestational weeks 0-12 was associated with lower arterial surface area; cumulative β = -1.46 cm2; 95% CI = -2.73, -0.19). Higher NO2 in late-pregnancy was associated with increased measures of the arterial area, arc length, tortuosity, and artery-vein distances groups, and decreased measures of the arterial branch group (e.g., 9-ppb increases in NO2 concentration in gestational weeks 18-37 were associated with lower numbers of arterial generations; cumulative β = -1.30 generations; 95% CI = -2.22, -0.38).
CONCLUSION: Residential traffic pollution exposure in early-pregnancy was associated with altered chorionic surface arterial vasculature, potentially leading to worse perfusion, while late-pregnancy positive associations may represent a compensatory response.

Keywords:  Air pollution; chorionic surface vasculature; placental structure; pregnancy

DOI:  https://doi.org/10.1016/j.envres.2025.122880
Int J Mol Sci. 2025 Sep 12. pii: 8879. [Epub ahead of print]26(18):

MicroRNAs Secreted by the Embryo in Spent Culture Medium Can Regulate mRNAs Involved in Endometrial Receptivity, Embryo Attachment, and Invasion.

Angela Caponnetto, Carmen Ferrara, Anna Fazzio, Luca Carli, Cristina Barbagallo, Michele Stella, Davide Barbagallo, Marco Ragusa, Michael Feichtinger, Cinzia Di Pietro, Rosalia Battaglia.

  MicroRNAs, secreted by the embryo in blastocoel fluid (BF) and embryo spent culture medium (SCM), regulate important cellular pathways controlling the stemness of inner cell mass, trophectoderm differentiation, and the dialogue between blastocyst and maternal tissues. In recent years, their role as non-invasive biomarkers of embryo quality has been deeply investigated. We compared the expression profiles of 96 microRNAs between BF and SCM from the same embryos, highlighting the differences between these two compartments. We found 10 and 6 microRNAs specifically expressed in BF and in SCM, respectively; 22 microRNAs significantly up-regulated in BF; and 2 significantly up-regulated in SCM. To investigate the role of SCM microRNAs in implantation, we focused on the microRNAs specifically expressed/up-regulated in SCM and absent in blank medium. We deepened our understanding of SCM microRNA's biological role by building a network of miRNA-mRNA interaction within the signalling pathways crucial in embryo implantation success. We demonstrated that BF and SCM contain different sets of microRNAs playing different and unique roles in embryo implantation and development. Finally, we suggest that there is not a single "ideal" technique to identify the most competent embryo, but an integrated approach is needed to obtain informative results on the health of the embryo.

Keywords:  cross-talk embryo maternal tissues; embryo culture medium; endometrium; implantation; miRNA

DOI:  https://doi.org/10.3390/ijms26188879
J Mol Endocrinol. 2025 Sep 26. pii: JME-24-0086. [Epub ahead of print]

Single cell analysis of uterine artery endothelial cells reveals cytokine induced emergence of specific immunomodulatory subtypes: implications for preeclampsia.

Dahn Rl, B M Lett, Clemente L, Austin Jl, Yi Fx, D S Boeldt, Stanic Ak, Ong Im, Bird Im.

  While pregnancy is known to be an inflammatory condition, preeclampsia (PE) is associated with higher chemokines and pro-inflammatory cytokines, and higher Th1/Th2 and Th17/Treg ratios. Since the uteroplacental space can secrete cytokines, including TNF and IL1B, a common assumption is the proinflammatory immune cell profile of Th1 and Th17 cells dominating over Th2 and Treg cells begins in that space. To date, a possible role for endothelium in this initiation process has not been considered. Nonetheless, recent publications show that endothelium can become immunomodulatory on exposure to TNF and IL1B, and in systemic hypertension, endothelium has been shown to exist as multiple cell subtypes. We have recently shown that uterine artery endothelial cells from late-pregnant sheep (P-UAEC) treated with TNF alone secrete many of the chemokines and cytokines further elevated in PE subjects. Herein we show that P-UAEC also exist in multiple subtypes with distinct chemokine and cytokine secretory and immunomodulatory properties. The 5 subtypes are differentially regulated by TNF-alpha (TNF) and IL1-beta (IL1B) that may favor subtype specific binding and interaction with distinct classes of Th cells, and an altered ability to respond to Th secreted cytokines (such as IL17 and IL10). Thus, our data demonstrates the possibility that certain endothelial cell subtypes can be pushed to express immunomodulatory proteins by early exposure to increases in TNF or IL1B of immune cell, trophoblast and decidual origin. This in turn begs the question if such endothelial changes could contribute to subsequent immune disturbances seen at the time of clinical presentation.

Keywords:  IFN-gamma; IL1-beta; TNF-alpha; endothelial dysfunction; hypertension; inflammation; preeclampsia; pregnancy; uterine artery

DOI:  https://doi.org/10.1530/JME-24-0086