Retinoic Acid-Mediated Signaling Regulates Allantoic and Fetoplacental Vascularization
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE304388 | GEO | 2026/02/17
REPOSITORIES: GEO
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Project description:Preeclampsia (PE), a hypertensive disorder in pregnancy, is linked to placental vascular remodelling, increasing risks of fetal growth restriction and long-term offspring health problems. The role of fetoplacental endothelial cell-derived extracellular vesicles (EVs) in PE remains underexplored. This study investigates whether EV composition in PE is altered, potentially contributing to impaired fetal development. Small EVs (sEVs) were isolated from primary fetoplacental endothelial cells (fpECs) of term (T), preterm (PT), and early-onset PE (EO-PE) pregnancies. sEVs were characterized using transmission electron microscopy, nanoparticle tracking analysis, and Western blotting, confirming spherical morphology, size (<200nm), and expression of canonical EV and endothelial markers. Proteomic profiling via nano-LC MS/MS and gene set enrichment analysis revealed consistent proteomes in fpEC-derived sEVs, but EO-PE-derived sEVs showed heterogeneity and functional alterations compared to T- and PT-derived sEVs. Notably, EO-PE sEVs were enriched in proteins linked to epithelial-to-mesenchymal transition and myogenesis, processes tied to tissue remodelling and vascular homeostasis, all hallmarks in PE. This signature may transmit signals of endothelial dysfunction to the fetus. In contrast, T-sEVs were enriched in cell cycle and DNA repair pathways. These findings underscore the role of fetoplacental-derived EVs in placental-fetal communication under pathophysiological conditions.
2026-03-09 | PXD068733 | Pride
Project description:Retinoic Acid-Mediated Signaling Regulates Allantoic and Fetoplacental Vascularization
| PRJNA1301236 | ENA
Project description:The labyrinthian fetoplacental capillary network is of vital importance for proper nourishment of the developing embryo. An inadequate function of the maternal-fetal circulation has emerged as one of the primary causes of placental insufficiency. Here, we show that the spatial zonation of the placental labyrinth vasculature is controlled by flow-regulated epigenetic mechanisms. The spatial and temporal analysis of gene transcription revealed a gradual change in the expression of epigenetic enzymes with the de novo DNA methyltransferase 3a (DNMT3A) as primary enzyme introducing DNA methylation in cells of the vascular system. Loss of Dnmt3a resulted in DNA hypomethylation and disturbance of the spatial-zonated placental gene expression. The resulting global DNA hypomethylation impaired the angiogenic capacity of endothelial cells. Global as well as endothelium-predominant deletion of Dnmt3a resulted in impaired placental vascularization and fetal growth retardation. A meta-analysis of human placental endothelial cell gene expression identified an association between preeclampsia and reduction of DNMT3A. Collectively, our study identified DMNT3A as critical methylome-regulator of placental endothelial cell gene expression and function with clinical implications for the pathogenesis of placental dysfunction, as it occurs during preeclampsia or fetal growth retardation.
2024-11-21 | GSE280085 | GEO
Project description:The labyrinthian fetoplacental capillary network is of vital importance for proper nourishment of the developing embryo. An inadequate function of the maternal-fetal circulation has emerged as one of the primary causes of placental insufficiency. Here, we show that the spatial zonation of the placental labyrinth vasculature is controlled by flow-regulated epigenetic mechanisms. The spatial and temporal analysis of gene transcription revealed a gradual change in the expression of epigenetic enzymes with the de novo DNA methyltransferase 3a (DNMT3A) as primary enzyme introducing DNA methylation in cells of the vascular system. Loss of Dnmt3a resulted in DNA hypomethylation and disturbance of the spatial-zonated placental gene expression. The resulting global DNA hypomethylation impaired the angiogenic capacity of endothelial cells. Global as well as endothelium-predominant deletion of Dnmt3a resulted in impaired placental vascularization and fetal growth retardation. A meta-analysis of human placental endothelial cell gene expression identified an association between preeclampsia and reduction of DNMT3A. Collectively, our study identified DMNT3A as critical methylome-regulator of placental endothelial cell gene expression and function with clinical implications for the pathogenesis of placental dysfunction, as it occurs during preeclampsia or fetal growth retardation.
2024-11-21 | GSE280086 | GEO
Project description:The labyrinthian fetoplacental capillary network is of vital importance for proper nourishment of the developing embryo. An inadequate function of the maternal-fetal circulation has emerged as one of the primary causes of placental insufficiency. Here, we show that the spatial zonation of the placental labyrinth vasculature is controlled by flow-regulated epigenetic mechanisms. The spatial and temporal analysis of gene transcription revealed a gradual change in the expression of epigenetic enzymes with the de novo DNA methyltransferase 3a (DNMT3A) as primary enzyme introducing DNA methylation in cells of the vascular system. Loss of Dnmt3a resulted in DNA hypomethylation and disturbance of the spatial-zonated placental gene expression. The resulting global DNA hypomethylation impaired the angiogenic capacity of endothelial cells. Global as well as endothelium-predominant deletion of Dnmt3a resulted in impaired placental vascularization and fetal growth retardation. A meta-analysis of human placental endothelial cell gene expression identified an association between preeclampsia and reduction of DNMT3A. Collectively, our study identified DMNT3A as critical methylome-regulator of placental endothelial cell gene expression and function with clinical implications for the pathogenesis of placental dysfunction, as it occurs during preeclampsia or fetal growth retardation.
2024-11-21 | GSE280168 | GEO
Project description:Retinoic acid (RA), the bioactive derivative of vitamin A, is essential for vertebrate heart development. Both excess and reduced RA signaling lead to cardiovascular malformations, particularly affecting the cardiac outflow tract (OFT). The cellular mechanisms underlying the effects of RA signaling during OFT morphogenesis are not fully understood. To address this question, we used transient maternal RA supplementation to rescue the early lethality resulting from inactivation of the murine retinaldehyde dehydrogenase 2 (Raldh2) gene. By embryonic day 13.5, Raldh2-/- hearts exhibited OFT septation defects. Although cardiac neural crest cells (cNCC) were present in OFT cushions of Raldh2-/- mutant embryos, we observed that cNCC were ectopically located in the peripheral region of the endocardial cushions, closer to the myocardium rather than immediately subjacent to the endocardium. Mislocated cNCC were aligned in parallel instead of perpendicular arrays to the endocardial surface within the proximal OFT. Supernumerary mesenchyme was generated both in and ex vivo within the cushions by Raldh2-/- mutant endocardium and found in place of the cNCC in a subendocardial, medial position. Although mislocated and misoriented, mutant cNCC resembled wildtype cells in their compaction density and individually elongated shape. Our data show that RA signaling acts on cNCC orientation relative to the septation plane and position within OFT cushions during septation process. Transcriptomic analysis and pathway-specific readout suggest that up-regulation of the Bmp pathway may be responsible for increased endothelial-to-mesenchymal transition, leading thereby to displacement of cNCC. E10.5 stage embryonic mouse outflow tracts were microdissected. Four pools of four outflow tracts were established for wildtype (WT) and mutant (Raldh2-/-) embryos derived from dams whose food had been supplemented with all-trans-RA (Sigma) directly mixed into powdered food at 0.1 mg/g food and offered between E7.5 and E8.5. Total RNA was extracted using Macherey-Nagel NucleoSpin® RNA columns without on-column DNase digestion.
2015-12-21 | E-GEOD-64556 | biostudies-arrayexpress
Project description:Retinoic acid (RA), the bioactive derivative of vitamin A, is essential for vertebrate heart development. Both excess and reduced RA signaling lead to cardiovascular malformations, particularly affecting the cardiac outflow tract (OFT). The cellular mechanisms underlying the effects of RA signaling during OFT morphogenesis are not fully understood. To address this question, we used transient maternal RA supplementation to rescue the early lethality resulting from inactivation of the murine retinaldehyde dehydrogenase 2 (Raldh2) gene. By embryonic day 13.5, Raldh2-/- hearts exhibited OFT septation defects. Although cardiac neural crest cells (cNCC) were present in OFT cushions of Raldh2-/- mutant embryos, we observed that cNCC were ectopically located in the peripheral region of the endocardial cushions, closer to the myocardium rather than immediately subjacent to the endocardium. Mislocated cNCC were aligned in parallel instead of perpendicular arrays to the endocardial surface within the proximal OFT. Supernumerary mesenchyme was generated both in and ex vivo within the cushions by Raldh2-/- mutant endocardium and found in place of the cNCC in a subendocardial, medial position. Although mislocated and misoriented, mutant cNCC resembled wildtype cells in their compaction density and individually elongated shape. Our data show that RA signaling acts on cNCC orientation relative to the septation plane and position within OFT cushions during septation process. Transcriptomic analysis and pathway-specific readout suggest that up-regulation of the Bmp pathway may be responsible for increased endothelial-to-mesenchymal transition, leading thereby to displacement of cNCC.
2015-12-21 | GSE64556 | GEO
Project description:Pericytes are a key player in vascularization, protecting endothelial cells from external harm and promoting the formation of new vessels when necessary. However, pericytic identity and its relation with other cell types, such as mesenchymal stromal/stem cells, is highly debated. This study compares the role of pericytes and unselected stromal cells in vascularization using multichannel microfluidic chips. In both angiogenesis and vasculogenesis, pericytes promote more vessel formation than stromal cells. Pericytes can wrap around endothelial vessels acting as mural cells, while stromal cells remain separated. Whole-transcriptome sequencing confirms an upregulation of pro-vascularization genes in endothelial cell-pericyte co-cultures, while metabolism increases and inflammation decreases in stromal cell co-cultures. Treatment of stromal-endothelial cell co-cultures with either conditioned media or isolated extracellular vesicles from pericytes replicates the increase in vasculogenesis of the direct co-cultures. Cytokine quantification reveals that IL-6 is significantly increased in pericyte conditions. Blocking it with siltuximab results in a reduction of pericyte vasculogenic potential comparable to stromal cell levels, revealing that pericyte pro-vascularization is mediated by IL-6. This study provides new insights into the relationship between pericytes and endothelial cells and the elusive identity of mesenchymal stromal cells. These findings are relevant for both vascular biology and tissue engineering.
2025-04-16 | GSE287099 | GEO
Project description:Orthotopic implantation tumor assays are frequently employed in tumor biology, drug screening, and personalized therapy researches. However, the limited representation of a complex tumor microenvironment in these implanted animal models hampers a comprehensive understanding of tumor progression and therapeutic response. In this research, we developed a 3D bioprinting method using gelatin methacryloyl (GelMA) hydrogel loaded with a prolonged released system of vascular endothelial growth factor (VEGF), embedding hepatocellular carcinoma cells, to fabricate lobule-like hepatorganoids that faithfully mimic the architecture of hepatic lobules. Moreover, we utilized GelMA hydrogel mixed with Matrigel, containing human umbilical vein endothelial cells (HUVECs), to induce vascularization on the organoids. Orthotopic implantation in mouse model was performed, allowing for an improved simulation of the vascularization process within hepatorganoids. Compared to control group, 3D bioprinted lobule-like hepatorganoids exhibited prolonged survival in mice, while serum analysis revealed significantly elevated levels of alpha-fetoprotein (AFP). Eventually, our findings demonstrate that this system effectively forms orthotopic implantion of liver tumors and facilitates vascularization, which may notably contribute to the understanding of tumor biology, drug screening, and personalized therapy.
2025-02-12 | GSE269768 | GEO
Project description:<p>Preeclampsia is a leading cause of morbidity and mortality in pregnant women, affecting 5-8% of gestations worldwide. Its development is influenced by maternal immune abnormalities, metabolic disorders and gut dysbiosis. In this study, we show that gut dysbiosis in pregnant C57BL/6J dams leads to increased fetal resorption, impaired placental development and altered vascularization. These adverse outcomes are associated with key pathological features of preeclampsia, including hypoxia, endoplasmic reticulum (ER) stress and reduction in uterine natural killer (NK) cell numbers. Furthermore, gut dysbiosis significantly perturbs placental carbohydrate metabolism, which impairs NK cell IFN-γ secretion. Notably, glucose supplementation restores placental NK cell function and reduces fetal resorption, suggesting that the observed impairment is reversible and dependent on a lower glycolytic rate. These findings highlight maternal gut microbiota as a key player in carbohydrate metabolism, with a pivotal role in modulating placental immunity and pregnancy outcome. The results provide valuable insights into potential metabolic biomarkers and suggest that targeting the gut microbiota may offer a strategy for preventing preeclampsia.</p>
2025-05-07 | MTBLS12316 | MetaboLights