Human fetoplacental arterial and venous endothelial cells are differentially programmed by gestational diabetes mellitus, resulting in cell-specific barrier function changes.

{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:30091044", "kind": "science-record", "revision": 8, "content_hash": "sha256:b4fa7f173b06b3dbfd3146ca59f641ca6b0459c27a6baa7759be908344a09014", "created_at": "2026-11-01T15:40:36Z", "updated_at": "2026-11-01T22:43:29Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "Human fetoplacental arterial and venous endothelial cells are differentially programmed by gestational diabetes mellitus, resulting in cell-specific barrier function changes.", "doi": "10.1007/s00125-018-4699-7", "pmid": "30091044", "authors": ["Silvija Cvitic", "Boris Novakovic", "Lavinia Gordon", "Christine M Ulz", "Magdalena Mühlberger", "Francisca I Diaz-Perez", "Jihoon E Joo", "Vendula Svendova", "Michael G Schimek", "Slave Trajanoski", "Richard Saffery", "Gernot Desoye", "Ursula Hiden"], "journal": "Diabetologia", "year": 2018, "abstract": "AIMS/HYPOTHESIS: An adverse intrauterine environment can result in permanent changes in the physiology of the offspring and predispose to diseases in adulthood. One such exposure, gestational diabetes mellitus (GDM), has been linked to development of metabolic disorders and cardiovascular disease in offspring. Epigenetic variation, including DNA methylation, is recognised as a leading mechanism underpinning fetal programming and we hypothesised that this plays a key role in fetoplacental endothelial dysfunction following exposure to GDM. Thus, we conducted a pilot epigenetic study to analyse concordant DNA methylation and gene expression changes in GDM-exposed fetoplacental endothelial cells.\nMETHODS: Genome-wide methylation analysis of primary fetoplacental arterial endothelial cells (AEC) and venous endothelial cells (VEC) from healthy pregnancies and GDM-complicated pregnancies in parallel with transcriptome analysis identified methylation and expression changes. Most-affected pathways and functions were identified by Ingenuity Pathway Analysis and validated using functional assays.\nRESULTS: Transcriptome and methylation analyses identified variation in gene expression linked to GDM-associated DNA methylation in 408 genes in AEC and 159 genes in VEC, implying a direct functional link. Pathway analysis found that genes altered by exposure to GDM clustered to functions associated with 'cell morphology' and 'cellular movement' in healthy AEC and VEC. Further functional analysis demonstrated that GDM-exposed cells had altered actin organisation and barrier function.\nCONCLUSIONS/INTERPRETATION: Our data indicate that exposure to GDM programs atypical morphology and barrier function in fetoplacental endothelial cells by DNA methylation and gene expression change. The effects differ between AEC and VEC, indicating a stringent cell-specific sensitivity to adverse exposures associated with developmental programming in utero.\nDATA AVAILABILITY: DNA methylation and gene expression datasets generated and analysed during the current study are available at the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) database ( http://www.ncbi.nlm.nih.gov/geo ) under accession numbers GSE106099 and GSE103552, respectively.", "claims": [{"id": "claim-method", "statement": "The limma package [21] was used to fit a linear model to compare dAEC and dVEC vs control samples, with patient as random effect and allowing for batch effects.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:30091044", "locator": "sections[5] \"DNA methylation analysis\" paragraph 2", "quote": "The limma package [21] was used to fit a linear model to compare dAEC and dVEC vs control samples, with patient as random effect and allowing for batch effects."}], "state": "complete"}, {"id": "claim-data-access", "statement": "DNA methylation and gene expression datasets generated and analysed during the current study are available at the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) database (http://www.ncbi.nlm.nih.gov/geo) under accession numbers GSE106099 and GSE103552, respectively.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:30091044", "locator": "sections[0] \"Abstract\" paragraph 5", "quote": "DNA methylation and gene expression datasets generated and analysed during the current study are available at the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) database (http://www.ncbi.nlm.nih.gov/geo) under accession numbers GSE106099 and GSE103552, respectively."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "complete", "objective": null, "steps": [{"id": "read_published_estimate", "order": 1, "name": "Read the published estimate from the source", "kind": "other", "state": "complete", "blocked_on": null, "description": "The claim, method and evidence span published with the source article.", "duration_hours": null, "parameters": {}, "inputs": ["source:pmid:30091044"], "outputs": ["the published estimate and its evidence"], "instruments": [], "reagents": []}, {"id": "obtain_source_data", "order": 2, "name": "Obtain the source data from the named repository", "kind": "data-preparation", "state": "complete", "blocked_on": null, "description": "The GEO series accession resolves and its sample accessions are listed. This lane did not download the dataset or read its licence.", "duration_hours": null, "parameters": {}, "inputs": ["data:geo:GSE103552"], "outputs": ["the source data with its repository provenance"], "instruments": [], "reagents": []}, {"id": "run_analysis", "order": 3, "name": "Run the published analysis", "kind": "analysis", "state": "complete", "blocked_on": null, "description": "Apply the paper's statistical method to the resolved series and compare the result with the published target.", "duration_hours": null, "parameters": {}, "inputs": ["data:geo:GSE103552"], "outputs": ["the replicated result and its comparison"], "instruments": [], "reagents": []}], "materials": [], "instruments": [], "reagents": [], "conditions": {}, "gaps": []}, "data": {"state": "partial", "assets": [{"id": "source:pmid:30091044", "role": "manuscript", "format": "xml", "media_type": "application/xml", "uri": "https://doi.org/10.1007/s00125-018-4699-7", "sha256": 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for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) database (http://www.ncbi.nlm.nih.gov/geo) under accession numbers GSE106099 and GSE103552, respectively.", "structure": {"repository": "GEO", "access_route": "GEO accession URL", "access_statement_verbatim": "DNA methylation and gene expression datasets generated and analysed during the current study are available at the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) database (http://www.ncbi.nlm.nih.gov/geo) under accession numbers GSE106099 and GSE103552, respectively.", "access_statement_kind": "data_availability_statement", "sample_accessions": ["GSM2773477", "GSM2773478", "GSM2773479", "GSM2773480", "GSM2773481", "GSM2773482", "GSM2773483", "GSM2773484", "GSM2773485", "GSM2773486", "GSM2773487", "GSM2773488", "GSM2773489", "GSM2773490", "GSM2773491", "GSM2773492", "GSM2773493", "GSM2773494", "GSM2773495", "GSM2773496", "GSM2773497", "GSM2773498", "GSM2773499", "GSM2773500", 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"version": null, "note": "DNA methylation and gene expression datasets generated and analysed during the current study are available at the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) database (http://www.ncbi.nlm.nih.gov/geo) under accession numbers GSE106099 and GSE103552, respectively.", "structure": {"repository": "GEO", "access_route": "GEO accession URL", "access_statement_verbatim": "DNA methylation and gene expression datasets generated and analysed during the current study are available at the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) database (http://www.ncbi.nlm.nih.gov/geo) under accession numbers GSE106099 and GSE103552, respectively.", "access_statement_kind": "data_availability_statement", "sample_accessions": ["GSM2829677", "GSM2829678", "GSM2829679", "GSM2829680", "GSM2829681", "GSM2829682", "GSM2829683", "GSM2829684", "GSM2829685", "GSM2829686", "GSM2829687", "GSM2829688", "GSM2829689", 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"read_table", "reader_status": "available", "identifier": "section[3]/table-wrap[1]#Tab1", "version": null, "note": "Maternal, neonatal and placental clinical variables for gene expression and DNA methylation analyses", "structure": {"pmcid": "PMC6182654", "section_index": 3, "section_title": "Sample collection", "row_count": 32, "column_count": 5}, "table": {"label": "Table 1", "caption": "Maternal, neonatal and placental clinical variables for gene expression and DNA methylation analyses", "rows": [["Variable", "Gene expression", "DNA methylation"], ["", "Normal pregnancy", "GDM pregnancy", "Normal pregnancy", "GDM pregnancy"], ["Maternal data"], ["No. of individuals used for cell isolation", "8", "14", "9", "9"], ["No. of cell isolations (AEC/VEC)", "8/8", "10/11", "9/9", "9/5"], ["Age (years)", "34.0 ± 7.3", "32.8 ± 7.9", "28.4 ± 6.3", "32.7 ± 6.6"], ["Gestational age (weeks)", "39.6 ± 1.5", "38.9 ± 1.2", "40.8 ± 1.5", "39.2 ± 1.3*"], ["Height (m)", "1.66 ± 0.09", "1.66 ± 0.06", 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"4/5", "4/5"], ["Offspring weight (g)", "3547 ± 428", "3275 ± 409", "3443 ± 482", "3318 ± 365"], ["Offspring length (cm)", "51.0 ± 2.1", "50.4 ± 2.0", "50.4 ± 2.7", "50.6 ± 2.7"], ["Placental weight (g)", "515 ± 190", "620 ± 188", "619 ± 195", "595 ± 159"], ["Fetal ponderal index", "26.7 ± 2.0", "25.5 ± 2.2", "26.8 ± 2.6", "25.9 ± 4.6"], ["Fetus/placenta weight ratio", "6.25 ± 1.37", "5.72 ± 1.74", "5.89 ± 1.44", "6.02 ± 1.78"], ["Cord blood insulin (pmol/l)", "ND", "223 ± 269", "150 ± 177", "181 ± 285"], ["Cord blood C-peptide (nmol/l)", "ND", "1.06 ± 0.93", "ND", "0.60 ± 0.23"], ["Cell culture data"], ["Cell isolation passage", "6.1 ± 1.2", "6.6 ± 1.1", "5.4 ± 1.0", "4.8 ± 0.6"]], "row_count": 32, "column_count": 5, "numeric_cells": 97, "header_rows": 2, "locator": "section[3]/table-wrap[1]#Tab1"}}, {"id": "asset:table:pmid:30091044:2", "role": "table", "format": "jats-table", "media_type": "application/vnd.jats.table+json", "uri": null, "sha256": 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maintenance", "6.94 × 10−6 to 3.87 × 10−2", "176"], ["Cellular assembly and organisationb", "2.86 × 10−5 to 3.87 × 10−2", "114"], ["Post-translational modification", "1.54 × 10−4 to 3.77 × 10−2", "26"], ["Cell morphologyb", "2.39 × 10−4 to 4.01 × 10−2", "92"], ["Cellular development", "2.39 × 10−4 to 4.40 × 10−2", "147"], ["VEC"], ["Cellular function and maintenance", "8.24 × 10−4 to 4.91 × 10−2", "53"], ["Molecular transport", "8.24 × 10−4 to 4.91 × 10−2", "51"], ["Cell morphologyb", "9.34 × 10−4 to 4.58 × 10−2", "45"], ["Cell-to-cell signalling and interaction", "9.34 × 10−4 to 4.94 × 10−2", "48"], ["Cellular compromise", "9.34 × 10−4 to 2.89 × 10−2", "14"], ["Gene expression"], ["AEC"], ["Cell cycle", "8.42 × 10−22 to 1.26 × 10−2", "159"], ["Cellular assembly and organisationb", "8.42 × 10−22 to 1.11 × 10−2", "106"], ["DNA replication, recombination and repair", "8.42 × 10−22 to 1.11 × 10−2", "159"], ["Cellular movementb", "2.54 × 10−8 to 1.11 × 10−2", "89"], ["Cellular growth and proliferation", "1.03 × 10−6 to 1.15 × 10−2", "234"], ["VEC"], ["Cell cycle", "1.75 × 10−6 to 1.83 × 10−2", "48"], ["Cell death and survival", "4.96 × 10−5 to 1.36 × 10−2", "25"], ["Cellular assembly and organisationb", "7.46 × 10−5 to 1.67 × 10−2", "46"], ["Cellular function and maintenance", "7.46 × 10−5 to 1.67 × 10−2", "38"], ["DNA replication, recombination and repair", "7.46 × 10−5 to 1.74 × 10−2", "24"]], "row_count": 27, "column_count": 3, "numeric_cells": 40, "header_rows": 1, "locator": "section[14]/table-wrap[1]#Tab2"}}, {"id": "asset:table:pmid:30091044:3", "role": "table", "format": "jats-table", "media_type": "application/vnd.jats.table+json", "uri": null, "sha256": "sha256:2343c4ea870ab49bd4465885fa6a1366df033b9a10f7d35fb4ce1795f6e4ce16", "bytes": 817, "access": "open", "state": "verified", "reader": "read_table", "reader_status": "available", "identifier": "section[17]/table-wrap[1]#Tab3", "version": null, "note": "Genes commonly regulated by GDM in AEC and VEC", "structure": {"pmcid": "PMC6182654", "section_index": 17, "section_title": "Concordant DNA methylation and expression changes in fetoplacental AEC and VEC", "row_count": 7, "column_count": 3}, "table": {"label": "Table 3", "caption": "Genes commonly regulated by GDM in AEC and VEC", "rows": [["Gene symbol", "Gene name", "Direction of expression and methylation change"], ["EGFR", "Epidermal growth factor receptor", "Concordant in AEC and VECUpregulated in AEC and downregulated in VEC"], ["GABBR1", "γ-Aminobutyric acid (GABA) B receptor, 1", "Concordant in AEC and VECUpregulated in AEC and VEC"], ["LMF1", "Lipase maturation factor 1", "Concordant in VECUpregulated in AEC and VEC"], ["NCKAP5", "NCK-associated protein 5", "Concordant in AEC and VECUpregulated in AEC and VEC"], ["SKIL", "SKI-like oncogene", "Concordant in VECUpregulated in AEC and VEC"], ["SULF2", "Sulfatase 2", "Concordant in VECUpregulated in AEC and VEC"]], "row_count": 7, "column_count": 3, "numeric_cells": 4, "header_rows": 1, "locator": "section[17]/table-wrap[1]#Tab3"}}, {"id": "asset:table:pmid:30091044:4", "role": "table", "format": "jats-table", "media_type": "application/vnd.jats.table+json", "uri": null, "sha256": "sha256:35ff173e911d31282c2b71c0c4c3a79c3fb3e78458c184f0a02eca29d8b52957", "bytes": 1872, "access": "open", "state": "verified", "reader": "read_table", "reader_status": "available", "identifier": "section[17]/table-wrap[2]#Tab4", "version": null, "note": "Top five significantly enriched molecular functions in Ingenuity Pathway Analysis for genes whose expression is potentially regulated by DNA methylation by GDM in AEC and VEC", "structure": {"pmcid": "PMC6182654", "section_index": 17, "section_title": "Concordant DNA methylation and expression changes in fetoplacental AEC and VEC", "row_count": 23, "column_count": 4}, "table": {"label": "Table 4", "caption": "Top five significantly enriched molecular functions in Ingenuity Pathway Analysis for genes whose expression is potentially regulated by DNA methylation by GDM in AEC and VEC", "rows": [["Regulation", "Molecular function", "p value", "Scorea"], ["AEC"], ["Hypomethylated/upregulated", "Cell morphologyb", "5.79 × 10−7 to 1.63 × 10−2", "40"], ["Cellular movementb", "2.54 × 10−5 to 1.56 × 10−2", "35"], ["Cell-to-cell signalling and interaction", "5.75 × 10−5 to 1.63 × 10−2", "28"], ["Carbohydrate metabolism", "1.98 × 10−4 to 1.63 × 10−2", "14"], ["Cellular development", "1.98 × 10−4 to 1.63 × 10−2", "33"], ["Hypermethylated/downregulated", "Cell-to-cell signalling and interaction", "2.18 × 10−5 to 4.61 × 10−2", "11"], ["Cellular compromise", "2.18 × 10−5 to 1.82 × 10−2", "10"], ["Molecular transport", "5.86 × 10−4 to 4.74 × 10−2", "10"], ["Cell cycle", "7.69 × 10−4 to 4.86 × 10−2", "11"], ["Cellular assembly and organisationb", "7.69 × 10−4 to 4.61 × 10−2", "16"], ["VEC"], ["Hypomethylated/upregulated", "Carbohydrate metabolism", "4.55 × 10−5 to 1.17 × 10−2", "4"], ["Small molecule biochemistry", "4.55 × 10−5 to 2.72 × 10−2", "11"], ["Cell morphologyb", "1.51 × 10−4 to 2.72 × 10−2", "23"], ["Cellular function and maintenance", "1.51 × 10−4 to 2.62 × 10−2", "20"], ["Cell-to-cell signalling and interaction", "1.58 × 10−4 to 2.72 × 10−2", "11"], ["Hypermethylated/downregulated", "Cell cycle", "1.48 × 10−4 to 4.85 × 10−2", "4"], ["Protein synthesis", "4.12 × 10−4 to 1.42 × 10−2", "6"], ["Cellular movementb", "4.76 × 10−4 to 4.58 × 10−2", "3"], ["Cell death and survival", "1.17 × 10−3 to 4.98 × 10−2", "5"], ["Cell morphologyb", "1.42 × 10−3 to 4.71 × 10−2", "4"]], "row_count": 23, "column_count": 4, "numeric_cells": 40, "header_rows": 1, "locator": "section[17]/table-wrap[2]#Tab4"}}], "gaps": ["asset:data:geo:GSE103552 not downloaded", "asset:data:geo:GSE103552 licence not read", "asset:data:geo:GSE106099 not downloaded", "asset:data:geo:GSE106099 licence not read"]}, "analysis": {"state": "complete", "methods": [{"id": "method-1", "family": "meta_analysis", "specific": 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No dataset was downloaded and no licence was read."}}, "can_run": {"dsl_operations": ["random_effects_pool"], "assets": ["source:pmid:30091044", "data:geo:GSE103552", "asset:table:pmid:30091044:1", "asset:table:pmid:30091044:2", "asset:table:pmid:30091044:3", "asset:table:pmid:30091044:4"], "steps": ["run_analysis"]}, "must_build": {"dsl_operations": [], "converters": [], "readers": [], "capabilities": [], "data_gaps": ["data:geo:GSE103552"]}, "gaps": []}, "review": {"state": "partial", "machine_critique": {"kind": "extraction_review", "reader": {"model": "MiniMax-M3.1-Flash", "provider": "minimax", "provider_family": "minimax", "read_at": null, "independence": "single_reader"}, "evidence_check": {"method": "verbatim", "availability": "verbatim"}, "calls": 0, "usage": {}}, "human_critique": null, "stages": [{"id": "extraction", "state": "complete", "reader": "MiniMax-M3.1-Flash", "provider": "minimax"}], "gaps": ["review.independent_reader", "review.machine_critique", "review.human_critique"]}, "execution": {"state": "absent", "status": "not_run", "mode": null, "runs": [], "gaps": ["execution.not_run"]}, "provenance": {"entities": [{"id": "pmid:30091044", "type": "paper", "label": "pmid:30091044"}, {"id": "source:pmid:30091044", "type": "manuscript", "label": "PMID 30091044 full text"}, {"id": "data:geo:GSE103552", "type": "dataset", "label": "GEO GSE103552"}], "activities": [{"id": "activity-reading-sci-2026-11-01", "type": "classification", "used": [{"id": "pmid:30091044", "type": "paper", "label": "pmid:30091044"}, {"id": "source:pmid:30091044", "type": "manuscript", "label": "PMID 30091044 full text"}, {"id": "data:geo:GSE103552", "type": "dataset", "label": "GEO GSE103552"}], "agent": "agent:corpus-assay-engine"}, {"id": "activity-read-30091044", "type": "extraction", "used": ["source:pmid:30091044"], "agent": "agent:minimax-reader"}, {"id": "activity-resolve-GSE103552", "type": "accession_resolution", "used": ["data:geo:GSE103552"], "agent": "agent:corpus-assay-engine"}], "agents": [{"id": "agent:corpus-assay-engine", "type": "software", "label": "Corpus assay engine"}, {"id": "agent:minimax-reader", "type": "software", "label": "MiniMax literature reader"}], "source_run_id": "reading-sci-2026-11-01", "dsl_catalogue_fingerprint": "343fb30756ba6ec3", "capability_table_fingerprint": "2cb3e42f047d2ecf", "snapshot_id": "ba34b49490d9bfaf"}, "lineage": {"parent_id": "pmid:30091044", "parent_hash": "sha256:0a14671ca7320b2ed8dba8b9ba33df13c442292be99d7b75a0fdd59cea9037a6", "fork_of": null, "generation": 7}, "gaps": ["asset:data:geo:GSE103552 licence not read", "asset:data:geo:GSE103552 not downloaded", "asset:data:geo:GSE106099 licence not read", "asset:data:geo:GSE106099 not downloaded", "execution.not_run", "review.human_critique", "review.independent_reader", "review.machine_critique"], "assays": [{"role": "analysis", "definition_id": "meta_analysis", "definition_version": "f2132e96ae6c7a4e", "definition_digest": null, "required_operations": ["random_effects_pool"], "support_state": "supported", "source_hashes": {"dsl_catalogue": "f2132e96ae6c7a4e"}, "confidence": 1.0, "evidence": ["The limma package [21] was used to fit a linear model to compare dAEC and dVEC vs control samples, with patient as random effect and allowing for batch effects."], "order_basis": "analysis_only", "id": "assay:1"}]}