{"gene":"ANGPT1","run_date":"2026-06-09T22:02:43","timeline":{"discoveries":[{"year":2017,"finding":"A missense mutation in ANGPT1 (p.A119S) reduces the formation of multimeric forms of the protein and impairs its ability to bind its natural receptor TIE2 (tunica interna endothelial cell kinase 2), establishing a mechanistic link between ANGPT1 multimerization/receptor binding and maintenance of vascular integrity (hereditary angioedema).","method":"Protein analysis of patient plasma, recombinant mutant protein expression, receptor binding assay","journal":"The Journal of allergy and clinical immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal plasma and recombinant protein analysis with binding assay in a single lab; two orthogonal methods (patient plasma and recombinant protein) supporting the same conclusion","pmids":["28601681"],"is_preprint":false},{"year":2015,"finding":"The histone H3K9 demethylase KDM3B transcriptionally represses ANGPT1 independently of its JmjC-domain demethylase activity, acting via interaction with the co-repressor SMRT to form a repressor complex at the ANGPT1 promoter; KDM3B depletion increases cell proliferation and motility.","method":"Reporter assay, co-immunoprecipitation (KDM3B–SMRT interaction), chromatin immunoprecipitation at ANGPT1 promoter, MTT and wound-healing assays with KDM3B knockdown","journal":"BMB reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus ChIP plus functional KD phenotype in single lab; multiple orthogonal methods supporting the same conclusion","pmids":["25413303"],"is_preprint":false},{"year":2012,"finding":"Enhanced Angpt1/Tie2 signaling in osteoblasts (via COMP-Angpt1 transgenic overexpression) affects hematopoietic lineage differentiation during early development and increases the long-term bone marrow reconstitution ability of LSK (Lin−Sca-1+c-Kit+) hematopoietic stem cells.","method":"Conditional transgenic mouse model (Col1a1-Cre × COMP-Angpt1), peripheral blood analysis, bone marrow transplantation/reconstitution assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean genetic gain-of-function in vivo with defined cellular phenotype; single lab, two functional readouts (lineage differentiation and reconstitution)","pmids":["23149415"],"is_preprint":false},{"year":2016,"finding":"Inhibition of ANGPT1 in follicular fluid from OHSS patients (using a neutralizing antibody) restores vascular branch points, integrin αvβ3 levels, claudin-5, VE-cadherin, and phosphorylated β-catenin, and partially reverses actin redistribution in endothelial cells, demonstrating that ANGPT1 modulates tight and adherens junction proteins to regulate vascular permeability.","method":"ANGPT1-neutralizing antibody in chorioallantoic membrane (CAM) assay and endothelial cell culture; immunofluorescence of junction proteins and cytoskeletal markers","journal":"Reproduction, fertility, and development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional antibody blockade in two complementary model systems (in vivo CAM and in vitro endothelial cells) in single lab","pmids":["25485810"],"is_preprint":false},{"year":2024,"finding":"In zebrafish, Angpt1 binds specifically to Tie1 (not other Tie receptors) as a ligand, activates Tie1 signaling (monitored by nuclear exclusion of EGFP-Foxo1a in sprouting endothelial cells), promotes endothelial cell migration and proliferation, and drives lymphatic specification during early lymphangiogenesis, at least in part by modulating Vegfc/Vegfr3 signaling.","method":"Comprehensive zebrafish mutant analysis (angpt1, tie1, other angiopoietin/Tie receptor mutants), ligand-binding assay, live EGFP-Foxo1a nuclear-import reporter, genetic epistasis with Vegfc/Vegfr3","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal genetic and live-imaging methods in a single comprehensive study; ligand–receptor binding confirmed, downstream signaling monitored, epistasis with Vegfc pathway established","pmids":["38742432"],"is_preprint":false},{"year":2025,"finding":"In RUNX1-MECOM-expressing leukemia cells, Angpt1 and its receptor Tek (Tie2) are co-expressed and form an autocrine signaling loop: exogenous Angpt1 stimulation phosphorylates endogenous Tek, which activates downstream Akt. HDAC inhibitors (TSA and VPA) downregulate both Tek and Angpt1 expression, disrupting this loop and inhibiting leukemia cell growth via cell-cycle arrest and apoptosis.","method":"Quantitative RT-PCR array, Western blot for Angpt1/Tek protein co-expression, Angpt1 stimulation with phospho-Tek and phospho-Akt detection, HDAC inhibitor treatment, in vitro proliferation and in vivo transplantation assay","journal":"Leukemia research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor phosphorylation assay plus downstream signaling plus in vivo validation in single lab; multiple orthogonal methods supporting autocrine loop","pmids":["40570741"],"is_preprint":false},{"year":2025,"finding":"Sympathetic innervation stimulates β-adrenergic receptors on perivascular cells to drive Angpt1 production; perivascular-derived Angpt1 maintains the quiescent state of post-natal skeletal muscle stem cells. Sympathetic denervation reduces perivascular Angpt1, leading to vascular remodeling, depletion of the muscle stem cell pool, and impaired tissue repair.","method":"Sympathetic denervation model, pharmacologic and genetic β-adrenergic receptor modulation, immunofluorescence/live imaging of muscle stem cell niche, loss-of-function for Angpt1","journal":"Developmental cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and pharmacologic tools in vivo with defined niche phenotype; single lab with multiple mechanistic readouts","pmids":["40752496"],"is_preprint":false},{"year":2024,"finding":"In pericytes, CCL28 reprograms retinoic acid (RA) metabolism and increases ANGPT1 expression via RXRα transcriptional activation of the ANGPT1 promoter (validated by ChIP-qPCR), thereby enhancing endothelial cell stability and promoting tumor vascular normalization after anti-angiogenesis therapy.","method":"CCL28 overexpression/knockout in vivo models, RNA sequencing of pericytes, ChIP-qPCR for RXRα binding to ANGPT1 promoter, LC-MS metabolomics, Western blot","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-qPCR directly shows RXRα occupancy at ANGPT1 promoter plus in vivo genetic models; single lab with multiple orthogonal methods","pmids":["39075504"],"is_preprint":false},{"year":2025,"finding":"Angpt1 carried by pericyte-derived extracellular vesicles (PCEVs) activates the PI3K/Akt pathway in endothelial cells; knockdown of Angpt1 in PCEVs suppresses PI3K/Akt activation and abolishes the protective effects on intestinal vascular barrier function and pericyte recruitment in sepsis.","method":"Proteomic analysis of PCEVs, Angpt1 knockdown in PCEVs, CLP sepsis rat model, in vitro endothelial assays, Western blot for phospho-PI3K and phospho-Akt","journal":"Stem cell research & therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function of Angpt1 in PCEVs with defined signaling and functional readouts in vivo and in vitro; single lab","pmids":["39940043"],"is_preprint":false},{"year":2025,"finding":"HMGB2 ablation in NK cells induces ANGPT1 expression, which activates the PI3K/AKT pathway; ANGPT1 knockdown in HMGB2-KO NK cells reduces PI3K/AKT activation and diminishes enhanced NK cytotoxicity (granzyme B, perforin, IFN-γ, TNF-α release and tumor lysis), establishing an ANGPT1/PI3K/AKT axis downstream of HMGB2 in NK cell function.","method":"CRISPR/Cas9 KO and RNA interference of HMGB2, ANGPT1 knockdown in KO-HMGB2 cells, flow cytometry for cytotoxic markers, tumor lysis assay","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — double KO epistasis (HMGB2 then ANGPT1) with functional cytotoxicity readout; single lab","pmids":["41280896"],"is_preprint":false}],"current_model":"ANGPT1 is a secreted glycoprotein that acts as a ligand for Tie2 (and, in zebrafish lymphatics, for Tie1), activating downstream PI3K/Akt signaling to stabilize endothelial cell junctions, promote vascular integrity, and regulate angiogenesis and lymphangiogenesis; its multimerization is required for efficient receptor binding, its transcription is repressed by a KDM3B–SMRT complex at its promoter and can be activated by RXRα downstream of retinoic acid signaling, it participates in autocrine Angpt1/Tie2 loops in certain leukemia cells, and in non-vascular contexts it acts from perivascular cells to maintain skeletal muscle stem cell quiescence via β-adrenergic–driven production."},"narrative":{"mechanistic_narrative":"ANGPT1 is a secreted, multimerizing glycoprotein ligand that signals through Tie receptor tyrosine kinases to stabilize the vasculature and regulate angiogenesis and lymphangiogenesis [PMID:28601681, PMID:38742432]. Efficient receptor engagement depends on its higher-order multimerization: a patient missense mutation (p.A119S) that impairs multimer formation reduces TIE2 binding and is associated with compromised vascular integrity [PMID:28601681]. Acting on endothelial cells, ANGPT1 activates the PI3K/Akt pathway and reinforces tight and adherens junctions—modulating claudin-5, VE-cadherin, integrin αvβ3, and β-catenin—to control vascular permeability and barrier function, including when delivered via pericyte-derived extracellular vesicles [PMID:25485810, PMID:39940043]. In zebrafish, Angpt1 binds specifically to Tie1 to drive endothelial migration, proliferation, and lymphatic specification in part through cross-talk with Vegfc/Vegfr3 signaling [PMID:38742432]. ANGPT1 transcription is gated by opposing regulators: a KDM3B–SMRT co-repressor complex represses the ANGPT1 promoter independently of KDM3B demethylase activity, while RXRα activates the promoter downstream of retinoic acid metabolism in pericytes to promote vascular normalization [PMID:25413303, PMID:39075504]. Beyond the vasculature, ANGPT1 functions in niche and immune contexts: perivascular ANGPT1 production driven by β-adrenergic signaling maintains skeletal muscle stem cell quiescence [PMID:40752496], osteoblastic Angpt1/Tie2 signaling supports hematopoietic stem cell reconstitution [PMID:23149415], an autocrine Angpt1/Tek loop sustains RUNX1-MECOM leukemia cell growth [PMID:40570741], and an ANGPT1/PI3K/AKT axis downstream of HMGB2 enhances NK cell cytotoxicity [PMID:41280896].","teleology":[{"year":2012,"claim":"Established that enhanced Angpt1/Tie2 signaling from a stromal (osteoblast) compartment shapes hematopoietic stem cell behavior, extending ANGPT1's role beyond endothelium into niche regulation.","evidence":"Col1a1-Cre × COMP-Angpt1 conditional transgenic mice with bone marrow transplantation/reconstitution assays","pmids":["23149415"],"confidence":"Medium","gaps":["Gain-of-function overexpression does not establish requirement of endogenous Angpt1","Receptor and downstream signaling in the niche not directly mapped"]},{"year":2015,"claim":"Identified a transcriptional brake on ANGPT1: a KDM3B–SMRT complex represses the promoter independently of demethylase activity, addressing how ANGPT1 expression is set in cells.","evidence":"Reporter assays, KDM3B–SMRT co-IP, ChIP at the ANGPT1 promoter, and KDM3B-knockdown proliferation/motility assays","pmids":["25413303"],"confidence":"Medium","gaps":["Functional consequence on secreted ANGPT1 protein and Tie2 signaling not shown","Cell-type generality of the repressor complex unknown"]},{"year":2016,"claim":"Showed mechanistically that ANGPT1 controls vascular permeability by tuning junctional and cytoskeletal proteins, connecting the ligand to endothelial barrier maintenance.","evidence":"ANGPT1-neutralizing antibody in CAM assay and endothelial cell culture with immunofluorescence of junction and cytoskeletal markers","pmids":["25485810"],"confidence":"Medium","gaps":["Direct receptor dependence (Tie2) not isolated in this assay","Quantitative ordering of junction protein changes not resolved"]},{"year":2017,"claim":"Linked ANGPT1 multimerization directly to receptor binding and human vascular pathology by characterizing a multimerization-impairing missense mutation.","evidence":"Patient plasma protein analysis plus recombinant mutant (p.A119S) expression and TIE2 binding assay","pmids":["28601681"],"confidence":"Medium","gaps":["Single variant; structural basis of multimerization not defined","Causal chain from reduced binding to angioedema phenotype inferred, not reconstituted"]},{"year":2024,"claim":"Resolved a receptor specificity question by demonstrating that, in zebrafish lymphatic development, Angpt1 acts as a Tie1 ligand that drives lymphatic specification via Vegfc/Vegfr3 cross-talk.","evidence":"Comprehensive zebrafish mutant analysis, ligand-binding assays, live EGFP-Foxo1a nuclear-import reporter, and genetic epistasis with Vegfc/Vegfr3","pmids":["38742432"],"confidence":"High","gaps":["Whether mammalian ANGPT1 uses Tie1 equivalently not established here","Direct biochemical affinity comparison across Tie receptors not quantified"]},{"year":2024,"claim":"Defined an activating transcriptional input to ANGPT1: RXRα binds the promoter downstream of CCL28-reprogrammed retinoic acid metabolism in pericytes to promote tumor vascular normalization.","evidence":"CCL28 in vivo overexpression/knockout, pericyte RNA-seq, ChIP-qPCR for RXRα at the ANGPT1 promoter, and LC-MS metabolomics","pmids":["39075504"],"confidence":"Medium","gaps":["Direct demonstration that the induced ANGPT1 is secreted and acts on adjacent endothelium via Tie2 not isolated","Generalizability beyond the tumor/pericyte context unknown"]},{"year":2025,"claim":"Demonstrated an autocrine Angpt1/Tek loop in RUNX1-MECOM leukemia, showing ANGPT1 signaling sustains malignant cell growth and is druggable via HDAC inhibition.","evidence":"RT-PCR array, Western blot co-expression, Angpt1 stimulation with phospho-Tek/phospho-Akt detection, HDAC inhibitor treatment, in vitro proliferation and in vivo transplantation","pmids":["40570741"],"confidence":"Medium","gaps":["Direct binding of autocrine Angpt1 to Tek not separately confirmed","HDAC inhibitor effects may be only partly through this loop"]},{"year":2025,"claim":"Showed perivascular ANGPT1, driven by sympathetic β-adrenergic input, maintains skeletal muscle stem cell quiescence, establishing a neuro-vascular-niche function.","evidence":"Sympathetic denervation model, pharmacologic and genetic β-adrenergic modulation, niche imaging, and Angpt1 loss-of-function","pmids":["40752496"],"confidence":"Medium","gaps":["Receptor mediating the quiescence effect not pinpointed","Whether effect is direct on stem cells or via vasculature not fully separated"]},{"year":2025,"claim":"Demonstrated extracellular-vesicle delivery of Angpt1 as a functional mode of action, with PCEV-borne Angpt1 driving endothelial PI3K/Akt activation and barrier protection in sepsis.","evidence":"PCEV proteomics, Angpt1 knockdown in PCEVs, CLP sepsis rat model, in vitro endothelial assays, phospho-PI3K/Akt Western blots","pmids":["39940043"],"confidence":"Medium","gaps":["Receptor engaged by EV-delivered Angpt1 not defined","Contribution relative to soluble secreted Angpt1 not quantified"]},{"year":2025,"claim":"Placed ANGPT1 in an immune-effector pathway, showing an ANGPT1/PI3K/AKT axis downstream of HMGB2 controls NK cell cytotoxicity.","evidence":"CRISPR/Cas9 and RNAi of HMGB2, ANGPT1 knockdown in HMGB2-KO cells, flow cytometry for cytotoxic markers, tumor lysis assay","pmids":["41280896"],"confidence":"Medium","gaps":["Whether ANGPT1 acts cell-autonomously via a Tie receptor in NK cells not shown","Mechanism of HMGB2 repression of ANGPT1 not defined"]},{"year":null,"claim":"It remains unresolved how ANGPT1 receptor choice (Tie2 vs Tie1) and signaling output are specified across mammalian tissues, and which receptor mediates its non-endothelial niche and immune functions.","evidence":"","pmids":[],"confidence":"Medium","gaps":["Mammalian Tie1 ligand role for ANGPT1 not established","Receptor identity in muscle stem cell, NK cell, and EV-mediated contexts undefined","Structural basis of multimerization-dependent binding not solved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,4]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[4,5,8]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[6,8]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,8,9]},{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[4]}],"complexes":[],"partners":["TIE2/TEK","TIE1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q15389","full_name":"Angiopoietin-1","aliases":[],"length_aa":498,"mass_kda":57.5,"function":"Binds and activates TEK/TIE2 receptor by inducing its dimerization and tyrosine phosphorylation. Plays an important role in the regulation of angiogenesis, endothelial cell survival, proliferation, migration, adhesion and cell spreading, reorganization of the actin cytoskeleton, but also maintenance of vascular quiescence. Required for normal angiogenesis and heart development during embryogenesis. After birth, activates or inhibits angiogenesis, depending on the context. Inhibits angiogenesis and promotes vascular stability in quiescent vessels, where endothelial cells have tight contacts. In quiescent vessels, ANGPT1 oligomers recruit TEK to cell-cell contacts, forming complexes with TEK molecules from adjoining cells, and this leads to preferential activation of phosphatidylinositol 3-kinase and the AKT1 signaling cascades. In migrating endothelial cells that lack cell-cell adhesions, ANGT1 recruits TEK to contacts with the extracellular matrix, leading to the formation of focal adhesion complexes, activation of PTK2/FAK and of the downstream kinases MAPK1/ERK2 and MAPK3/ERK1, and ultimately to the stimulation of sprouting angiogenesis. Mediates blood vessel maturation/stability. Implicated in endothelial developmental processes later and distinct from that of VEGF. Appears to play a crucial role in mediating reciprocal interactions between the endothelium and surrounding matrix and mesenchyme","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/Q15389/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ANGPT1","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"ACTR2","stoichiometry":0.2},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"PLK1","stoichiometry":0.2},{"gene":"RND3","stoichiometry":0.2},{"gene":"STK25","stoichiometry":0.2},{"gene":"TJP1","stoichiometry":0.2},{"gene":"TUBG1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/ANGPT1","total_profiled":1310},"omim":[{"mim_id":"620715","title":"BLEEDING DISORDER, VASCULAR-TYPE; BDVAS","url":"https://www.omim.org/entry/620715"},{"mim_id":"619361","title":"ANGIOEDEMA, HEREDITARY, 5; HAE5","url":"https://www.omim.org/entry/619361"},{"mim_id":"613753","title":"MICRO RNA 211; MIR211","url":"https://www.omim.org/entry/613753"},{"mim_id":"612456","title":"APOLIPOPROTEIN L DOMAIN-CONTAINING 1; APOLD1","url":"https://www.omim.org/entry/612456"},{"mim_id":"609336","title":"ANGIOPOIETIN-LIKE 6; ANGPTL6","url":"https://www.omim.org/entry/609336"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"seminal vesicle","ntpm":31.7}],"url":"https://www.proteinatlas.org/search/ANGPT1"},"hgnc":{"alias_symbol":["KIAA0003","Ang1","AGPT-1"],"prev_symbol":[]},"alphafold":{"accession":"Q15389","domains":[{"cath_id":"3.90.215.10","chopping":"285-494","consensus_level":"high","plddt":95.469,"start":285,"end":494},{"cath_id":"1.20.5","chopping":"88-246","consensus_level":"medium","plddt":92.4423,"start":88,"end":246}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15389","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q15389-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q15389-F1-predicted_aligned_error_v6.png","plddt_mean":83.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ANGPT1","jax_strain_url":"https://www.jax.org/strain/search?query=ANGPT1"},"sequence":{"accession":"Q15389","fasta_url":"https://rest.uniprot.org/uniprotkb/Q15389.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q15389/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15389"}},"corpus_meta":[{"pmid":"28601681","id":"PMC_28601681","title":"Mutation of the angiopoietin-1 gene (ANGPT1) associates with a new type of hereditary angioedema.","date":"2017","source":"The Journal of allergy and clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/28601681","citation_count":217,"is_preprint":false},{"pmid":"34335960","id":"PMC_34335960","title":"Exosomal lncRNA-H19 promotes osteogenesis and angiogenesis through mediating Angpt1/Tie2-NO signaling in CBS-heterozygous mice.","date":"2021","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/34335960","citation_count":117,"is_preprint":false},{"pmid":"27703260","id":"PMC_27703260","title":"Dual targeting of ANGPT1 and TGFBR2 genes by miR-204 controls angiogenesis in breast cancer.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/27703260","citation_count":63,"is_preprint":false},{"pmid":"33164880","id":"PMC_33164880","title":"Blocking exosomal miRNA-153-3p derived from bone marrow mesenchymal stem cells ameliorates hypoxia-induced myocardial and microvascular damage by targeting the ANGPT1-mediated VEGF/PI3k/Akt/eNOS pathway.","date":"2020","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/33164880","citation_count":47,"is_preprint":false},{"pmid":"33869178","id":"PMC_33869178","title":"Exosomal miR-3682-3p Suppresses Angiogenesis by Targeting ANGPT1 via the RAS-MEK1/2-ERK1/2 Pathway in Hepatocellular Carcinoma.","date":"2021","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/33869178","citation_count":31,"is_preprint":false},{"pmid":"28045923","id":"PMC_28045923","title":"Germline Genetic Variants in TEK, ANGPT1, ANGPT2, MMP9, FGF2 and VEGFA Are Associated with Pathologic Complete Response to Bevacizumab in Breast Cancer Patients.","date":"2017","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/28045923","citation_count":19,"is_preprint":false},{"pmid":"34404035","id":"PMC_34404035","title":"Transplantation of 3D bio-printed cardiac mesh improves 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disease","date":"2025-08-29","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.25.672093","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":18011,"output_tokens":2910,"usd":0.048842,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10310,"output_tokens":3750,"usd":0.07265,"stage2_stop_reason":"end_turn"},"total_usd":0.121492,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2017,\n      \"finding\": \"A missense mutation in ANGPT1 (p.A119S) reduces the formation of multimeric forms of the protein and impairs its ability to bind its natural receptor TIE2 (tunica interna endothelial cell kinase 2), establishing a mechanistic link between ANGPT1 multimerization/receptor binding and maintenance of vascular integrity (hereditary angioedema).\",\n      \"method\": \"Protein analysis of patient plasma, recombinant mutant protein expression, receptor binding assay\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal plasma and recombinant protein analysis with binding assay in a single lab; two orthogonal methods (patient plasma and recombinant protein) supporting the same conclusion\",\n      \"pmids\": [\"28601681\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The histone H3K9 demethylase KDM3B transcriptionally represses ANGPT1 independently of its JmjC-domain demethylase activity, acting via interaction with the co-repressor SMRT to form a repressor complex at the ANGPT1 promoter; KDM3B depletion increases cell proliferation and motility.\",\n      \"method\": \"Reporter assay, co-immunoprecipitation (KDM3B–SMRT interaction), chromatin immunoprecipitation at ANGPT1 promoter, MTT and wound-healing assays with KDM3B knockdown\",\n      \"journal\": \"BMB reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus ChIP plus functional KD phenotype in single lab; multiple orthogonal methods supporting the same conclusion\",\n      \"pmids\": [\"25413303\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Enhanced Angpt1/Tie2 signaling in osteoblasts (via COMP-Angpt1 transgenic overexpression) affects hematopoietic lineage differentiation during early development and increases the long-term bone marrow reconstitution ability of LSK (Lin−Sca-1+c-Kit+) hematopoietic stem cells.\",\n      \"method\": \"Conditional transgenic mouse model (Col1a1-Cre × COMP-Angpt1), peripheral blood analysis, bone marrow transplantation/reconstitution assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic gain-of-function in vivo with defined cellular phenotype; single lab, two functional readouts (lineage differentiation and reconstitution)\",\n      \"pmids\": [\"23149415\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Inhibition of ANGPT1 in follicular fluid from OHSS patients (using a neutralizing antibody) restores vascular branch points, integrin αvβ3 levels, claudin-5, VE-cadherin, and phosphorylated β-catenin, and partially reverses actin redistribution in endothelial cells, demonstrating that ANGPT1 modulates tight and adherens junction proteins to regulate vascular permeability.\",\n      \"method\": \"ANGPT1-neutralizing antibody in chorioallantoic membrane (CAM) assay and endothelial cell culture; immunofluorescence of junction proteins and cytoskeletal markers\",\n      \"journal\": \"Reproduction, fertility, and development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional antibody blockade in two complementary model systems (in vivo CAM and in vitro endothelial cells) in single lab\",\n      \"pmids\": [\"25485810\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In zebrafish, Angpt1 binds specifically to Tie1 (not other Tie receptors) as a ligand, activates Tie1 signaling (monitored by nuclear exclusion of EGFP-Foxo1a in sprouting endothelial cells), promotes endothelial cell migration and proliferation, and drives lymphatic specification during early lymphangiogenesis, at least in part by modulating Vegfc/Vegfr3 signaling.\",\n      \"method\": \"Comprehensive zebrafish mutant analysis (angpt1, tie1, other angiopoietin/Tie receptor mutants), ligand-binding assay, live EGFP-Foxo1a nuclear-import reporter, genetic epistasis with Vegfc/Vegfr3\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal genetic and live-imaging methods in a single comprehensive study; ligand–receptor binding confirmed, downstream signaling monitored, epistasis with Vegfc pathway established\",\n      \"pmids\": [\"38742432\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In RUNX1-MECOM-expressing leukemia cells, Angpt1 and its receptor Tek (Tie2) are co-expressed and form an autocrine signaling loop: exogenous Angpt1 stimulation phosphorylates endogenous Tek, which activates downstream Akt. HDAC inhibitors (TSA and VPA) downregulate both Tek and Angpt1 expression, disrupting this loop and inhibiting leukemia cell growth via cell-cycle arrest and apoptosis.\",\n      \"method\": \"Quantitative RT-PCR array, Western blot for Angpt1/Tek protein co-expression, Angpt1 stimulation with phospho-Tek and phospho-Akt detection, HDAC inhibitor treatment, in vitro proliferation and in vivo transplantation assay\",\n      \"journal\": \"Leukemia research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor phosphorylation assay plus downstream signaling plus in vivo validation in single lab; multiple orthogonal methods supporting autocrine loop\",\n      \"pmids\": [\"40570741\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Sympathetic innervation stimulates β-adrenergic receptors on perivascular cells to drive Angpt1 production; perivascular-derived Angpt1 maintains the quiescent state of post-natal skeletal muscle stem cells. Sympathetic denervation reduces perivascular Angpt1, leading to vascular remodeling, depletion of the muscle stem cell pool, and impaired tissue repair.\",\n      \"method\": \"Sympathetic denervation model, pharmacologic and genetic β-adrenergic receptor modulation, immunofluorescence/live imaging of muscle stem cell niche, loss-of-function for Angpt1\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and pharmacologic tools in vivo with defined niche phenotype; single lab with multiple mechanistic readouts\",\n      \"pmids\": [\"40752496\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In pericytes, CCL28 reprograms retinoic acid (RA) metabolism and increases ANGPT1 expression via RXRα transcriptional activation of the ANGPT1 promoter (validated by ChIP-qPCR), thereby enhancing endothelial cell stability and promoting tumor vascular normalization after anti-angiogenesis therapy.\",\n      \"method\": \"CCL28 overexpression/knockout in vivo models, RNA sequencing of pericytes, ChIP-qPCR for RXRα binding to ANGPT1 promoter, LC-MS metabolomics, Western blot\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-qPCR directly shows RXRα occupancy at ANGPT1 promoter plus in vivo genetic models; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"39075504\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Angpt1 carried by pericyte-derived extracellular vesicles (PCEVs) activates the PI3K/Akt pathway in endothelial cells; knockdown of Angpt1 in PCEVs suppresses PI3K/Akt activation and abolishes the protective effects on intestinal vascular barrier function and pericyte recruitment in sepsis.\",\n      \"method\": \"Proteomic analysis of PCEVs, Angpt1 knockdown in PCEVs, CLP sepsis rat model, in vitro endothelial assays, Western blot for phospho-PI3K and phospho-Akt\",\n      \"journal\": \"Stem cell research & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function of Angpt1 in PCEVs with defined signaling and functional readouts in vivo and in vitro; single lab\",\n      \"pmids\": [\"39940043\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HMGB2 ablation in NK cells induces ANGPT1 expression, which activates the PI3K/AKT pathway; ANGPT1 knockdown in HMGB2-KO NK cells reduces PI3K/AKT activation and diminishes enhanced NK cytotoxicity (granzyme B, perforin, IFN-γ, TNF-α release and tumor lysis), establishing an ANGPT1/PI3K/AKT axis downstream of HMGB2 in NK cell function.\",\n      \"method\": \"CRISPR/Cas9 KO and RNA interference of HMGB2, ANGPT1 knockdown in KO-HMGB2 cells, flow cytometry for cytotoxic markers, tumor lysis assay\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — double KO epistasis (HMGB2 then ANGPT1) with functional cytotoxicity readout; single lab\",\n      \"pmids\": [\"41280896\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ANGPT1 is a secreted glycoprotein that acts as a ligand for Tie2 (and, in zebrafish lymphatics, for Tie1), activating downstream PI3K/Akt signaling to stabilize endothelial cell junctions, promote vascular integrity, and regulate angiogenesis and lymphangiogenesis; its multimerization is required for efficient receptor binding, its transcription is repressed by a KDM3B–SMRT complex at its promoter and can be activated by RXRα downstream of retinoic acid signaling, it participates in autocrine Angpt1/Tie2 loops in certain leukemia cells, and in non-vascular contexts it acts from perivascular cells to maintain skeletal muscle stem cell quiescence via β-adrenergic–driven production.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ANGPT1 is a secreted, multimerizing glycoprotein ligand that signals through Tie receptor tyrosine kinases to stabilize the vasculature and regulate angiogenesis and lymphangiogenesis [#0, #4]. Efficient receptor engagement depends on its higher-order multimerization: a patient missense mutation (p.A119S) that impairs multimer formation reduces TIE2 binding and is associated with compromised vascular integrity [#0]. Acting on endothelial cells, ANGPT1 activates the PI3K/Akt pathway and reinforces tight and adherens junctions—modulating claudin-5, VE-cadherin, integrin \\u03b1v\\u03b23, and \\u03b2-catenin—to control vascular permeability and barrier function, including when delivered via pericyte-derived extracellular vesicles [#3, #8]. In zebrafish, Angpt1 binds specifically to Tie1 to drive endothelial migration, proliferation, and lymphatic specification in part through cross-talk with Vegfc/Vegfr3 signaling [#4]. ANGPT1 transcription is gated by opposing regulators: a KDM3B\\u2013SMRT co-repressor complex represses the ANGPT1 promoter independently of KDM3B demethylase activity, while RXR\\u03b1 activates the promoter downstream of retinoic acid metabolism in pericytes to promote vascular normalization [#1, #7]. Beyond the vasculature, ANGPT1 functions in niche and immune contexts: perivascular ANGPT1 production driven by \\u03b2-adrenergic signaling maintains skeletal muscle stem cell quiescence [#6], osteoblastic Angpt1/Tie2 signaling supports hematopoietic stem cell reconstitution [#2], an autocrine Angpt1/Tek loop sustains RUNX1-MECOM leukemia cell growth [#5], and an ANGPT1/PI3K/AKT axis downstream of HMGB2 enhances NK cell cytotoxicity [#9].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Established that enhanced Angpt1/Tie2 signaling from a stromal (osteoblast) compartment shapes hematopoietic stem cell behavior, extending ANGPT1's role beyond endothelium into niche regulation.\",\n      \"evidence\": \"Col1a1-Cre \\u00d7 COMP-Angpt1 conditional transgenic mice with bone marrow transplantation/reconstitution assays\",\n      \"pmids\": [\"23149415\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Gain-of-function overexpression does not establish requirement of endogenous Angpt1\", \"Receptor and downstream signaling in the niche not directly mapped\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified a transcriptional brake on ANGPT1: a KDM3B\\u2013SMRT complex represses the promoter independently of demethylase activity, addressing how ANGPT1 expression is set in cells.\",\n      \"evidence\": \"Reporter assays, KDM3B\\u2013SMRT co-IP, ChIP at the ANGPT1 promoter, and KDM3B-knockdown proliferation/motility assays\",\n      \"pmids\": [\"25413303\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence on secreted ANGPT1 protein and Tie2 signaling not shown\", \"Cell-type generality of the repressor complex unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed mechanistically that ANGPT1 controls vascular permeability by tuning junctional and cytoskeletal proteins, connecting the ligand to endothelial barrier maintenance.\",\n      \"evidence\": \"ANGPT1-neutralizing antibody in CAM assay and endothelial cell culture with immunofluorescence of junction and cytoskeletal markers\",\n      \"pmids\": [\"25485810\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct receptor dependence (Tie2) not isolated in this assay\", \"Quantitative ordering of junction protein changes not resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Linked ANGPT1 multimerization directly to receptor binding and human vascular pathology by characterizing a multimerization-impairing missense mutation.\",\n      \"evidence\": \"Patient plasma protein analysis plus recombinant mutant (p.A119S) expression and TIE2 binding assay\",\n      \"pmids\": [\"28601681\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single variant; structural basis of multimerization not defined\", \"Causal chain from reduced binding to angioedema phenotype inferred, not reconstituted\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Resolved a receptor specificity question by demonstrating that, in zebrafish lymphatic development, Angpt1 acts as a Tie1 ligand that drives lymphatic specification via Vegfc/Vegfr3 cross-talk.\",\n      \"evidence\": \"Comprehensive zebrafish mutant analysis, ligand-binding assays, live EGFP-Foxo1a nuclear-import reporter, and genetic epistasis with Vegfc/Vegfr3\",\n      \"pmids\": [\"38742432\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether mammalian ANGPT1 uses Tie1 equivalently not established here\", \"Direct biochemical affinity comparison across Tie receptors not quantified\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined an activating transcriptional input to ANGPT1: RXR\\u03b1 binds the promoter downstream of CCL28-reprogrammed retinoic acid metabolism in pericytes to promote tumor vascular normalization.\",\n      \"evidence\": \"CCL28 in vivo overexpression/knockout, pericyte RNA-seq, ChIP-qPCR for RXR\\u03b1 at the ANGPT1 promoter, and LC-MS metabolomics\",\n      \"pmids\": [\"39075504\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct demonstration that the induced ANGPT1 is secreted and acts on adjacent endothelium via Tie2 not isolated\", \"Generalizability beyond the tumor/pericyte context unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated an autocrine Angpt1/Tek loop in RUNX1-MECOM leukemia, showing ANGPT1 signaling sustains malignant cell growth and is druggable via HDAC inhibition.\",\n      \"evidence\": \"RT-PCR array, Western blot co-expression, Angpt1 stimulation with phospho-Tek/phospho-Akt detection, HDAC inhibitor treatment, in vitro proliferation and in vivo transplantation\",\n      \"pmids\": [\"40570741\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding of autocrine Angpt1 to Tek not separately confirmed\", \"HDAC inhibitor effects may be only partly through this loop\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed perivascular ANGPT1, driven by sympathetic \\u03b2-adrenergic input, maintains skeletal muscle stem cell quiescence, establishing a neuro-vascular-niche function.\",\n      \"evidence\": \"Sympathetic denervation model, pharmacologic and genetic \\u03b2-adrenergic modulation, niche imaging, and Angpt1 loss-of-function\",\n      \"pmids\": [\"40752496\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor mediating the quiescence effect not pinpointed\", \"Whether effect is direct on stem cells or via vasculature not fully separated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated extracellular-vesicle delivery of Angpt1 as a functional mode of action, with PCEV-borne Angpt1 driving endothelial PI3K/Akt activation and barrier protection in sepsis.\",\n      \"evidence\": \"PCEV proteomics, Angpt1 knockdown in PCEVs, CLP sepsis rat model, in vitro endothelial assays, phospho-PI3K/Akt Western blots\",\n      \"pmids\": [\"39940043\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor engaged by EV-delivered Angpt1 not defined\", \"Contribution relative to soluble secreted Angpt1 not quantified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Placed ANGPT1 in an immune-effector pathway, showing an ANGPT1/PI3K/AKT axis downstream of HMGB2 controls NK cell cytotoxicity.\",\n      \"evidence\": \"CRISPR/Cas9 and RNAi of HMGB2, ANGPT1 knockdown in HMGB2-KO cells, flow cytometry for cytotoxic markers, tumor lysis assay\",\n      \"pmids\": [\"41280896\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ANGPT1 acts cell-autonomously via a Tie receptor in NK cells not shown\", \"Mechanism of HMGB2 repression of ANGPT1 not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how ANGPT1 receptor choice (Tie2 vs Tie1) and signaling output are specified across mammalian tissues, and which receptor mediates its non-endothelial niche and immune functions.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mammalian Tie1 ligand role for ANGPT1 not established\", \"Receptor identity in muscle stem cell, NK cell, and EV-mediated contexts undefined\", \"Structural basis of multimerization-dependent binding not solved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [4, 5, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [6, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 8, 9]},\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"TIE2/TEK\", \"TIE1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}