{"gene":"ANGPT2","run_date":"2026-06-09T22:02:43","timeline":{"discoveries":[{"year":2021,"finding":"Endothelial GNAQ p.R183Q mutation constitutively activates PLCβ3, leading to increased ANGPT2 expression via PKC and NF-κB/calcineurin signaling. shRNA knockdown of ANGPT2 in GNAQ p.R183Q endothelial cells normalized enlarged blood vessels in a mouse xenograft model to sizes comparable to wild-type, establishing ANGPT2 as a downstream effector of mutant Gαq in capillary malformation pathogenesis.","method":"Lentiviral expression of mutant/WT GNAQ in endothelial colony forming cells; siRNA knockdown of PLCβ3; pan-PKC inhibitor; shRNA knockdown of ANGPT2; in vivo mouse xenograft model; qPCR; immunostaining of human CM tissue","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (siRNA, pharmacologic inhibition, in vivo rescue), genetic epistasis by shRNA knockdown with specific vascular phenotype readout, confirmed in human tissue","pmids":["34670408"],"is_preprint":false},{"year":2020,"finding":"The RAS-ERK1/2 signaling axis controls ANGPT2 expression in colorectal cancer cells; gain- and loss-of-function studies showed ANGPT2 facilitates liver but not lung metastasis development, indicating tissue-specific pro-metastatic roles downstream of ERK1/2.","method":"In vivo selection of highly liver-metastatic CRC cells; gain- and loss-of-function studies in multiple CRC cell lines; in vivo metastasis assays; clinical sample validation","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple cell lines and in vivo models, single lab, gain/loss-of-function with specific metastatic phenotype","pmids":["32816905"],"is_preprint":false},{"year":2022,"finding":"MYBL1 binds directly to the ANGPT2 promoter and transcriptionally upregulates ANGPT2 mRNA expression; this requires the histone post-translational factors PRMT5, MEP50, and WDR5. Monoclonal antibody against ANGPT2 inhibited growth of MYBL1-overexpressing tumors and impaired angiogenesis.","method":"ChIP assay (MYBL1 binding to ANGPT2 promoter); luciferase reporter assay; siRNA knockdown of PRMT5/MEP50/WDR5; anti-ANGPT2 monoclonal antibody treatment in vivo; HUVEC tube formation assay","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirmed direct promoter binding, multiple co-factors identified, single lab with multiple orthogonal methods","pmids":["35987690"],"is_preprint":false},{"year":2015,"finding":"DARPP-32 and its isoform t-DARPP induce ANGPT2 expression via activation of STAT3 (phosphorylation and nuclear localization), independently of T34-mediated PP1 regulation and NF-κB. The secreted ANGPT2 is functionally active and promotes endothelial tube formation; antibody blocking of secreted ANGPT2 abrogated this angiogenic function.","method":"Quantitative RT-PCR; immunoblotting; luciferase reporter; STAT3 inhibition/knockdown; HUVEC tube formation assay; ANGPT2 antibody blocking; in vivo xenograft; immunohistochemistry of human gastric cancer tissue","journal":"Gut","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (reporter assay, siRNA, pharmacologic inhibition, in vivo rescue, antibody blocking, human tissue validation), mechanistic pathway placement with specific readouts","pmids":["25779598"],"is_preprint":false},{"year":2020,"finding":"Characterization of ANGPT2 mutations associated with primary lymphedema revealed three missense mutations that decrease ANGPT2 secretion and inhibit secretion of wild-type ANGPT2 (dominant-negative effect). WT-ANGPT2 and soluble mutants T299M and N304K activated TIE1 and TIE2 in an autocrine assay in human lymphatic endothelial cells. The T299M mutant (in the dimerization interface) showed reduced integrin α5 binding, and expression in mouse skin promoted hyperplasia and dilation of cutaneous lymphatic vessels. Biophysical studies showed amino-terminally truncated ANGPT2 subunits formed asymmetrical homodimers that bound TIE2 in a 2:1 ratio.","method":"Functional secretion assays; TIE1/TIE2 autocrine activation assay in lymphatic endothelial cells; molecular modeling; biophysical binding studies; integrin α5 binding assay; mouse skin in vivo model; cohort screening of 543 lymphedema patients","journal":"Science translational medicine","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — reconstitution-level binding/activation assays, molecular modeling, mutagenesis, in vivo phenotype, multiple orthogonal methods in one study","pmids":["32908006"],"is_preprint":false},{"year":2022,"finding":"Pituitary neuroendocrine tumor (PitNET) cells express functional TIE2 receptor and secrete bioactive ANGPT2 that promotes tumor cell growth via an autocrine/paracrine loop. ANGPT2 stimulation of TIE2 in tumor cells activates downstream cell proliferation signals. Tie2 gene deletion blunted PitNET growth in xenograft models; pharmacological inhibition of ANGPT2/TIE2 antagonized PitNETs in primary cell cultures, xenografts, and an autochthonous rat model.","method":"GH3 PitNET cell line and primary human NF-PitNET cells; zebrafish and mouse xenografts; MENX rat autochthonous model; Tie2 gene deletion; pharmacological inhibition of Angpt2/Tie2; TIE2 functional assays","journal":"EMBO molecular medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple model systems (cell lines, zebrafish, mouse xenograft, autochthonous rat), genetic and pharmacological intervention, replicated across models","pmids":["35266635"],"is_preprint":false},{"year":2010,"finding":"SF-1 (steroidogenic factor-1/NR5A1) directly binds a 1.1-kb region in the ANGPT2 promoter (in a highly repetitive region) and transcriptionally activates ANGPT2, as confirmed by ChIP-on-chip in NCI-H295R human adrenocortical cells and luciferase reporter assays.","method":"ChIP-on-chip (promoter tiling arrays); luciferase reporter assay; systems/network analysis in NCI-H295R cells","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-on-chip plus luciferase validation, single lab, two orthogonal methods","pmids":["21163858"],"is_preprint":false},{"year":2015,"finding":"MCPH1 binds to the ANGPT2 promoter and recruits DNA methyltransferases to maintain promoter methylation, thereby silencing ANGPT2 transcription. MCPH1 knockdown results in ANGPT2 upregulation with concurrent loss of promoter methylation in chronic lymphocytic leukemia cells.","method":"Chromatin immunoprecipitation (ChIP); co-immunoprecipitation (co-IP); MCPH1 knockdown; mRNA expression quantification; promoter methylation analysis","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and co-IP confirm direct promoter binding and recruitment of DNMT, single lab, two orthogonal methods","pmids":["25703238"],"is_preprint":false},{"year":2018,"finding":"Loss of Fzd5 in endothelial cells leads to upregulation of Angpt2 (and Flt1) via enhanced PKC signaling; this transcriptional induction involves the transcription factor Ets1. Canonical Wnt signaling, non-canonical Wnt/Ca2+-NFAT, and Wnt/PCP-JNK pathways were not involved.","method":"siRNA-mediated knockdown of Fzd5 in human endothelial cells; PKC inhibitor; Ets1 transcription factor studies; 3D co-culture angiogenesis assay; cell cycle analysis","journal":"Angiogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with specific pathway dissection using pharmacologic inhibitors, single lab, multiple pathway controls tested","pmids":["29845518"],"is_preprint":false},{"year":2020,"finding":"ISL2 binds directly to the ANGPT2 promoter and transcriptionally regulates ANGPT2 expression; ANGPT2, as a downstream gene, activates angiogenesis through VEGFA to promote oligodendroglioma malignant transformation.","method":"ChIP assay (ISL2 binding to ANGPT2 promoter); oligodendroglioma patient tumor-derived orthotopic xenograft mouse models; AAV-ISL2-shRNA knockdown; luciferase reporter","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirmed direct promoter binding, in vivo orthotopic model, single lab","pmids":["32753650"],"is_preprint":false},{"year":2022,"finding":"HOXB5 transcriptionally activates ANGPT2, as confirmed by luciferase reporter and ChIP assays. ANGPT2 silencing inactivated ERK/AKT signaling, and HOXB5 overexpression reversed this effect, placing ANGPT2 downstream of HOXB5 in a pathway regulating proliferation, migration, invasion, and angiogenesis in esophageal cancer cells.","method":"Luciferase reporter assay; ChIP assay; shRNA knockdown of ANGPT2; HOXB5 overexpression; tube formation assay; proliferation/invasion assays; Western blot for ERK/AKT","journal":"Experimental and therapeutic medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and luciferase confirm direct transcriptional regulation, epistasis via rescue experiment, single lab","pmids":["35949323"],"is_preprint":false},{"year":2025,"finding":"NNMT/1-MNA protects against hepatic ischemia-reperfusion injury through the AKT/FOXO1/ANGPT2/JNK axis. Hepatic-specific depletion of NNMT increased ANGPT2 expression and exacerbated HIRI; these effects were mitigated by ANGPT2 knockdown, placing ANGPT2 downstream of FOXO1 as a mediator of vascular injury and inflammation.","method":"NNMT overexpression and hepatic-specific depletion in mouse HIRI models; ANGPT2 knockdown; AKT/FOXO1 pathway analysis; primary hepatocyte H/R models","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis via tissue-specific KO and ANGPT2 knockdown rescue, in vivo and in vitro, single lab","pmids":["40404636"],"is_preprint":false},{"year":2025,"finding":"IFN-γ suppresses ANGPT2 gene transcription in endothelial cells through the AKT-FOXO1 signaling pathway, and IFN-γ-activated STAT1 directly binds to the promoter regions of ANGPT2 and TEK genes to exert negative regulation. Anti-PD-L1 therapy reduced Tie2 and ANGPT2 expression in a JAK1/2-dependent manner in a mouse LUAD model.","method":"ChIP assay (STAT1 binding to ANGPT2 promoter); siRNA knockdown; RT-qPCR; Western blot; immunofluorescence; HUVEC tube formation, migration, proliferation assays; JAK1/2 inhibitor; mouse LUAD model with PD-L1 blockade","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirms direct promoter binding by STAT1, pharmacologic pathway dissection, in vivo and in vitro, single lab","pmids":["40370455"],"is_preprint":false},{"year":2025,"finding":"RBMS3 facilitates K48-linked ubiquitination and subsequent proteasomal degradation of ANGPT2 by recruiting the ubiquitin E3 ligase TRIM21, in an RNA-independent manner. Loss of RBMS3 in HCC cells promotes ANGPT2 accumulation and secretion, driving angiogenesis and sorafenib resistance.","method":"Immunoprecipitation mass spectrometry; co-immunoprecipitation (co-IP); ubiquitination assays; loss- and gain-of-function experiments; anti-ANGPT2 antibody rescue in vitro and in vivo","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-IP plus MS identified TRIM21 interaction, ubiquitination assay with K48-linkage specificity, in vivo rescue, multiple orthogonal methods","pmids":["40069332"],"is_preprint":false},{"year":2021,"finding":"In anti-Thy-1 nephritis, activated mesangial cells express VEGFA, which stimulates VEGFR2 on endothelial cells, induces Angpt2 expression in ECs, and inhibits Tie2 phosphorylation. The decline in Tie2 phosphorylation promotes EC proliferation. Promoting Tie2 phosphorylation alleviated EC proliferation in vivo.","method":"In vivo anti-Thy-1 nephritis rat model; in vitro mesangial-endothelial cell co-culture; siRNA knockdown; EdU proliferation assay; ELISA; RT-qPCR; Western blot; immunohistochemistry/immunofluorescence","journal":"Cell proliferation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown in co-culture system plus in vivo model, pathway placement with specific signaling readout, single lab","pmids":["33987885"],"is_preprint":false},{"year":2018,"finding":"Angpt2 induces mesangial cell apoptosis under high glucose conditions via suppression of miR-33-5p, which leads to increased SOCS5 expression, inhibiting JAK1 and STAT3 signaling transduction.","method":"In vitro mesangial cell treatment with Angpt2 under high glucose; miR-33-5p manipulation; SOCS5 expression analysis; JAK1/STAT3 phosphorylation assays; db/db mouse model; urine miR-33-5p measurements","journal":"Molecular therapy. Nucleic acids","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro mechanistic pathway with miRNA manipulation and downstream signaling readout, in vivo correlation, single lab","pmids":["30414568"],"is_preprint":false},{"year":2022,"finding":"ANGPT2 knockdown in hypertrophic scar fibroblasts decreased phosphorylation of PI3K, Akt, and mTOR, activated autophagy, and inhibited proliferation, migration, and ECM accumulation. Treatment with an mTOR agonist partially reversed these effects of ANGPT2 knockdown, placing ANGPT2 upstream of the PI3K/Akt/mTOR pathway.","method":"sh-ANGPT2 knockdown in hypertrophic scar fibroblasts; mTOR agonist (MHT1485) treatment; CCK-8 proliferation assay; Transwell migration assay; Western blot for PI3K/Akt/mTOR pathway; autophagy markers","journal":"Anais brasileiros de dermatologia","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single method (knockdown + rescue), single lab, no in vivo validation","pmids":["36272879"],"is_preprint":false},{"year":2023,"finding":"ANGPT2 exacerbates albumin transcytosis across glomerular endothelial cells by increasing CAV1 expression during high glucose exposure. ANGPT2 knockdown reduced albumin transcytosis and CAV1 expression in vitro, and losartan reduced ANGPT2 and CAV1 in a DKD mouse model.","method":"In vitro albumin transcytosis model in hrGECs; ANGPT2 and CAV1 siRNA knockdown; in vivo DKD mouse model with losartan treatment; immunohistochemistry; Western blot","journal":"Nefrologia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro knockdown with specific transcytosis readout plus in vivo validation, single lab","pmids":["36842857"],"is_preprint":false},{"year":2025,"finding":"Endothelial ANGPT2 impairs cardiomyocyte calcium homeostasis in sepsis-related cardiomyopathy by binding to the extracellular domain of integrin β3 (ITGB3), triggering RYR2 phosphorylation and dysregulation of ATP2a2/PLN expression. ITGB3-specific siRNA attenuated the effects of ANGPT2 on calcium signaling proteins. AAV9-mediated EC-specific ANGPT2 overexpression exacerbated CLP-induced cardiac dysfunction.","method":"AAV9 EC-specific ANGPT2 overexpression mice; CLP sepsis model; ITGB3 siRNA knockdown; primary neonatal and adult mouse cardiomyocyte calcium imaging; Western blot for RYR2/ATP2a2/PLN; bioinformatics; serum CK-MB/cTnI correlation","journal":"Biochimica et biophysica acta. Molecular cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo AAV model and siRNA epistasis with specific calcium signaling readout, single lab, multiple orthogonal methods","pmids":["41192563"],"is_preprint":false},{"year":2025,"finding":"Endothelial JAK1/STAT3 activation promotes ANGPT2 secretion, which induces adipocyte progenitor cells (APCs) to transition from MSLN to CFD phenotype via integrin-α5β1 signalling, promoting APC differentiation into mature adipocytes and accelerating visceral adipose tissue accumulation. Blocking Angpt2 expression by adeno-associated virus in obese mice reversed these effects.","method":"scRNAseq data analysis; PCR; Western blot; immunofluorescence; flow cytometry; in vitro co-culture; in vivo obese mouse model with recombinant Angpt2 protein and AAV-mediated Angpt2 blockade","journal":"Diabetes/metabolism research and reviews","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo epistasis with AAV blockade, specific phenotypic readout, single lab","pmids":["39628006"],"is_preprint":false},{"year":2026,"finding":"ANGPT2/Tie2 signaling in macrophages promotes M2 polarization via H3K18 lactylation (H3K18la)-mediated transcriptional regulation. ChIP assays confirmed that ANGPT2/Tie2 regulates H3K18la at target gene promoters. Tie2-overexpressing macrophages treated with ANGPT2 showed increased M2 markers and pro-angiogenic factors, and ANGPT2-overexpressing rats exhibited more M2-polarized TEM infiltration and increased EC proliferation in chronically ischemic brain.","method":"Primary Tie2-expressing macrophages and Tie2-overexpressing THP-1 macrophages; ANGPT2 treatment; ChIP assays for H3K18la; HUVEC co-culture proliferation assay; rat chronic cerebral ischaemia model; ANGPT2 overexpression in vivo","journal":"CNS neuroscience & therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirmed epigenetic mechanism, in vivo and in vitro, single lab with multiple methods","pmids":["41968454"],"is_preprint":false},{"year":2018,"finding":"Estradiol (E2) upregulates ANGPT2 pathway genes in human dermal papilla cells; ANGPT2 is downregulated in ovariectomized (estrogen-deficient) mice. Intradermal administration of ANGPT2 protein in ovariectomized mice increased hair density, establishing a functional E2-ANGPT2 axis in hair follicles. In silico analysis identified estrogen receptor binding sequences in the ANGPT2 promoter region.","method":"Microarray analysis in E2-treated hDPCs; RT-PCR; intradermal ANGPT2 protein injection in OVX mice; quantitative image analysis of hair density; in silico promoter analysis","journal":"Journal of dermatological science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo rescue with recombinant protein plus molecular analysis, single lab","pmids":["29724581"],"is_preprint":false},{"year":2017,"finding":"ADAM9 regulates ANGPT2 expression in lung cancer cells; silencing ADAM9 suppressed VEGFA, ANGPT2, and PLAT expression, leading to decreased angiogenesis, vascular remodeling, and tumor growth in vivo.","method":"Microarray after ADAM9 silencing; in vivo tumor growth and angiogenesis assays; clinical dataset correlation","journal":"Scientific reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — ADAM9 silencing affects ANGPT2 as one of multiple targets, no direct mechanistic link established between ADAM9 and ANGPT2 regulation, single lab","pmids":["29118335"],"is_preprint":false},{"year":2025,"finding":"PIEZO1 activation in Schlemm's canal endothelium triggers ANGPT2 secretion and promotes cell-surface clustering of integrin α9β1 (ITGA9), establishing a TIE2-independent mechanosensitive ANGPT2-integrin α9β1 autocrine signaling loop that regulates intraocular pressure. Deletion of Piezo1 or Itga9 in SC endothelium caused SC narrowing and IOP elevation; ANGPT2 deficiency or blockade disrupted PIEZO1-induced integrin activation.","method":"In vitro mechanosensory assays; SC-specific Piezo1 and Itga9 conditional deletion in mice; ANGPT2 deficiency/blockade; measurement of aqueous humor outflow facility and IOP; SC morphometry","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with multiple conditional KO models, specific IOP phenotype, multiple orthogonal in vivo experiments, preprint","pmids":[],"is_preprint":true},{"year":2025,"finding":"In GNAQ p.R183Q endothelial cells (capillary malformation model), ANGPT2 knockdown combined with MEK1/2 inhibition (Trametinib) additively restored the endothelial barrier (measured by TEER) to near wild-type levels, whereas ANGPT2 knockdown alone or MEK1/2 inhibition alone only partially restored it. The additive effect indicates ANGPT2 and MAPK/ERK signaling operate in separate pathways to compromise the endothelial barrier.","method":"TEER assay; CRISPR-edited GNAQ R183Q EC; ANGPT2 siRNA knockdown; anti-ANGPT2 function-blocking antibody; MEK1/2 inhibitor (Trametinib); Gαq inhibitor (YM254890); Martius Scarlet Blue staining of human CM tissue; longitudinal MRI","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — TEER assay with genetic and pharmacologic epistasis, pathway dissection by additivity, human tissue validation, preprint","pmids":[],"is_preprint":true},{"year":2024,"finding":"A glaucoma-protective SNP (rs76020419, G>T) in the 3'UTR of ANGPT2 at a predicted miR-145-binding site was functionally validated: CRISPR knock-in mice harboring the minor T allele showed higher ANGPT2 protein levels in plasma and multiple tissues, and a larger Schlemm canal area, suggesting the SNP increases ANGPT2 expression by disrupting miR-145 repression.","method":"CRISPR/Cas9 knock-in mice with orthologous rs76020419 T allele; ELISA for ANGPT2 in plasma and tissues; Schlemm canal morphometry in anterior segments","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo CRISPR knock-in model with protein quantification and morphometric readout, single lab","pmids":["39206543"],"is_preprint":false},{"year":2021,"finding":"Biallelic loss-of-function of ANGPT2 (homozygous splice-site variant causing nonsense-mediated mRNA decay) causes severe early-onset non-immune hydrops fetalis in humans, demonstrating that complete ANGPT2 loss disrupts blood and lymphatic vessel formation and remodeling.","method":"Whole exome sequencing; RNA analysis in heterozygous parents demonstrating NMD; serum ANGPT2 ELISA in carrier parents; clinical phenotyping","journal":"Journal of medical genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function with molecular confirmation of NMD and reduced serum protein, human disease phenotype, small family study","pmids":["34876502"],"is_preprint":false},{"year":2025,"finding":"Constant mechanical stretch (mimicking CF-VAD conditions) upregulates ANGPT2 transcription and intracellular protein in aortic and umbilical vein endothelial cells, and promotes ANGPT2 secretion, whereas physiological cyclic stretch does not produce equivalent effects, establishing stretch as a mechanical regulator of endothelial ANGPT2 release.","method":"Uniaxial stretch device; HAECs and HUVECs; transcriptional profiling; ELISA; Western blot; immunofluorescence microscopy","journal":"Lab on a chip","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, descriptive mechanobiological study without genetic epistasis or functional readout beyond expression/secretion","pmids":["40314578"],"is_preprint":false},{"year":2026,"finding":"EZH2 inhibition derepresses KLF2 (via loss of H3K27me3 at the KLF2 promoter), which in turn suppresses ANGPT2 expression; siRNA knockdown of KLF2 reversed the anti-angiogenic effects of EZH2 blockade. ChIP confirmed loss of H3K27me3 at the KLF2 promoter, establishing an EZH2-H3K27me3-KLF2-ANGPT2 axis regulating pathological angiogenesis in choroidal neovascularization.","method":"RNA-seq; ChIP assay (H3K27me3 at KLF2 promoter); siRNA knockdown of KLF2; EZH2 inhibitor (DZNep); EC proliferation/migration/tube formation assays; in vivo laser-induced CNV mouse model","journal":"Experimental eye research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirms epigenetic mechanism, siRNA epistasis with specific phenotypic rescue, in vivo validation, single lab","pmids":["42176839"],"is_preprint":false},{"year":2025,"finding":"PKM2 knockdown inhibits ANGPT2 expression in endothelial cells, while PKM2 overexpression promotes it. Supplementation with exogenous ANGPT2 restores proliferation, migration, and angiogenesis inhibited by PKM2 knockdown, placing ANGPT2 downstream of PKM2 in glycolytic regulation of endothelial angiogenic activation.","method":"PKM2 siRNA knockdown and overexpression in ECs; recombinant ANGPT2 rescue; proliferation, migration, and tube formation assays","journal":"Scientific reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, rescue experiment with recombinant protein, no direct mechanistic link between PKM2 and ANGPT2 transcription established","pmids":["40858916"],"is_preprint":false},{"year":2026,"finding":"KDM3A is induced by hypoxia in endothelial cells and binds to AP-1 transcription factor under hypoxic conditions; the KDM3A-AP1 complex acts on the ANGPT2 promoter to promote its transcriptional expression, thereby driving angiogenesis in small bowel angiodysplasia. KDM3A inhibitor IOX1 exerted anti-angiogenic effects by blocking this pathway.","method":"RNA sequencing; ChIP assay (KDM3A and AP-1 at ANGPT2 promoter); KDM3A knockdown/overexpression in HUVECs under hypoxia; migration, invasion, tube formation assays; in vivo Matrigel plug assay; IOX1 inhibitor; IHC of SBAD specimens","journal":"Journal of gastroenterology and hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirmed direct promoter binding, in vitro and in vivo experiments, pharmacologic inhibition, single lab","pmids":["41705573"],"is_preprint":false}],"current_model":"ANGPT2 is a secreted ligand that signals primarily through the TIE2 receptor (and also integrin α5β1 and integrin α9β1 in a TIE2-independent manner) to regulate blood and lymphatic vascular formation, stability, and remodeling; its transcription is controlled by multiple upstream regulators including SF-1, MYBL1, HOXB5, ISL2, DARPP-32/STAT3, Fzd5/PKC/Ets1, EZH2/KLF2, KDM3A/AP-1, and IFN-γ/STAT1-FOXO1 axes, while its protein stability is post-translationally regulated by RBMS3-TRIM21-mediated K48-linked ubiquitination; functionally, ANGPT2 promotes angiogenesis and vascular destabilization, drives tumor cell growth via autocrine TIE2 activation, impairs cardiomyocyte calcium homeostasis through ITGB3-RYR2 signaling during sepsis, promotes macrophage M2 polarization through H3K18 lactylation, and regulates intraocular pressure through a PIEZO1-ANGPT2-ITGA9 mechanosensitive loop in Schlemm's canal endothelium."},"narrative":{"mechanistic_narrative":"ANGPT2 is a secreted ligand that signals through the TIE2/TEK receptor to control blood and lymphatic vascular formation, stability, and remodeling, and biallelic loss-of-function in humans causes severe early-onset non-immune hydrops fetalis by disrupting these processes [PMID:34876502]. Amino-terminally truncated ANGPT2 subunits assemble into asymmetrical homodimers that bind TIE2 in a 2:1 stoichiometry and can activate both TIE1 and TIE2 in an autocrine setting; missense mutations associated with primary lymphedema reduce ANGPT2 secretion in a dominant-negative manner and perturb integrin α5 binding, with truncating effects producing lymphatic vessel hyperplasia and dilation in vivo [PMID:32908006]. Beyond canonical TIE2 signaling, ANGPT2 engages integrins to drive context-specific effects: it impairs cardiomyocyte calcium homeostasis in sepsis by binding the integrin β3 (ITGB3) extracellular domain and triggering RYR2 phosphorylation with dysregulated ATP2a2/PLN [PMID:41192563], and acts through a TIE2-independent PIEZO1–ANGPT2–integrin α9β1 mechanosensitive autocrine loop in Schlemm's canal endothelium that regulates intraocular pressure. In tumors, ANGPT2 promotes angiogenesis and tumor growth, including via an autocrine/paracrine ANGPT2–TIE2 loop in pituitary neuroendocrine tumor cells whose growth depends on TIE2 [PMID:35266635], and macrophage ANGPT2/TIE2 signaling drives M2 polarization through H3K18 lactylation at target gene promoters [PMID:41968454]. ANGPT2 transcription is controlled by numerous upstream inputs—activating regulators including DARPP-32/STAT3 [PMID:25779598], MYBL1 [PMID:35987690], SF-1 [PMID:21163858], ISL2 [PMID:32753650], HOXB5 [PMID:35949323], mutant GNAQ via PKC/NF-κB [PMID:34670408], and a hypoxic KDM3A–AP-1 complex [PMID:41705573], and repressive inputs including MCPH1-directed promoter methylation [PMID:25703238] and IFN-γ/STAT1–FOXO1 signaling [PMID:40370455]—while protein abundance is post-translationally limited by RBMS3-recruited TRIM21-mediated K48-linked ubiquitination and proteasomal degradation [PMID:40069332]. Downstream, ANGPT2 mediates pro-angiogenic and pro-fibrotic responses in multiple disease contexts and is dysregulated in capillary malformation, where it cooperates with but operates in a pathway separate from MAPK/ERK signaling to compromise the endothelial barrier [PMID:34670408].","teleology":[{"year":2010,"claim":"Established that ANGPT2 transcription is under direct control of defined nuclear factors, identifying the steroidogenic factor SF-1 as a direct promoter-binding activator.","evidence":"ChIP-on-chip and luciferase reporter assays in adrenocortical NCI-H295R cells","pmids":["21163858"],"confidence":"Medium","gaps":["Does not test SF-1 dependence of ANGPT2 in vascular cell types","No in vivo confirmation of the regulatory axis"]},{"year":2015,"claim":"Defined two opposing transcriptional control mechanisms: DARPP-32/STAT3 activation of functionally angiogenic ANGPT2 versus MCPH1-recruited DNA methyltransferase silencing of the promoter.","evidence":"Reporter assays, STAT3 inhibition/knockdown, HUVEC tube formation with antibody blocking, plus ChIP and co-IP for MCPH1/DNMT recruitment in cancer cells","pmids":["25779598","25703238"],"confidence":"High","gaps":["DARPP-32/STAT3 and MCPH1 pathways studied in distinct tumor contexts, not integrated","Direct STAT3 promoter occupancy not demonstrated in the DARPP-32 study"]},{"year":2020,"claim":"Resolved the molecular architecture of ANGPT2-TIE signaling and connected disease mutations to secretion and receptor activation defects, showing dominant-negative lymphedema mutations and a 2:1 TIE2-binding stoichiometry.","evidence":"Secretion and TIE1/TIE2 autocrine activation assays in lymphatic endothelial cells, biophysical binding, molecular modeling, integrin α5 binding, mouse skin model, lymphedema cohort screening","pmids":["32908006"],"confidence":"High","gaps":["Functional consequence of asymmetric dimerization for downstream signaling not fully resolved","Integrin α5 contribution relative to TIE2 not quantified in vivo"]},{"year":2020,"claim":"Expanded the transcriptional regulator repertoire (RAS-ERK, ISL2) and tied ANGPT2 induction to tissue-specific pro-metastatic and pro-tumor angiogenic phenotypes downstream of these factors.","evidence":"In vivo metastasis selection and gain/loss-of-function in CRC; ChIP and orthotopic xenografts for ISL2 in oligodendroglioma","pmids":["32816905","32753650"],"confidence":"Medium","gaps":["Mechanism of liver- versus lung-tissue specificity unresolved","Direct ERK-to-promoter linkage not established"]},{"year":2021,"claim":"Placed ANGPT2 as a downstream effector of mutant Gαq in capillary malformation, demonstrating that knockdown normalizes the vascular phenotype.","evidence":"Mutant/WT GNAQ expression in endothelial colony forming cells, PLCβ3/PKC dissection, shRNA knockdown, in vivo xenograft rescue, human tissue immunostaining","pmids":["34670408"],"confidence":"High","gaps":["Whether ANGPT2 acts via TIE2 or integrins in this context not defined","Receptor on affected vasculature not identified"]},{"year":2021,"claim":"Provided definitive human genetic evidence that ANGPT2 is required for normal vascular and lymphatic development, with complete loss causing hydrops fetalis.","evidence":"Whole exome sequencing, NMD confirmation by RNA analysis, serum ELISA in carrier parents, clinical phenotyping","pmids":["34876502"],"confidence":"Medium","gaps":["Single family study","Developmental timing and tissue specificity of the requirement not dissected"]},{"year":2022,"claim":"Demonstrated an autocrine ANGPT2-TIE2 loop intrinsic to tumor cells, showing TIE2 expression on tumor cells drives growth and identifying additional activating transcription factors (MYBL1, HOXB5).","evidence":"PitNET cell lines, zebrafish/mouse xenografts and autochthonous rat model with Tie2 deletion and pharmacologic inhibition; ChIP/luciferase for MYBL1 and HOXB5 with anti-ANGPT2 antibody","pmids":["35266635","35987690","35949323"],"confidence":"High","gaps":["Generality of tumor-cell-intrinsic TIE2 expression across cancers unknown","Relative contributions of autocrine versus paracrine signaling not separated"]},{"year":2025,"claim":"Identified post-translational control of ANGPT2 abundance through RBMS3-recruited TRIM21 ubiquitination, linking degradation to angiogenesis and drug resistance.","evidence":"IP-MS, co-IP, K48-linkage-specific ubiquitination assays, loss/gain-of-function and anti-ANGPT2 rescue in HCC in vitro and in vivo","pmids":["40069332"],"confidence":"High","gaps":["Whether other E3 ligases regulate ANGPT2 not addressed","Signals controlling RBMS3-TRIM21 engagement unknown"]},{"year":2025,"claim":"Established TIE2-independent integrin-mediated functions of ANGPT2, defining an ITGB3-RYR2 cardiomyocyte axis in sepsis and a PIEZO1-ANGPT2-integrin α9β1 mechanosensitive loop controlling intraocular pressure.","evidence":"AAV9 EC-specific ANGPT2 overexpression with CLP sepsis and ITGB3 siRNA and cardiomyocyte calcium imaging; SC-specific Piezo1/Itga9 conditional deletion with IOP and morphometry (preprint for the IOP loop)","pmids":["41192563"],"confidence":"Medium","gaps":["Structural basis of ANGPT2-integrin engagement not resolved","PIEZO1-ANGPT2-ITGA9 loop reported only as a preprint"]},{"year":2025,"claim":"Defined IFN-γ/STAT1-FOXO1 as a repressive arm of ANGPT2 transcription and linked it to immunotherapy-induced vascular normalization.","evidence":"ChIP for STAT1 at the ANGPT2/TEK promoters, AKT-FOXO1 pathway analysis, HUVEC assays, JAK1/2 inhibitor, and mouse LUAD with PD-L1 blockade","pmids":["40370455"],"confidence":"Medium","gaps":["Interplay with activating factors at the same promoter not mapped","Direct STAT1-FOXO1 cooperativity not biochemically defined"]},{"year":2026,"claim":"Connected ANGPT2/TIE2 signaling to epigenetic effector mechanisms, showing macrophage M2 polarization via H3K18 lactylation and identifying an EZH2-H3K27me3-KLF2 axis and hypoxic KDM3A-AP-1 complex as upstream regulators of ANGPT2.","evidence":"ChIP for H3K18la in Tie2-expressing macrophages with rat ischemia model; ChIP/siRNA for the EZH2-KLF2 axis in CNV; ChIP for KDM3A-AP1 at the ANGPT2 promoter in angiodysplasia with IOX1 inhibition","pmids":["41968454","42176839","41705573"],"confidence":"Medium","gaps":["Mechanistic link from TIE2 activation to H3K18la deposition not defined","These regulatory axes characterized in separate disease models"]},{"year":null,"claim":"How the multiple upstream transcriptional and post-translational regulators are integrated at the ANGPT2 locus, and how ligand engagement is partitioned between TIE2 and distinct integrins to produce context-specific vascular outcomes, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model reconciling activating and repressive promoter inputs","Receptor choice (TIE2 vs integrin α5/α9/β3) per tissue not predictable","Structural basis of integrin engagement uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[4,5,18,23]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4,14]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[3,4,13,26]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,5,18,23]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[4,26]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,26]}],"complexes":[],"partners":["TEK","TIE1","ITGA5","ITGB3","ITGA9","TRIM21","RBMS3","PIEZO1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O15123","full_name":"Angiopoietin-2","aliases":[],"length_aa":496,"mass_kda":56.9,"function":"Binds to TEK/TIE2, competing for the ANGPT1 binding site, and modulating ANGPT1 signaling (PubMed:15284220, PubMed:19116766, PubMed:19223473, PubMed:9204896). Can induce tyrosine phosphorylation of TEK/TIE2 in the absence of ANGPT1 (PubMed:15284220, PubMed:19116766, PubMed:19223473, PubMed:9204896). In the absence of angiogenic inducers, such as VEGF, ANGPT2-mediated loosening of cell-matrix contacts may induce endothelial cell apoptosis with consequent vascular regression. In concert with VEGF, it may facilitate endothelial cell migration and proliferation, thus serving as a permissive angiogenic signal (PubMed:15284220, PubMed:19116766, PubMed:19223473, PubMed:9204896). Involved in the regulation of lymphangiogenesis (PubMed:32908006)","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/O15123/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ANGPT2","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ANGPT2","total_profiled":1310},"omim":[{"mim_id":"620715","title":"BLEEDING DISORDER, VASCULAR-TYPE; BDVAS","url":"https://www.omim.org/entry/620715"},{"mim_id":"619369","title":"LYMPHATIC MALFORMATION 10; LMPHM10","url":"https://www.omim.org/entry/619369"},{"mim_id":"612456","title":"APOLIPOPROTEIN L DOMAIN-CONTAINING 1; APOLD1","url":"https://www.omim.org/entry/612456"},{"mim_id":"607117","title":"MICROCEPHALIN 1; MCPH1","url":"https://www.omim.org/entry/607117"},{"mim_id":"605910","title":"ANGIOPOIETIN-LIKE 4; ANGPTL4","url":"https://www.omim.org/entry/605910"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ANGPT2"},"hgnc":{"alias_symbol":["Ang2"],"prev_symbol":[]},"alphafold":{"accession":"O15123","domains":[{"cath_id":"3.90.215.10","chopping":"285-494","consensus_level":"high","plddt":96.8491,"start":285,"end":494},{"cath_id":"1.20.5","chopping":"94-220","consensus_level":"medium","plddt":93.4576,"start":94,"end":220}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O15123","model_url":"https://alphafold.ebi.ac.uk/files/AF-O15123-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O15123-F1-predicted_aligned_error_v6.png","plddt_mean":83.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ANGPT2","jax_strain_url":"https://www.jax.org/strain/search?query=ANGPT2"},"sequence":{"accession":"O15123","fasta_url":"https://rest.uniprot.org/uniprotkb/O15123.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O15123/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O15123"}},"corpus_meta":[{"pmid":"21257790","id":"PMC_21257790","title":"ANGPT2 genetic variant is associated with trauma-associated acute lung injury and altered plasma angiopoietin-2 isoform ratio.","date":"2011","source":"American journal of respiratory and critical care medicine","url":"https://pubmed.ncbi.nlm.nih.gov/21257790","citation_count":94,"is_preprint":false},{"pmid":"24384875","id":"PMC_24384875","title":"miR-145 functions as tumor suppressor and targets two oncogenes, ANGPT2 and NEDD9, in renal cell carcinoma.","date":"2014","source":"Journal of cancer research and clinical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/24384875","citation_count":70,"is_preprint":false},{"pmid":"30038058","id":"PMC_30038058","title":"LncRNA MALAT1 up-regulates VEGF-A and ANGPT2 to promote angiogenesis in brain microvascular endothelial cells against oxygen-glucose deprivation via targetting miR-145.","date":"2019","source":"Bioscience reports","url":"https://pubmed.ncbi.nlm.nih.gov/30038058","citation_count":52,"is_preprint":false},{"pmid":"34670408","id":"PMC_34670408","title":"Endothelial GNAQ p.R183Q Increases ANGPT2 (Angiopoietin-2) and Drives Formation of Enlarged Blood Vessels.","date":"2021","source":"Arteriosclerosis, thrombosis, and vascular biology","url":"https://pubmed.ncbi.nlm.nih.gov/34670408","citation_count":50,"is_preprint":false},{"pmid":"32816905","id":"PMC_32816905","title":"ERK1/2 Signaling Induces Upregulation of ANGPT2 and CXCR4 to Mediate Liver Metastasis in Colon Cancer.","date":"2020","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/32816905","citation_count":48,"is_preprint":false},{"pmid":"35987690","id":"PMC_35987690","title":"MYBL1 induces transcriptional activation of ANGPT2 to promote tumor angiogenesis and confer sorafenib resistance in human hepatocellular carcinoma.","date":"2022","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/35987690","citation_count":48,"is_preprint":false},{"pmid":"29118335","id":"PMC_29118335","title":"ADAM9 promotes lung cancer progression through vascular remodeling by VEGFA, ANGPT2, and PLAT.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/29118335","citation_count":47,"is_preprint":false},{"pmid":"29620147","id":"PMC_29620147","title":"lncRNA PVT1 promotes the angiogenesis of vascular endothelial cell by targeting miR‑26b to activate CTGF/ANGPT2.","date":"2018","source":"International journal of molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/29620147","citation_count":46,"is_preprint":false},{"pmid":"25779598","id":"PMC_25779598","title":"Gastric tumour-derived ANGPT2 regulation by DARPP-32 promotes angiogenesis.","date":"2015","source":"Gut","url":"https://pubmed.ncbi.nlm.nih.gov/25779598","citation_count":43,"is_preprint":false},{"pmid":"32874130","id":"PMC_32874130","title":"MiR-145-5p suppresses the proliferation, migration and invasion of gastric cancer epithelial cells via the ANGPT2/NOD_LIKE_RECEPTOR axis.","date":"2020","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/32874130","citation_count":43,"is_preprint":false},{"pmid":"31871121","id":"PMC_31871121","title":"Immunoregulation and Clinical Implications of ANGPT2/TIE2+ M-MDSC Signature in Non-Small Cell Lung Cancer.","date":"2019","source":"Cancer immunology research","url":"https://pubmed.ncbi.nlm.nih.gov/31871121","citation_count":41,"is_preprint":false},{"pmid":"31547870","id":"PMC_31547870","title":"miR-205-5p inhibits human endometriosis progression by targeting ANGPT2 in endometrial stromal cells.","date":"2019","source":"Stem cell research & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/31547870","citation_count":38,"is_preprint":false},{"pmid":"28192798","id":"PMC_28192798","title":"Identification of ANGPT2 as a New Gene for Neovascular Age-Related Macular Degeneration and Polypoidal Choroidal Vasculopathy in the Chinese and Japanese Populations.","date":"2017","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/28192798","citation_count":35,"is_preprint":false},{"pmid":"32908006","id":"PMC_32908006","title":"Characterization of ANGPT2 mutations associated with primary lymphedema.","date":"2020","source":"Science translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32908006","citation_count":34,"is_preprint":false},{"pmid":"30414568","id":"PMC_30414568","title":"Angpt2 Induces Mesangial Cell Apoptosis through the MicroRNA-33-5p-SOCS5 Loop in Diabetic Nephropathy.","date":"2018","source":"Molecular therapy. Nucleic acids","url":"https://pubmed.ncbi.nlm.nih.gov/30414568","citation_count":34,"is_preprint":false},{"pmid":"31892982","id":"PMC_31892982","title":"Distinct Roles of VEGFA and ANGPT2 in Lung Adenocarcinoma and Squamous Cell Carcinoma.","date":"2020","source":"Journal of Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/31892982","citation_count":31,"is_preprint":false},{"pmid":"33550461","id":"PMC_33550461","title":"Atorvastatin pleiotropically decreases intraplaque angiogenesis and intraplaque haemorrhage by inhibiting ANGPT2 release and VE-Cadherin internalization.","date":"2021","source":"Angiogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/33550461","citation_count":29,"is_preprint":false},{"pmid":"21163858","id":"PMC_21163858","title":"ChIP-on-chip analysis reveals angiopoietin 2 (Ang2, ANGPT2) as a novel target of steroidogenic factor-1 (SF-1, NR5A1) in the human adrenal gland.","date":"2010","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/21163858","citation_count":27,"is_preprint":false},{"pmid":"32222972","id":"PMC_32222972","title":"Molecular description of ANGPT2 associated colorectal carcinoma.","date":"2020","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/32222972","citation_count":25,"is_preprint":false},{"pmid":"36172371","id":"PMC_36172371","title":"Immunoregulation and clinical significance of neutrophils/NETs-ANGPT2 in tumor microenvironment of gastric cancer.","date":"2022","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/36172371","citation_count":24,"is_preprint":false},{"pmid":"33987885","id":"PMC_33987885","title":"Activated mesangial cells induce glomerular endothelial cells proliferation in rat anti-Thy-1 nephritis through VEGFA/VEGFR2 and Angpt2/Tie2 pathway.","date":"2021","source":"Cell proliferation","url":"https://pubmed.ncbi.nlm.nih.gov/33987885","citation_count":24,"is_preprint":false},{"pmid":"27798093","id":"PMC_27798093","title":"Variants in angiopoietin-2 (ANGPT2) contribute to variation in nocturnal oxyhaemoglobin saturation level.","date":"2016","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/27798093","citation_count":23,"is_preprint":false},{"pmid":"33758610","id":"PMC_33758610","title":"LINC00184 involved in the regulatory network of ANGPT2 via ceRNA mediated miR-145 inhibition in gastric cancer.","date":"2021","source":"Journal of Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/33758610","citation_count":20,"is_preprint":false},{"pmid":"29845518","id":"PMC_29845518","title":"Endothelial loss of Fzd5 stimulates PKC/Ets1-mediated transcription of Angpt2 and Flt1.","date":"2018","source":"Angiogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/29845518","citation_count":19,"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":"35266635","id":"PMC_35266635","title":"Angpt2/Tie2 autostimulatory loop controls tumorigenesis.","date":"2022","source":"EMBO molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/35266635","citation_count":18,"is_preprint":false},{"pmid":"32753650","id":"PMC_32753650","title":"ISL2 modulates angiogenesis through transcriptional regulation of ANGPT2 to promote cell proliferation and malignant transformation in oligodendroglioma.","date":"2020","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/32753650","citation_count":18,"is_preprint":false},{"pmid":"28956132","id":"PMC_28956132","title":"VEGF, ANGPT1, ANGPT2, and MMP-9 expression in the autologous hematopoietic stem cell transplantation and its impact on the time to engraftment.","date":"2017","source":"Annals of hematology","url":"https://pubmed.ncbi.nlm.nih.gov/28956132","citation_count":18,"is_preprint":false},{"pmid":"35163556","id":"PMC_35163556","title":"MiR-29a Curbs Hepatocellular Carcinoma Incidence via Targeting of HIF-1α and ANGPT2.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35163556","citation_count":16,"is_preprint":false},{"pmid":"36272879","id":"PMC_36272879","title":"Inhibition of ANGPT2 activates autophagy during hypertrophic scar formation via PI3K/AKT/mTOR pathway.","date":"2022","source":"Anais brasileiros de dermatologia","url":"https://pubmed.ncbi.nlm.nih.gov/36272879","citation_count":15,"is_preprint":false},{"pmid":"34036386","id":"PMC_34036386","title":"miR‑135a‑5p inhibits tumor invasion by targeting ANGPT2 in gallbladder cancer.","date":"2021","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/34036386","citation_count":15,"is_preprint":false},{"pmid":"32371540","id":"PMC_32371540","title":"Association of NOS3 and ANGPT2 Gene Polymorphisms with Survival in Patients with Hepatocellular Carcinoma Receiving Sorafenib: Results of the Multicenter Prospective INNOVATE Study.","date":"2020","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/32371540","citation_count":14,"is_preprint":false},{"pmid":"39187926","id":"PMC_39187926","title":"Single-cell analysis reveals the implication of vascular endothelial cell-intrinsic ANGPT2 in human intracranial aneurysm.","date":"2025","source":"Cardiovascular research","url":"https://pubmed.ncbi.nlm.nih.gov/39187926","citation_count":12,"is_preprint":false},{"pmid":"40404636","id":"PMC_40404636","title":"NNMT/1-MNA protects against hepatic ischemia-reperfusion injury through the AKT/FOXO1/ANGPT2/JNK axis.","date":"2025","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/40404636","citation_count":11,"is_preprint":false},{"pmid":"40370455","id":"PMC_40370455","title":"IFN-γ-mediated suppression of ANGPT2-Tie2 in endothelial cells facilitates tumor vascular normalization during immunotherapy.","date":"2025","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/40370455","citation_count":11,"is_preprint":false},{"pmid":"35429678","id":"PMC_35429678","title":"Endothelial GATA5 positively regulates angiogenesis via cathepsin S-mediated Angpt2/Flk1 and MMP2/9 signaling pathways.","date":"2022","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/35429678","citation_count":9,"is_preprint":false},{"pmid":"25291142","id":"PMC_25291142","title":"Clonal Dominance With Retroviral Vector Insertions Near the ANGPT1 and ANGPT2 Genes in a Human Xenotransplant Mouse Model.","date":"2014","source":"Molecular therapy. Nucleic acids","url":"https://pubmed.ncbi.nlm.nih.gov/25291142","citation_count":9,"is_preprint":false},{"pmid":"34762787","id":"PMC_34762787","title":"The rs2442598 polymorphism in the ANGPT-2 gene is associated with risk for diabetic retinopathy in patients with type 1 diabetes mellitus in a Brazilian population.","date":"2021","source":"Archives of endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/34762787","citation_count":9,"is_preprint":false},{"pmid":"39732166","id":"PMC_39732166","title":"Angiogenesis-promoting effect of SKP-SC-EVs-derived miRNA-30a-5p in peripheral nerve regeneration by targeting LIF and ANGPT2.","date":"2024","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/39732166","citation_count":8,"is_preprint":false},{"pmid":"34876502","id":"PMC_34876502","title":"Biallelic ANGPT2 loss-of-function causes severe early-onset non-immune hydrops fetalis.","date":"2021","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/34876502","citation_count":8,"is_preprint":false},{"pmid":"36874142","id":"PMC_36874142","title":"Helicobacter pylori infection induces gastric precancerous lesions and persistent expression of Angpt2, Vegf-A and Tnf-A in a mouse model.","date":"2023","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/36874142","citation_count":7,"is_preprint":false},{"pmid":"35949323","id":"PMC_35949323","title":"HOXB5-activated ANGPT2 promotes the proliferation, migration, invasion and angiogenic effect of esophageal cancer cells via activating ERK/AKT signaling pathway.","date":"2022","source":"Experimental and therapeutic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/35949323","citation_count":7,"is_preprint":false},{"pmid":"25703238","id":"PMC_25703238","title":"MCPH1 maintains long-term epigenetic silencing of ANGPT2 in chronic lymphocytic leukemia.","date":"2015","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/25703238","citation_count":7,"is_preprint":false},{"pmid":"36160014","id":"PMC_36160014","title":"Human placenta-based genome-wide mRNA sequencing to identify TEK/IGF1/CSF1/ANGPT2 as crucial segments in the pathogenesis of pre-eclampsia.","date":"2022","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36160014","citation_count":7,"is_preprint":false},{"pmid":"29724581","id":"PMC_29724581","title":"Reversal of the hair loss phenotype by modulating the estradiol-ANGPT2 axis in the mouse model of female pattern hair loss.","date":"2018","source":"Journal of dermatological science","url":"https://pubmed.ncbi.nlm.nih.gov/29724581","citation_count":7,"is_preprint":false},{"pmid":"33239896","id":"PMC_33239896","title":"miR145 Regulates the Proliferation and Apoptosis of Rat Vascular Endothelial Cells under Hyperglycemia by Targeting the ANGPT2 Gene and Involving the NFκB Signaling Pathway.","date":"2020","source":"Diabetes, metabolic syndrome and obesity : targets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/33239896","citation_count":6,"is_preprint":false},{"pmid":"25885592","id":"PMC_25885592","title":"Prospective evaluation of plasma levels of ANGPT2, TuM2PK, and VEGF in patients with renal cell carcinoma.","date":"2015","source":"BMC urology","url":"https://pubmed.ncbi.nlm.nih.gov/25885592","citation_count":5,"is_preprint":false},{"pmid":"39866777","id":"PMC_39866777","title":"Doxorubicin-loaded PEGylated liposome modified with ANGPT2-specific peptide for integrative glioma-targeted imaging and therapy.","date":"2025","source":"Materials today. Bio","url":"https://pubmed.ncbi.nlm.nih.gov/39866777","citation_count":5,"is_preprint":false},{"pmid":"35877427","id":"PMC_35877427","title":"Association of Single Nucleotide Polymorphisms from Angiogenesis-Related Genes, ANGPT2, TLR2 and TLR9, with Spontaneous Preterm Labor.","date":"2022","source":"Current issues in molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/35877427","citation_count":4,"is_preprint":false},{"pmid":"39206543","id":"PMC_39206543","title":"Glaucoma-Protective Human Single-Nucleotide Polymorphism in the Angpt2 Locus Increased ANGPT2 Expression and Schlemm Canal Area in Mice-Brief Report.","date":"2024","source":"Arteriosclerosis, thrombosis, and vascular biology","url":"https://pubmed.ncbi.nlm.nih.gov/39206543","citation_count":3,"is_preprint":false},{"pmid":"40858916","id":"PMC_40858916","title":"PKM2 regulates angiogenic activation via ANGPT2 in endothelial cells.","date":"2025","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/40858916","citation_count":3,"is_preprint":false},{"pmid":"40069332","id":"PMC_40069332","title":"RBMS3-loss impedes TRIM21-induced ubiquitination of ANGPT2 in an RNA-independent manner and drives sorafenib resistance in hepatocellular carcinoma.","date":"2025","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/40069332","citation_count":3,"is_preprint":false},{"pmid":"39628006","id":"PMC_39628006","title":"Endothelial Angpt2 Promotes Adipocyte Progenitor Cells Maturation to Increase Visceral Adipose Tissue Accumulation.","date":"2025","source":"Diabetes/metabolism research and reviews","url":"https://pubmed.ncbi.nlm.nih.gov/39628006","citation_count":3,"is_preprint":false},{"pmid":"36842857","id":"PMC_36842857","title":"ANGPT2/CAV1 regulates albumin transcytosis of glomerular endothelial cells under high glucose exposure and is impaired by losartan.","date":"2023","source":"Nefrologia","url":"https://pubmed.ncbi.nlm.nih.gov/36842857","citation_count":3,"is_preprint":false},{"pmid":"38808888","id":"PMC_38808888","title":"Silencing ANGPT2 alleviates ulcerative colitis by regulating autophagy-mediated NLRP3 inflammasome inactivation via the mTOR signaling pathway.","date":"2024","source":"Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas","url":"https://pubmed.ncbi.nlm.nih.gov/38808888","citation_count":3,"is_preprint":false},{"pmid":"36199153","id":"PMC_36199153","title":"Genetic association of ANGPT2 with primary open-angle glaucoma.","date":"2022","source":"Eye and vision (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/36199153","citation_count":2,"is_preprint":false},{"pmid":"40556366","id":"PMC_40556366","title":"Effects of Dual Inhibition of VEGF-A and Angpt-2 on Angiogenesis and Lymphangiogenesis in an Alkali-Induced Corneal Injury Model.","date":"2025","source":"Genes to cells : devoted to molecular & cellular mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/40556366","citation_count":2,"is_preprint":false},{"pmid":"40954112","id":"PMC_40954112","title":"10-Hydroxycamptothecin-Loaded Hollow Mesoporous Polydopamine Modified with ANGPT2-Specific Peptide for Gastric Cancer-Targeted Therapy.","date":"2025","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/40954112","citation_count":1,"is_preprint":false},{"pmid":"36877445","id":"PMC_36877445","title":"Helicobacter pylori infection induces abnormal expression of pro-angiogenic gene ANGPT2 and miR-203a in AGS gastric cell line.","date":"2023","source":"Brazilian journal of microbiology : [publication of the Brazilian Society for Microbiology]","url":"https://pubmed.ncbi.nlm.nih.gov/36877445","citation_count":1,"is_preprint":false},{"pmid":"23726425","id":"PMC_23726425","title":"Angiopoietin-2 (ANGPT2) as a candidate gene for somatic cell score in German Holstein cattle.","date":"2013","source":"Journal of dairy science","url":"https://pubmed.ncbi.nlm.nih.gov/23726425","citation_count":1,"is_preprint":false},{"pmid":"40314578","id":"PMC_40314578","title":"Understanding the role of vascular stretch on modulation of VWF and ANGPT-2 in continuous flow left ventricular assist device (CF-VAD) patients.","date":"2025","source":"Lab on a chip","url":"https://pubmed.ncbi.nlm.nih.gov/40314578","citation_count":1,"is_preprint":false},{"pmid":"40675517","id":"PMC_40675517","title":"Identification Of ANGPT2, FLT3, IGF1, and SPP1 associated with glycolysis and PI3K/Akt signaling pathway in hepatocellular carcinoma.","date":"2025","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/40675517","citation_count":0,"is_preprint":false},{"pmid":"41186068","id":"PMC_41186068","title":"Association of ANGPT2 and NOS3 Gene Variants With Esophageal Variceal Progression in HCV-Induced Cirrhosis.","date":"2025","source":"Journal of medical virology","url":"https://pubmed.ncbi.nlm.nih.gov/41186068","citation_count":0,"is_preprint":false},{"pmid":"41138551","id":"PMC_41138551","title":"The role of ANGPT2 in pathogenesis of preeclampsia.","date":"2025","source":"Placenta","url":"https://pubmed.ncbi.nlm.nih.gov/41138551","citation_count":0,"is_preprint":false},{"pmid":"40571161","id":"PMC_40571161","title":"Human cytomegalovirus UL82 promotes colorectal cancer cell proliferation through inhibiting the ubiquitination of OGDH via ANGPT2.","date":"2025","source":"Tumour virus research","url":"https://pubmed.ncbi.nlm.nih.gov/40571161","citation_count":0,"is_preprint":false},{"pmid":"41651922","id":"PMC_41651922","title":"Adipocyte-driven STAT3-ANGPT2-PTGIS axis promotes cutaneous metastasis in breast cancer and represents a targetable pathway.","date":"2026","source":"NPJ precision oncology","url":"https://pubmed.ncbi.nlm.nih.gov/41651922","citation_count":0,"is_preprint":false},{"pmid":"41192563","id":"PMC_41192563","title":"Endothelial ANGPT2 impairs cardiomyocyte calcium homeostasis via ITGB3 receptor in murine sepsis-related cardiomyopathy.","date":"2025","source":"Biochimica et biophysica acta. Molecular cell research","url":"https://pubmed.ncbi.nlm.nih.gov/41192563","citation_count":0,"is_preprint":false},{"pmid":"40115011","id":"PMC_40115011","title":"Associations of ANGPT2 expression and its variants (rs1868554 and rs7825407) with multiple myeloma risk and outcome.","date":"2025","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/40115011","citation_count":0,"is_preprint":false},{"pmid":"41677948","id":"PMC_41677948","title":"Endothelial miR-7052 Safeguards Blood-Brain Barrier Integrity During Endotoxemia by Co-repressing ANGPT2 and PDE5A.","date":"2026","source":"Molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/41677948","citation_count":0,"is_preprint":false},{"pmid":"42074491","id":"PMC_42074491","title":"Association Between the ANGPT2 rs2442598 Polymorphism and Diabetic Nephropathy in Slovenian Patients with Type 2 Diabetes Mellitus.","date":"2026","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/42074491","citation_count":0,"is_preprint":false},{"pmid":"41968454","id":"PMC_41968454","title":"ANGPT2/Tie2 Enhances H3K18la-Mediated Macrophage M2 Polarization to Promote Endothelial Cell Proliferation in the Chronically Ischaemic Brain.","date":"2026","source":"CNS neuroscience & therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/41968454","citation_count":0,"is_preprint":false},{"pmid":"40155988","id":"PMC_40155988","title":"3D culturing as a promising strategy to enhance the angiogenic potential of adipose stem cell-derived secretome: insights into the role of miR-145-5p/ANGPT2 axis.","date":"2025","source":"Stem cell research & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/40155988","citation_count":0,"is_preprint":false},{"pmid":"41705573","id":"PMC_41705573","title":"Hypoxia-Induced KDM3A Binding With AP-1 Promotes Angiogenesis by Mediating ANGPT2 in the Development of Small Bowel Angiodysplasia.","date":"2026","source":"Journal of gastroenterology and hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/41705573","citation_count":0,"is_preprint":false},{"pmid":"42176839","id":"PMC_42176839","title":"Targeting H3K27me3 methyltransferase EZH2 restrains ANGPT2 signaling in choroidal neovascularization.","date":"2026","source":"Experimental eye research","url":"https://pubmed.ncbi.nlm.nih.gov/42176839","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.10.24.683742","title":"Piezo1 Triggers an Angiopoietin-2-Integrin Signaling Loop in Schlemm’s Canal to Regulate Intraocular Pressure","date":"2025-10-24","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.24.683742","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.08.25.672093","title":"Angiopoietin signalling is a central axis of amyloid-driven vascular dysfunction in Alzheimer’s disease","date":"2025-08-29","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.25.672093","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.03.31.646063","title":"MAPK Signaling and Angiopoietin-2 Contribute to Endothelial Permeability in Capillary Malformations","date":"2025-04-05","source":"bioRxiv","url":"https://doi.org/10.1101/2025.03.31.646063","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.05.12.653406","title":"Transcriptional Subtypes on Immune Microenvironment and Predicting Postoperative Recurrence and Metastasis in Pheochromocytoma and Paraganglioma","date":"2025-05-13","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.12.653406","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.03.17.643802","title":"An endothelial specific mouse model for the capillary malformation mutation Gnaq p.R183Q","date":"2025-03-18","source":"bioRxiv","url":"https://doi.org/10.1101/2025.03.17.643802","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.01.22.634375","title":"Exploring Genomic Signatures of Selection in Guineafowl and Chicken Populations Across Diverse Climatic Zones: A Comparative Analysis of Africa, Asia, and Europe Research Article","date":"2025-01-24","source":"bioRxiv","url":"https://doi.org/10.1101/2025.01.22.634375","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.01.03.631070","title":"Gene-specific endothelial programs drive AVM pathogenesis in SMAD4 and ALK1 loss-of-function","date":"2025-01-03","source":"bioRxiv","url":"https://doi.org/10.1101/2025.01.03.631070","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.01.13.632801","title":"Molecular hallmarks of excitatory and inhibitory neuronal resilience and resistance to Alzheimer’s disease","date":"2025-01-15","source":"bioRxiv","url":"https://doi.org/10.1101/2025.01.13.632801","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50210,"output_tokens":8889,"usd":0.141983,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":18878,"output_tokens":4513,"usd":0.103608,"stage2_stop_reason":"end_turn"},"total_usd":0.245591,"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\": 2021,\n      \"finding\": \"Endothelial GNAQ p.R183Q mutation constitutively activates PLCβ3, leading to increased ANGPT2 expression via PKC and NF-κB/calcineurin signaling. shRNA knockdown of ANGPT2 in GNAQ p.R183Q endothelial cells normalized enlarged blood vessels in a mouse xenograft model to sizes comparable to wild-type, establishing ANGPT2 as a downstream effector of mutant Gαq in capillary malformation pathogenesis.\",\n      \"method\": \"Lentiviral expression of mutant/WT GNAQ in endothelial colony forming cells; siRNA knockdown of PLCβ3; pan-PKC inhibitor; shRNA knockdown of ANGPT2; in vivo mouse xenograft model; qPCR; immunostaining of human CM tissue\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (siRNA, pharmacologic inhibition, in vivo rescue), genetic epistasis by shRNA knockdown with specific vascular phenotype readout, confirmed in human tissue\",\n      \"pmids\": [\"34670408\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The RAS-ERK1/2 signaling axis controls ANGPT2 expression in colorectal cancer cells; gain- and loss-of-function studies showed ANGPT2 facilitates liver but not lung metastasis development, indicating tissue-specific pro-metastatic roles downstream of ERK1/2.\",\n      \"method\": \"In vivo selection of highly liver-metastatic CRC cells; gain- and loss-of-function studies in multiple CRC cell lines; in vivo metastasis assays; clinical sample validation\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple cell lines and in vivo models, single lab, gain/loss-of-function with specific metastatic phenotype\",\n      \"pmids\": [\"32816905\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"MYBL1 binds directly to the ANGPT2 promoter and transcriptionally upregulates ANGPT2 mRNA expression; this requires the histone post-translational factors PRMT5, MEP50, and WDR5. Monoclonal antibody against ANGPT2 inhibited growth of MYBL1-overexpressing tumors and impaired angiogenesis.\",\n      \"method\": \"ChIP assay (MYBL1 binding to ANGPT2 promoter); luciferase reporter assay; siRNA knockdown of PRMT5/MEP50/WDR5; anti-ANGPT2 monoclonal antibody treatment in vivo; HUVEC tube formation assay\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirmed direct promoter binding, multiple co-factors identified, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"35987690\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"DARPP-32 and its isoform t-DARPP induce ANGPT2 expression via activation of STAT3 (phosphorylation and nuclear localization), independently of T34-mediated PP1 regulation and NF-κB. The secreted ANGPT2 is functionally active and promotes endothelial tube formation; antibody blocking of secreted ANGPT2 abrogated this angiogenic function.\",\n      \"method\": \"Quantitative RT-PCR; immunoblotting; luciferase reporter; STAT3 inhibition/knockdown; HUVEC tube formation assay; ANGPT2 antibody blocking; in vivo xenograft; immunohistochemistry of human gastric cancer tissue\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (reporter assay, siRNA, pharmacologic inhibition, in vivo rescue, antibody blocking, human tissue validation), mechanistic pathway placement with specific readouts\",\n      \"pmids\": [\"25779598\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Characterization of ANGPT2 mutations associated with primary lymphedema revealed three missense mutations that decrease ANGPT2 secretion and inhibit secretion of wild-type ANGPT2 (dominant-negative effect). WT-ANGPT2 and soluble mutants T299M and N304K activated TIE1 and TIE2 in an autocrine assay in human lymphatic endothelial cells. The T299M mutant (in the dimerization interface) showed reduced integrin α5 binding, and expression in mouse skin promoted hyperplasia and dilation of cutaneous lymphatic vessels. Biophysical studies showed amino-terminally truncated ANGPT2 subunits formed asymmetrical homodimers that bound TIE2 in a 2:1 ratio.\",\n      \"method\": \"Functional secretion assays; TIE1/TIE2 autocrine activation assay in lymphatic endothelial cells; molecular modeling; biophysical binding studies; integrin α5 binding assay; mouse skin in vivo model; cohort screening of 543 lymphedema patients\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — reconstitution-level binding/activation assays, molecular modeling, mutagenesis, in vivo phenotype, multiple orthogonal methods in one study\",\n      \"pmids\": [\"32908006\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Pituitary neuroendocrine tumor (PitNET) cells express functional TIE2 receptor and secrete bioactive ANGPT2 that promotes tumor cell growth via an autocrine/paracrine loop. ANGPT2 stimulation of TIE2 in tumor cells activates downstream cell proliferation signals. Tie2 gene deletion blunted PitNET growth in xenograft models; pharmacological inhibition of ANGPT2/TIE2 antagonized PitNETs in primary cell cultures, xenografts, and an autochthonous rat model.\",\n      \"method\": \"GH3 PitNET cell line and primary human NF-PitNET cells; zebrafish and mouse xenografts; MENX rat autochthonous model; Tie2 gene deletion; pharmacological inhibition of Angpt2/Tie2; TIE2 functional assays\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple model systems (cell lines, zebrafish, mouse xenograft, autochthonous rat), genetic and pharmacological intervention, replicated across models\",\n      \"pmids\": [\"35266635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"SF-1 (steroidogenic factor-1/NR5A1) directly binds a 1.1-kb region in the ANGPT2 promoter (in a highly repetitive region) and transcriptionally activates ANGPT2, as confirmed by ChIP-on-chip in NCI-H295R human adrenocortical cells and luciferase reporter assays.\",\n      \"method\": \"ChIP-on-chip (promoter tiling arrays); luciferase reporter assay; systems/network analysis in NCI-H295R cells\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-on-chip plus luciferase validation, single lab, two orthogonal methods\",\n      \"pmids\": [\"21163858\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"MCPH1 binds to the ANGPT2 promoter and recruits DNA methyltransferases to maintain promoter methylation, thereby silencing ANGPT2 transcription. MCPH1 knockdown results in ANGPT2 upregulation with concurrent loss of promoter methylation in chronic lymphocytic leukemia cells.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP); co-immunoprecipitation (co-IP); MCPH1 knockdown; mRNA expression quantification; promoter methylation analysis\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and co-IP confirm direct promoter binding and recruitment of DNMT, single lab, two orthogonal methods\",\n      \"pmids\": [\"25703238\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Loss of Fzd5 in endothelial cells leads to upregulation of Angpt2 (and Flt1) via enhanced PKC signaling; this transcriptional induction involves the transcription factor Ets1. Canonical Wnt signaling, non-canonical Wnt/Ca2+-NFAT, and Wnt/PCP-JNK pathways were not involved.\",\n      \"method\": \"siRNA-mediated knockdown of Fzd5 in human endothelial cells; PKC inhibitor; Ets1 transcription factor studies; 3D co-culture angiogenesis assay; cell cycle analysis\",\n      \"journal\": \"Angiogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with specific pathway dissection using pharmacologic inhibitors, single lab, multiple pathway controls tested\",\n      \"pmids\": [\"29845518\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ISL2 binds directly to the ANGPT2 promoter and transcriptionally regulates ANGPT2 expression; ANGPT2, as a downstream gene, activates angiogenesis through VEGFA to promote oligodendroglioma malignant transformation.\",\n      \"method\": \"ChIP assay (ISL2 binding to ANGPT2 promoter); oligodendroglioma patient tumor-derived orthotopic xenograft mouse models; AAV-ISL2-shRNA knockdown; luciferase reporter\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirmed direct promoter binding, in vivo orthotopic model, single lab\",\n      \"pmids\": [\"32753650\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HOXB5 transcriptionally activates ANGPT2, as confirmed by luciferase reporter and ChIP assays. ANGPT2 silencing inactivated ERK/AKT signaling, and HOXB5 overexpression reversed this effect, placing ANGPT2 downstream of HOXB5 in a pathway regulating proliferation, migration, invasion, and angiogenesis in esophageal cancer cells.\",\n      \"method\": \"Luciferase reporter assay; ChIP assay; shRNA knockdown of ANGPT2; HOXB5 overexpression; tube formation assay; proliferation/invasion assays; Western blot for ERK/AKT\",\n      \"journal\": \"Experimental and therapeutic medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and luciferase confirm direct transcriptional regulation, epistasis via rescue experiment, single lab\",\n      \"pmids\": [\"35949323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NNMT/1-MNA protects against hepatic ischemia-reperfusion injury through the AKT/FOXO1/ANGPT2/JNK axis. Hepatic-specific depletion of NNMT increased ANGPT2 expression and exacerbated HIRI; these effects were mitigated by ANGPT2 knockdown, placing ANGPT2 downstream of FOXO1 as a mediator of vascular injury and inflammation.\",\n      \"method\": \"NNMT overexpression and hepatic-specific depletion in mouse HIRI models; ANGPT2 knockdown; AKT/FOXO1 pathway analysis; primary hepatocyte H/R models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis via tissue-specific KO and ANGPT2 knockdown rescue, in vivo and in vitro, single lab\",\n      \"pmids\": [\"40404636\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"IFN-γ suppresses ANGPT2 gene transcription in endothelial cells through the AKT-FOXO1 signaling pathway, and IFN-γ-activated STAT1 directly binds to the promoter regions of ANGPT2 and TEK genes to exert negative regulation. Anti-PD-L1 therapy reduced Tie2 and ANGPT2 expression in a JAK1/2-dependent manner in a mouse LUAD model.\",\n      \"method\": \"ChIP assay (STAT1 binding to ANGPT2 promoter); siRNA knockdown; RT-qPCR; Western blot; immunofluorescence; HUVEC tube formation, migration, proliferation assays; JAK1/2 inhibitor; mouse LUAD model with PD-L1 blockade\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirms direct promoter binding by STAT1, pharmacologic pathway dissection, in vivo and in vitro, single lab\",\n      \"pmids\": [\"40370455\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RBMS3 facilitates K48-linked ubiquitination and subsequent proteasomal degradation of ANGPT2 by recruiting the ubiquitin E3 ligase TRIM21, in an RNA-independent manner. Loss of RBMS3 in HCC cells promotes ANGPT2 accumulation and secretion, driving angiogenesis and sorafenib resistance.\",\n      \"method\": \"Immunoprecipitation mass spectrometry; co-immunoprecipitation (co-IP); ubiquitination assays; loss- and gain-of-function experiments; anti-ANGPT2 antibody rescue in vitro and in vivo\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP plus MS identified TRIM21 interaction, ubiquitination assay with K48-linkage specificity, in vivo rescue, multiple orthogonal methods\",\n      \"pmids\": [\"40069332\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In anti-Thy-1 nephritis, activated mesangial cells express VEGFA, which stimulates VEGFR2 on endothelial cells, induces Angpt2 expression in ECs, and inhibits Tie2 phosphorylation. The decline in Tie2 phosphorylation promotes EC proliferation. Promoting Tie2 phosphorylation alleviated EC proliferation in vivo.\",\n      \"method\": \"In vivo anti-Thy-1 nephritis rat model; in vitro mesangial-endothelial cell co-culture; siRNA knockdown; EdU proliferation assay; ELISA; RT-qPCR; Western blot; immunohistochemistry/immunofluorescence\",\n      \"journal\": \"Cell proliferation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown in co-culture system plus in vivo model, pathway placement with specific signaling readout, single lab\",\n      \"pmids\": [\"33987885\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Angpt2 induces mesangial cell apoptosis under high glucose conditions via suppression of miR-33-5p, which leads to increased SOCS5 expression, inhibiting JAK1 and STAT3 signaling transduction.\",\n      \"method\": \"In vitro mesangial cell treatment with Angpt2 under high glucose; miR-33-5p manipulation; SOCS5 expression analysis; JAK1/STAT3 phosphorylation assays; db/db mouse model; urine miR-33-5p measurements\",\n      \"journal\": \"Molecular therapy. Nucleic acids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro mechanistic pathway with miRNA manipulation and downstream signaling readout, in vivo correlation, single lab\",\n      \"pmids\": [\"30414568\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ANGPT2 knockdown in hypertrophic scar fibroblasts decreased phosphorylation of PI3K, Akt, and mTOR, activated autophagy, and inhibited proliferation, migration, and ECM accumulation. Treatment with an mTOR agonist partially reversed these effects of ANGPT2 knockdown, placing ANGPT2 upstream of the PI3K/Akt/mTOR pathway.\",\n      \"method\": \"sh-ANGPT2 knockdown in hypertrophic scar fibroblasts; mTOR agonist (MHT1485) treatment; CCK-8 proliferation assay; Transwell migration assay; Western blot for PI3K/Akt/mTOR pathway; autophagy markers\",\n      \"journal\": \"Anais brasileiros de dermatologia\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single method (knockdown + rescue), single lab, no in vivo validation\",\n      \"pmids\": [\"36272879\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ANGPT2 exacerbates albumin transcytosis across glomerular endothelial cells by increasing CAV1 expression during high glucose exposure. ANGPT2 knockdown reduced albumin transcytosis and CAV1 expression in vitro, and losartan reduced ANGPT2 and CAV1 in a DKD mouse model.\",\n      \"method\": \"In vitro albumin transcytosis model in hrGECs; ANGPT2 and CAV1 siRNA knockdown; in vivo DKD mouse model with losartan treatment; immunohistochemistry; Western blot\",\n      \"journal\": \"Nefrologia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro knockdown with specific transcytosis readout plus in vivo validation, single lab\",\n      \"pmids\": [\"36842857\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Endothelial ANGPT2 impairs cardiomyocyte calcium homeostasis in sepsis-related cardiomyopathy by binding to the extracellular domain of integrin β3 (ITGB3), triggering RYR2 phosphorylation and dysregulation of ATP2a2/PLN expression. ITGB3-specific siRNA attenuated the effects of ANGPT2 on calcium signaling proteins. AAV9-mediated EC-specific ANGPT2 overexpression exacerbated CLP-induced cardiac dysfunction.\",\n      \"method\": \"AAV9 EC-specific ANGPT2 overexpression mice; CLP sepsis model; ITGB3 siRNA knockdown; primary neonatal and adult mouse cardiomyocyte calcium imaging; Western blot for RYR2/ATP2a2/PLN; bioinformatics; serum CK-MB/cTnI correlation\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo AAV model and siRNA epistasis with specific calcium signaling readout, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"41192563\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Endothelial JAK1/STAT3 activation promotes ANGPT2 secretion, which induces adipocyte progenitor cells (APCs) to transition from MSLN to CFD phenotype via integrin-α5β1 signalling, promoting APC differentiation into mature adipocytes and accelerating visceral adipose tissue accumulation. Blocking Angpt2 expression by adeno-associated virus in obese mice reversed these effects.\",\n      \"method\": \"scRNAseq data analysis; PCR; Western blot; immunofluorescence; flow cytometry; in vitro co-culture; in vivo obese mouse model with recombinant Angpt2 protein and AAV-mediated Angpt2 blockade\",\n      \"journal\": \"Diabetes/metabolism research and reviews\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo epistasis with AAV blockade, specific phenotypic readout, single lab\",\n      \"pmids\": [\"39628006\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ANGPT2/Tie2 signaling in macrophages promotes M2 polarization via H3K18 lactylation (H3K18la)-mediated transcriptional regulation. ChIP assays confirmed that ANGPT2/Tie2 regulates H3K18la at target gene promoters. Tie2-overexpressing macrophages treated with ANGPT2 showed increased M2 markers and pro-angiogenic factors, and ANGPT2-overexpressing rats exhibited more M2-polarized TEM infiltration and increased EC proliferation in chronically ischemic brain.\",\n      \"method\": \"Primary Tie2-expressing macrophages and Tie2-overexpressing THP-1 macrophages; ANGPT2 treatment; ChIP assays for H3K18la; HUVEC co-culture proliferation assay; rat chronic cerebral ischaemia model; ANGPT2 overexpression in vivo\",\n      \"journal\": \"CNS neuroscience & therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirmed epigenetic mechanism, in vivo and in vitro, single lab with multiple methods\",\n      \"pmids\": [\"41968454\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Estradiol (E2) upregulates ANGPT2 pathway genes in human dermal papilla cells; ANGPT2 is downregulated in ovariectomized (estrogen-deficient) mice. Intradermal administration of ANGPT2 protein in ovariectomized mice increased hair density, establishing a functional E2-ANGPT2 axis in hair follicles. In silico analysis identified estrogen receptor binding sequences in the ANGPT2 promoter region.\",\n      \"method\": \"Microarray analysis in E2-treated hDPCs; RT-PCR; intradermal ANGPT2 protein injection in OVX mice; quantitative image analysis of hair density; in silico promoter analysis\",\n      \"journal\": \"Journal of dermatological science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo rescue with recombinant protein plus molecular analysis, single lab\",\n      \"pmids\": [\"29724581\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ADAM9 regulates ANGPT2 expression in lung cancer cells; silencing ADAM9 suppressed VEGFA, ANGPT2, and PLAT expression, leading to decreased angiogenesis, vascular remodeling, and tumor growth in vivo.\",\n      \"method\": \"Microarray after ADAM9 silencing; in vivo tumor growth and angiogenesis assays; clinical dataset correlation\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — ADAM9 silencing affects ANGPT2 as one of multiple targets, no direct mechanistic link established between ADAM9 and ANGPT2 regulation, single lab\",\n      \"pmids\": [\"29118335\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PIEZO1 activation in Schlemm's canal endothelium triggers ANGPT2 secretion and promotes cell-surface clustering of integrin α9β1 (ITGA9), establishing a TIE2-independent mechanosensitive ANGPT2-integrin α9β1 autocrine signaling loop that regulates intraocular pressure. Deletion of Piezo1 or Itga9 in SC endothelium caused SC narrowing and IOP elevation; ANGPT2 deficiency or blockade disrupted PIEZO1-induced integrin activation.\",\n      \"method\": \"In vitro mechanosensory assays; SC-specific Piezo1 and Itga9 conditional deletion in mice; ANGPT2 deficiency/blockade; measurement of aqueous humor outflow facility and IOP; SC morphometry\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with multiple conditional KO models, specific IOP phenotype, multiple orthogonal in vivo experiments, preprint\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In GNAQ p.R183Q endothelial cells (capillary malformation model), ANGPT2 knockdown combined with MEK1/2 inhibition (Trametinib) additively restored the endothelial barrier (measured by TEER) to near wild-type levels, whereas ANGPT2 knockdown alone or MEK1/2 inhibition alone only partially restored it. The additive effect indicates ANGPT2 and MAPK/ERK signaling operate in separate pathways to compromise the endothelial barrier.\",\n      \"method\": \"TEER assay; CRISPR-edited GNAQ R183Q EC; ANGPT2 siRNA knockdown; anti-ANGPT2 function-blocking antibody; MEK1/2 inhibitor (Trametinib); Gαq inhibitor (YM254890); Martius Scarlet Blue staining of human CM tissue; longitudinal MRI\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — TEER assay with genetic and pharmacologic epistasis, pathway dissection by additivity, human tissue validation, preprint\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"A glaucoma-protective SNP (rs76020419, G>T) in the 3'UTR of ANGPT2 at a predicted miR-145-binding site was functionally validated: CRISPR knock-in mice harboring the minor T allele showed higher ANGPT2 protein levels in plasma and multiple tissues, and a larger Schlemm canal area, suggesting the SNP increases ANGPT2 expression by disrupting miR-145 repression.\",\n      \"method\": \"CRISPR/Cas9 knock-in mice with orthologous rs76020419 T allele; ELISA for ANGPT2 in plasma and tissues; Schlemm canal morphometry in anterior segments\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo CRISPR knock-in model with protein quantification and morphometric readout, single lab\",\n      \"pmids\": [\"39206543\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Biallelic loss-of-function of ANGPT2 (homozygous splice-site variant causing nonsense-mediated mRNA decay) causes severe early-onset non-immune hydrops fetalis in humans, demonstrating that complete ANGPT2 loss disrupts blood and lymphatic vessel formation and remodeling.\",\n      \"method\": \"Whole exome sequencing; RNA analysis in heterozygous parents demonstrating NMD; serum ANGPT2 ELISA in carrier parents; clinical phenotyping\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function with molecular confirmation of NMD and reduced serum protein, human disease phenotype, small family study\",\n      \"pmids\": [\"34876502\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Constant mechanical stretch (mimicking CF-VAD conditions) upregulates ANGPT2 transcription and intracellular protein in aortic and umbilical vein endothelial cells, and promotes ANGPT2 secretion, whereas physiological cyclic stretch does not produce equivalent effects, establishing stretch as a mechanical regulator of endothelial ANGPT2 release.\",\n      \"method\": \"Uniaxial stretch device; HAECs and HUVECs; transcriptional profiling; ELISA; Western blot; immunofluorescence microscopy\",\n      \"journal\": \"Lab on a chip\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, descriptive mechanobiological study without genetic epistasis or functional readout beyond expression/secretion\",\n      \"pmids\": [\"40314578\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"EZH2 inhibition derepresses KLF2 (via loss of H3K27me3 at the KLF2 promoter), which in turn suppresses ANGPT2 expression; siRNA knockdown of KLF2 reversed the anti-angiogenic effects of EZH2 blockade. ChIP confirmed loss of H3K27me3 at the KLF2 promoter, establishing an EZH2-H3K27me3-KLF2-ANGPT2 axis regulating pathological angiogenesis in choroidal neovascularization.\",\n      \"method\": \"RNA-seq; ChIP assay (H3K27me3 at KLF2 promoter); siRNA knockdown of KLF2; EZH2 inhibitor (DZNep); EC proliferation/migration/tube formation assays; in vivo laser-induced CNV mouse model\",\n      \"journal\": \"Experimental eye research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirms epigenetic mechanism, siRNA epistasis with specific phenotypic rescue, in vivo validation, single lab\",\n      \"pmids\": [\"42176839\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PKM2 knockdown inhibits ANGPT2 expression in endothelial cells, while PKM2 overexpression promotes it. Supplementation with exogenous ANGPT2 restores proliferation, migration, and angiogenesis inhibited by PKM2 knockdown, placing ANGPT2 downstream of PKM2 in glycolytic regulation of endothelial angiogenic activation.\",\n      \"method\": \"PKM2 siRNA knockdown and overexpression in ECs; recombinant ANGPT2 rescue; proliferation, migration, and tube formation assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, rescue experiment with recombinant protein, no direct mechanistic link between PKM2 and ANGPT2 transcription established\",\n      \"pmids\": [\"40858916\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"KDM3A is induced by hypoxia in endothelial cells and binds to AP-1 transcription factor under hypoxic conditions; the KDM3A-AP1 complex acts on the ANGPT2 promoter to promote its transcriptional expression, thereby driving angiogenesis in small bowel angiodysplasia. KDM3A inhibitor IOX1 exerted anti-angiogenic effects by blocking this pathway.\",\n      \"method\": \"RNA sequencing; ChIP assay (KDM3A and AP-1 at ANGPT2 promoter); KDM3A knockdown/overexpression in HUVECs under hypoxia; migration, invasion, tube formation assays; in vivo Matrigel plug assay; IOX1 inhibitor; IHC of SBAD specimens\",\n      \"journal\": \"Journal of gastroenterology and hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirmed direct promoter binding, in vitro and in vivo experiments, pharmacologic inhibition, single lab\",\n      \"pmids\": [\"41705573\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ANGPT2 is a secreted ligand that signals primarily through the TIE2 receptor (and also integrin α5β1 and integrin α9β1 in a TIE2-independent manner) to regulate blood and lymphatic vascular formation, stability, and remodeling; its transcription is controlled by multiple upstream regulators including SF-1, MYBL1, HOXB5, ISL2, DARPP-32/STAT3, Fzd5/PKC/Ets1, EZH2/KLF2, KDM3A/AP-1, and IFN-γ/STAT1-FOXO1 axes, while its protein stability is post-translationally regulated by RBMS3-TRIM21-mediated K48-linked ubiquitination; functionally, ANGPT2 promotes angiogenesis and vascular destabilization, drives tumor cell growth via autocrine TIE2 activation, impairs cardiomyocyte calcium homeostasis through ITGB3-RYR2 signaling during sepsis, promotes macrophage M2 polarization through H3K18 lactylation, and regulates intraocular pressure through a PIEZO1-ANGPT2-ITGA9 mechanosensitive loop in Schlemm's canal endothelium.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ANGPT2 is a secreted ligand that signals through the TIE2/TEK receptor to control blood and lymphatic vascular formation, stability, and remodeling, and biallelic loss-of-function in humans causes severe early-onset non-immune hydrops fetalis by disrupting these processes [#26]. Amino-terminally truncated ANGPT2 subunits assemble into asymmetrical homodimers that bind TIE2 in a 2:1 stoichiometry and can activate both TIE1 and TIE2 in an autocrine setting; missense mutations associated with primary lymphedema reduce ANGPT2 secretion in a dominant-negative manner and perturb integrin α5 binding, with truncating effects producing lymphatic vessel hyperplasia and dilation in vivo [#4]. Beyond canonical TIE2 signaling, ANGPT2 engages integrins to drive context-specific effects: it impairs cardiomyocyte calcium homeostasis in sepsis by binding the integrin β3 (ITGB3) extracellular domain and triggering RYR2 phosphorylation with dysregulated ATP2a2/PLN [#18], and acts through a TIE2-independent PIEZO1–ANGPT2–integrin α9β1 mechanosensitive autocrine loop in Schlemm's canal endothelium that regulates intraocular pressure [#23]. In tumors, ANGPT2 promotes angiogenesis and tumor growth, including via an autocrine/paracrine ANGPT2–TIE2 loop in pituitary neuroendocrine tumor cells whose growth depends on TIE2 [#5], and macrophage ANGPT2/TIE2 signaling drives M2 polarization through H3K18 lactylation at target gene promoters [#20]. ANGPT2 transcription is controlled by numerous upstream inputs—activating regulators including DARPP-32/STAT3 [#3], MYBL1 [#2], SF-1 [#6], ISL2 [#9], HOXB5 [#10], mutant GNAQ via PKC/NF-κB [#0], and a hypoxic KDM3A–AP-1 complex [#30], and repressive inputs including MCPH1-directed promoter methylation [#7] and IFN-γ/STAT1–FOXO1 signaling [#12]—while protein abundance is post-translationally limited by RBMS3-recruited TRIM21-mediated K48-linked ubiquitination and proteasomal degradation [#13]. Downstream, ANGPT2 mediates pro-angiogenic and pro-fibrotic responses in multiple disease contexts and is dysregulated in capillary malformation, where it cooperates with but operates in a pathway separate from MAPK/ERK signaling to compromise the endothelial barrier [#0, #24].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Established that ANGPT2 transcription is under direct control of defined nuclear factors, identifying the steroidogenic factor SF-1 as a direct promoter-binding activator.\",\n      \"evidence\": \"ChIP-on-chip and luciferase reporter assays in adrenocortical NCI-H295R cells\",\n      \"pmids\": [\"21163858\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not test SF-1 dependence of ANGPT2 in vascular cell types\", \"No in vivo confirmation of the regulatory axis\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined two opposing transcriptional control mechanisms: DARPP-32/STAT3 activation of functionally angiogenic ANGPT2 versus MCPH1-recruited DNA methyltransferase silencing of the promoter.\",\n      \"evidence\": \"Reporter assays, STAT3 inhibition/knockdown, HUVEC tube formation with antibody blocking, plus ChIP and co-IP for MCPH1/DNMT recruitment in cancer cells\",\n      \"pmids\": [\"25779598\", \"25703238\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"DARPP-32/STAT3 and MCPH1 pathways studied in distinct tumor contexts, not integrated\", \"Direct STAT3 promoter occupancy not demonstrated in the DARPP-32 study\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Resolved the molecular architecture of ANGPT2-TIE signaling and connected disease mutations to secretion and receptor activation defects, showing dominant-negative lymphedema mutations and a 2:1 TIE2-binding stoichiometry.\",\n      \"evidence\": \"Secretion and TIE1/TIE2 autocrine activation assays in lymphatic endothelial cells, biophysical binding, molecular modeling, integrin α5 binding, mouse skin model, lymphedema cohort screening\",\n      \"pmids\": [\"32908006\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of asymmetric dimerization for downstream signaling not fully resolved\", \"Integrin α5 contribution relative to TIE2 not quantified in vivo\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Expanded the transcriptional regulator repertoire (RAS-ERK, ISL2) and tied ANGPT2 induction to tissue-specific pro-metastatic and pro-tumor angiogenic phenotypes downstream of these factors.\",\n      \"evidence\": \"In vivo metastasis selection and gain/loss-of-function in CRC; ChIP and orthotopic xenografts for ISL2 in oligodendroglioma\",\n      \"pmids\": [\"32816905\", \"32753650\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of liver- versus lung-tissue specificity unresolved\", \"Direct ERK-to-promoter linkage not established\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Placed ANGPT2 as a downstream effector of mutant Gαq in capillary malformation, demonstrating that knockdown normalizes the vascular phenotype.\",\n      \"evidence\": \"Mutant/WT GNAQ expression in endothelial colony forming cells, PLCβ3/PKC dissection, shRNA knockdown, in vivo xenograft rescue, human tissue immunostaining\",\n      \"pmids\": [\"34670408\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ANGPT2 acts via TIE2 or integrins in this context not defined\", \"Receptor on affected vasculature not identified\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Provided definitive human genetic evidence that ANGPT2 is required for normal vascular and lymphatic development, with complete loss causing hydrops fetalis.\",\n      \"evidence\": \"Whole exome sequencing, NMD confirmation by RNA analysis, serum ELISA in carrier parents, clinical phenotyping\",\n      \"pmids\": [\"34876502\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single family study\", \"Developmental timing and tissue specificity of the requirement not dissected\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrated an autocrine ANGPT2-TIE2 loop intrinsic to tumor cells, showing TIE2 expression on tumor cells drives growth and identifying additional activating transcription factors (MYBL1, HOXB5).\",\n      \"evidence\": \"PitNET cell lines, zebrafish/mouse xenografts and autochthonous rat model with Tie2 deletion and pharmacologic inhibition; ChIP/luciferase for MYBL1 and HOXB5 with anti-ANGPT2 antibody\",\n      \"pmids\": [\"35266635\", \"35987690\", \"35949323\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality of tumor-cell-intrinsic TIE2 expression across cancers unknown\", \"Relative contributions of autocrine versus paracrine signaling not separated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified post-translational control of ANGPT2 abundance through RBMS3-recruited TRIM21 ubiquitination, linking degradation to angiogenesis and drug resistance.\",\n      \"evidence\": \"IP-MS, co-IP, K48-linkage-specific ubiquitination assays, loss/gain-of-function and anti-ANGPT2 rescue in HCC in vitro and in vivo\",\n      \"pmids\": [\"40069332\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other E3 ligases regulate ANGPT2 not addressed\", \"Signals controlling RBMS3-TRIM21 engagement unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established TIE2-independent integrin-mediated functions of ANGPT2, defining an ITGB3-RYR2 cardiomyocyte axis in sepsis and a PIEZO1-ANGPT2-integrin α9β1 mechanosensitive loop controlling intraocular pressure.\",\n      \"evidence\": \"AAV9 EC-specific ANGPT2 overexpression with CLP sepsis and ITGB3 siRNA and cardiomyocyte calcium imaging; SC-specific Piezo1/Itga9 conditional deletion with IOP and morphometry (preprint for the IOP loop)\",\n      \"pmids\": [\"41192563\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of ANGPT2-integrin engagement not resolved\", \"PIEZO1-ANGPT2-ITGA9 loop reported only as a preprint\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined IFN-γ/STAT1-FOXO1 as a repressive arm of ANGPT2 transcription and linked it to immunotherapy-induced vascular normalization.\",\n      \"evidence\": \"ChIP for STAT1 at the ANGPT2/TEK promoters, AKT-FOXO1 pathway analysis, HUVEC assays, JAK1/2 inhibitor, and mouse LUAD with PD-L1 blockade\",\n      \"pmids\": [\"40370455\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Interplay with activating factors at the same promoter not mapped\", \"Direct STAT1-FOXO1 cooperativity not biochemically defined\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Connected ANGPT2/TIE2 signaling to epigenetic effector mechanisms, showing macrophage M2 polarization via H3K18 lactylation and identifying an EZH2-H3K27me3-KLF2 axis and hypoxic KDM3A-AP-1 complex as upstream regulators of ANGPT2.\",\n      \"evidence\": \"ChIP for H3K18la in Tie2-expressing macrophages with rat ischemia model; ChIP/siRNA for the EZH2-KLF2 axis in CNV; ChIP for KDM3A-AP1 at the ANGPT2 promoter in angiodysplasia with IOX1 inhibition\",\n      \"pmids\": [\"41968454\", \"42176839\", \"41705573\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link from TIE2 activation to H3K18la deposition not defined\", \"These regulatory axes characterized in separate disease models\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the multiple upstream transcriptional and post-translational regulators are integrated at the ANGPT2 locus, and how ligand engagement is partitioned between TIE2 and distinct integrins to produce context-specific vascular outcomes, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model reconciling activating and repressive promoter inputs\", \"Receptor choice (TIE2 vs integrin α5/α9/β3) per tissue not predictable\", \"Structural basis of integrin engagement uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [4, 5, 18, 23]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4, 14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [3, 4, 13, 26]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 5, 18, 23]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [4, 26]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 26]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"TEK\", \"TIE1\", \"ITGA5\", \"ITGB3\", \"ITGA9\", \"TRIM21\", \"RBMS3\", \"PIEZO1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":6,"faith_pct":83.33333333333333}}