Affinage

ANGPT2

Angiopoietin-2 · UniProt O15123

Length
496 aa
Mass
56.9 kDa
Annotated
2026-06-09
74 papers in source corpus 29 papers cited in narrative 31 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/6 claims corpus-supported (83%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2010 Medium

    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

    PMID:21163858

    Open questions at the time
    • Does not test SF-1 dependence of ANGPT2 in vascular cell types
    • No in vivo confirmation of the regulatory axis
  2. 2015 High

    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

    PMID:25703238 PMID:25779598

    Open questions at the time
    • DARPP-32/STAT3 and MCPH1 pathways studied in distinct tumor contexts, not integrated
    • Direct STAT3 promoter occupancy not demonstrated in the DARPP-32 study
  3. 2020 High

    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

    PMID:32908006

    Open questions at the time
    • Functional consequence of asymmetric dimerization for downstream signaling not fully resolved
    • Integrin α5 contribution relative to TIE2 not quantified in vivo
  4. 2020 Medium

    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

    PMID:32753650 PMID:32816905

    Open questions at the time
    • Mechanism of liver- versus lung-tissue specificity unresolved
    • Direct ERK-to-promoter linkage not established
  5. 2021 High

    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

    PMID:34670408

    Open questions at the time
    • Whether ANGPT2 acts via TIE2 or integrins in this context not defined
    • Receptor on affected vasculature not identified
  6. 2021 Medium

    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

    PMID:34876502

    Open questions at the time
    • Single family study
    • Developmental timing and tissue specificity of the requirement not dissected
  7. 2022 High

    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

    PMID:35266635 PMID:35949323 PMID:35987690

    Open questions at the time
    • Generality of tumor-cell-intrinsic TIE2 expression across cancers unknown
    • Relative contributions of autocrine versus paracrine signaling not separated
  8. 2025 High

    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

    PMID:40069332

    Open questions at the time
    • Whether other E3 ligases regulate ANGPT2 not addressed
    • Signals controlling RBMS3-TRIM21 engagement unknown
  9. 2025 Medium

    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)

    PMID:41192563

    Open questions at the time
    • Structural basis of ANGPT2-integrin engagement not resolved
    • PIEZO1-ANGPT2-ITGA9 loop reported only as a preprint
  10. 2025 Medium

    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

    PMID:40370455

    Open questions at the time
    • Interplay with activating factors at the same promoter not mapped
    • Direct STAT1-FOXO1 cooperativity not biochemically defined
  11. 2026 Medium

    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

    PMID:41705573 PMID:41968454 PMID:42176839

    Open questions at the time
    • Mechanistic link from TIE2 activation to H3K18la deposition not defined
    • These regulatory axes characterized in separate disease models

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 4 GO:0098772 molecular function regulator activity 2
Localization
GO:0005576 extracellular region 4
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1266738 Developmental Biology 2 R-HSA-1643685 Disease 2
Partners
ITGA5ITGA9ITGB3PIEZO1RBMS3TEKTIE1TRIM21

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2021 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. 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 Arteriosclerosis, thrombosis, and vascular biology High 34670408
2020 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. 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 Cancer research Medium 32816905
2022 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. 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 Cell death & disease Medium 35987690
2015 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. 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 Gut High 25779598
2020 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. 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 Science translational medicine High 32908006
2022 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. 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 EMBO molecular medicine High 35266635
2010 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. ChIP-on-chip (promoter tiling arrays); luciferase reporter assay; systems/network analysis in NCI-H295R cells FASEB journal Medium 21163858
2015 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. Chromatin immunoprecipitation (ChIP); co-immunoprecipitation (co-IP); MCPH1 knockdown; mRNA expression quantification; promoter methylation analysis The FEBS journal Medium 25703238
2018 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. siRNA-mediated knockdown of Fzd5 in human endothelial cells; PKC inhibitor; Ets1 transcription factor studies; 3D co-culture angiogenesis assay; cell cycle analysis Angiogenesis Medium 29845518
2020 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. ChIP assay (ISL2 binding to ANGPT2 promoter); oligodendroglioma patient tumor-derived orthotopic xenograft mouse models; AAV-ISL2-shRNA knockdown; luciferase reporter Oncogene Medium 32753650
2022 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. Luciferase reporter assay; ChIP assay; shRNA knockdown of ANGPT2; HOXB5 overexpression; tube formation assay; proliferation/invasion assays; Western blot for ERK/AKT Experimental and therapeutic medicine Medium 35949323
2025 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. NNMT overexpression and hepatic-specific depletion in mouse HIRI models; ANGPT2 knockdown; AKT/FOXO1 pathway analysis; primary hepatocyte H/R models Nature communications Medium 40404636
2025 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. 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 Frontiers in immunology Medium 40370455
2025 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. Immunoprecipitation mass spectrometry; co-immunoprecipitation (co-IP); ubiquitination assays; loss- and gain-of-function experiments; anti-ANGPT2 antibody rescue in vitro and in vivo Oncogene High 40069332
2021 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. 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 Cell proliferation Medium 33987885
2018 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. 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 Molecular therapy. Nucleic acids Medium 30414568
2022 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. 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 Anais brasileiros de dermatologia Low 36272879
2023 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. In vitro albumin transcytosis model in hrGECs; ANGPT2 and CAV1 siRNA knockdown; in vivo DKD mouse model with losartan treatment; immunohistochemistry; Western blot Nefrologia Medium 36842857
2025 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. 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 Biochimica et biophysica acta. Molecular cell research Medium 41192563
2025 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. 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 Diabetes/metabolism research and reviews Medium 39628006
2026 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. 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 CNS neuroscience & therapeutics Medium 41968454
2018 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. 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 of dermatological science Medium 29724581
2017 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. Microarray after ADAM9 silencing; in vivo tumor growth and angiogenesis assays; clinical dataset correlation Scientific reports Low 29118335
2025 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. 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 bioRxivpreprint Medium
2025 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. 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 bioRxivpreprint Medium
2024 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. CRISPR/Cas9 knock-in mice with orthologous rs76020419 T allele; ELISA for ANGPT2 in plasma and tissues; Schlemm canal morphometry in anterior segments Arteriosclerosis, thrombosis, and vascular biology Medium 39206543
2021 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. Whole exome sequencing; RNA analysis in heterozygous parents demonstrating NMD; serum ANGPT2 ELISA in carrier parents; clinical phenotyping Journal of medical genetics Medium 34876502
2025 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. Uniaxial stretch device; HAECs and HUVECs; transcriptional profiling; ELISA; Western blot; immunofluorescence microscopy Lab on a chip Low 40314578
2026 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. 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 Experimental eye research Medium 42176839
2025 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. PKM2 siRNA knockdown and overexpression in ECs; recombinant ANGPT2 rescue; proliferation, migration, and tube formation assays Scientific reports Low 40858916
2026 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. 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 of gastroenterology and hepatology Medium 41705573

Source papers

Stage 0 corpus · 74 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 ANGPT2 genetic variant is associated with trauma-associated acute lung injury and altered plasma angiopoietin-2 isoform ratio. American journal of respiratory and critical care medicine 94 21257790
2014 miR-145 functions as tumor suppressor and targets two oncogenes, ANGPT2 and NEDD9, in renal cell carcinoma. Journal of cancer research and clinical oncology 70 24384875
2019 LncRNA MALAT1 up-regulates VEGF-A and ANGPT2 to promote angiogenesis in brain microvascular endothelial cells against oxygen-glucose deprivation via targetting miR-145. Bioscience reports 52 30038058
2021 Endothelial GNAQ p.R183Q Increases ANGPT2 (Angiopoietin-2) and Drives Formation of Enlarged Blood Vessels. Arteriosclerosis, thrombosis, and vascular biology 50 34670408
2022 MYBL1 induces transcriptional activation of ANGPT2 to promote tumor angiogenesis and confer sorafenib resistance in human hepatocellular carcinoma. Cell death & disease 48 35987690
2020 ERK1/2 Signaling Induces Upregulation of ANGPT2 and CXCR4 to Mediate Liver Metastasis in Colon Cancer. Cancer research 48 32816905
2017 ADAM9 promotes lung cancer progression through vascular remodeling by VEGFA, ANGPT2, and PLAT. Scientific reports 47 29118335
2018 lncRNA PVT1 promotes the angiogenesis of vascular endothelial cell by targeting miR‑26b to activate CTGF/ANGPT2. International journal of molecular medicine 46 29620147
2020 MiR-145-5p suppresses the proliferation, migration and invasion of gastric cancer epithelial cells via the ANGPT2/NOD_LIKE_RECEPTOR axis. Cancer cell international 43 32874130
2015 Gastric tumour-derived ANGPT2 regulation by DARPP-32 promotes angiogenesis. Gut 43 25779598
2019 Immunoregulation and Clinical Implications of ANGPT2/TIE2+ M-MDSC Signature in Non-Small Cell Lung Cancer. Cancer immunology research 41 31871121
2019 miR-205-5p inhibits human endometriosis progression by targeting ANGPT2 in endometrial stromal cells. Stem cell research & therapy 38 31547870
2017 Identification of ANGPT2 as a New Gene for Neovascular Age-Related Macular Degeneration and Polypoidal Choroidal Vasculopathy in the Chinese and Japanese Populations. Investigative ophthalmology & visual science 35 28192798
2020 Characterization of ANGPT2 mutations associated with primary lymphedema. Science translational medicine 34 32908006
2018 Angpt2 Induces Mesangial Cell Apoptosis through the MicroRNA-33-5p-SOCS5 Loop in Diabetic Nephropathy. Molecular therapy. Nucleic acids 34 30414568
2020 Distinct Roles of VEGFA and ANGPT2 in Lung Adenocarcinoma and Squamous Cell Carcinoma. Journal of Cancer 31 31892982
2021 Atorvastatin pleiotropically decreases intraplaque angiogenesis and intraplaque haemorrhage by inhibiting ANGPT2 release and VE-Cadherin internalization. Angiogenesis 29 33550461
2010 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. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 27 21163858
2020 Molecular description of ANGPT2 associated colorectal carcinoma. International journal of cancer 25 32222972
2022 Immunoregulation and clinical significance of neutrophils/NETs-ANGPT2 in tumor microenvironment of gastric cancer. Frontiers in immunology 24 36172371
2021 Activated mesangial cells induce glomerular endothelial cells proliferation in rat anti-Thy-1 nephritis through VEGFA/VEGFR2 and Angpt2/Tie2 pathway. Cell proliferation 24 33987885
2016 Variants in angiopoietin-2 (ANGPT2) contribute to variation in nocturnal oxyhaemoglobin saturation level. Human molecular genetics 23 27798093
2021 LINC00184 involved in the regulatory network of ANGPT2 via ceRNA mediated miR-145 inhibition in gastric cancer. Journal of Cancer 20 33758610
2018 Endothelial loss of Fzd5 stimulates PKC/Ets1-mediated transcription of Angpt2 and Flt1. Angiogenesis 19 29845518
2017 Germline Genetic Variants in TEK, ANGPT1, ANGPT2, MMP9, FGF2 and VEGFA Are Associated with Pathologic Complete Response to Bevacizumab in Breast Cancer Patients. PloS one 19 28045923
2022 Angpt2/Tie2 autostimulatory loop controls tumorigenesis. EMBO molecular medicine 18 35266635
2020 ISL2 modulates angiogenesis through transcriptional regulation of ANGPT2 to promote cell proliferation and malignant transformation in oligodendroglioma. Oncogene 18 32753650
2017 VEGF, ANGPT1, ANGPT2, and MMP-9 expression in the autologous hematopoietic stem cell transplantation and its impact on the time to engraftment. Annals of hematology 18 28956132
2022 MiR-29a Curbs Hepatocellular Carcinoma Incidence via Targeting of HIF-1α and ANGPT2. International journal of molecular sciences 16 35163556
2022 Inhibition of ANGPT2 activates autophagy during hypertrophic scar formation via PI3K/AKT/mTOR pathway. Anais brasileiros de dermatologia 15 36272879
2021 miR‑135a‑5p inhibits tumor invasion by targeting ANGPT2 in gallbladder cancer. Molecular medicine reports 15 34036386
2020 Association of NOS3 and ANGPT2 Gene Polymorphisms with Survival in Patients with Hepatocellular Carcinoma Receiving Sorafenib: Results of the Multicenter Prospective INNOVATE Study. Clinical cancer research : an official journal of the American Association for Cancer Research 14 32371540
2025 Single-cell analysis reveals the implication of vascular endothelial cell-intrinsic ANGPT2 in human intracranial aneurysm. Cardiovascular research 12 39187926
2025 IFN-γ-mediated suppression of ANGPT2-Tie2 in endothelial cells facilitates tumor vascular normalization during immunotherapy. Frontiers in immunology 11 40370455
2025 NNMT/1-MNA protects against hepatic ischemia-reperfusion injury through the AKT/FOXO1/ANGPT2/JNK axis. Nature communications 11 40404636
2022 Endothelial GATA5 positively regulates angiogenesis via cathepsin S-mediated Angpt2/Flk1 and MMP2/9 signaling pathways. Biochemical and biophysical research communications 9 35429678
2021 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. Archives of endocrinology and metabolism 9 34762787
2014 Clonal Dominance With Retroviral Vector Insertions Near the ANGPT1 and ANGPT2 Genes in a Human Xenotransplant Mouse Model. Molecular therapy. Nucleic acids 9 25291142
2024 Angiogenesis-promoting effect of SKP-SC-EVs-derived miRNA-30a-5p in peripheral nerve regeneration by targeting LIF and ANGPT2. The Journal of biological chemistry 8 39732166
2021 Biallelic ANGPT2 loss-of-function causes severe early-onset non-immune hydrops fetalis. Journal of medical genetics 8 34876502
2023 Helicobacter pylori infection induces gastric precancerous lesions and persistent expression of Angpt2, Vegf-A and Tnf-A in a mouse model. Frontiers in oncology 7 36874142
2022 HOXB5-activated ANGPT2 promotes the proliferation, migration, invasion and angiogenic effect of esophageal cancer cells via activating ERK/AKT signaling pathway. Experimental and therapeutic medicine 7 35949323
2022 Human placenta-based genome-wide mRNA sequencing to identify TEK/IGF1/CSF1/ANGPT2 as crucial segments in the pathogenesis of pre-eclampsia. Frontiers in genetics 7 36160014
2018 Reversal of the hair loss phenotype by modulating the estradiol-ANGPT2 axis in the mouse model of female pattern hair loss. Journal of dermatological science 7 29724581
2015 MCPH1 maintains long-term epigenetic silencing of ANGPT2 in chronic lymphocytic leukemia. The FEBS journal 7 25703238
2020 miR145 Regulates the Proliferation and Apoptosis of Rat Vascular Endothelial Cells under Hyperglycemia by Targeting the ANGPT2 Gene and Involving the NFκB Signaling Pathway. Diabetes, metabolic syndrome and obesity : targets and therapy 6 33239896
2025 Doxorubicin-loaded PEGylated liposome modified with ANGPT2-specific peptide for integrative glioma-targeted imaging and therapy. Materials today. Bio 5 39866777
2015 Prospective evaluation of plasma levels of ANGPT2, TuM2PK, and VEGF in patients with renal cell carcinoma. BMC urology 5 25885592
2022 Association of Single Nucleotide Polymorphisms from Angiogenesis-Related Genes, ANGPT2, TLR2 and TLR9, with Spontaneous Preterm Labor. Current issues in molecular biology 4 35877427
2025 Endothelial Angpt2 Promotes Adipocyte Progenitor Cells Maturation to Increase Visceral Adipose Tissue Accumulation. Diabetes/metabolism research and reviews 3 39628006
2025 RBMS3-loss impedes TRIM21-induced ubiquitination of ANGPT2 in an RNA-independent manner and drives sorafenib resistance in hepatocellular carcinoma. Oncogene 3 40069332
2025 PKM2 regulates angiogenic activation via ANGPT2 in endothelial cells. Scientific reports 3 40858916
2024 Silencing ANGPT2 alleviates ulcerative colitis by regulating autophagy-mediated NLRP3 inflammasome inactivation via the mTOR signaling pathway. Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas 3 38808888
2024 Glaucoma-Protective Human Single-Nucleotide Polymorphism in the Angpt2 Locus Increased ANGPT2 Expression and Schlemm Canal Area in Mice-Brief Report. Arteriosclerosis, thrombosis, and vascular biology 3 39206543
2023 ANGPT2/CAV1 regulates albumin transcytosis of glomerular endothelial cells under high glucose exposure and is impaired by losartan. Nefrologia 3 36842857
2025 Effects of Dual Inhibition of VEGF-A and Angpt-2 on Angiogenesis and Lymphangiogenesis in an Alkali-Induced Corneal Injury Model. Genes to cells : devoted to molecular & cellular mechanisms 2 40556366
2022 Genetic association of ANGPT2 with primary open-angle glaucoma. Eye and vision (London, England) 2 36199153
2025 Understanding the role of vascular stretch on modulation of VWF and ANGPT-2 in continuous flow left ventricular assist device (CF-VAD) patients. Lab on a chip 1 40314578
2025 10-Hydroxycamptothecin-Loaded Hollow Mesoporous Polydopamine Modified with ANGPT2-Specific Peptide for Gastric Cancer-Targeted Therapy. Journal of medicinal chemistry 1 40954112
2023 Helicobacter pylori infection induces abnormal expression of pro-angiogenic gene ANGPT2 and miR-203a in AGS gastric cell line. Brazilian journal of microbiology : [publication of the Brazilian Society for Microbiology] 1 36877445
2013 Angiopoietin-2 (ANGPT2) as a candidate gene for somatic cell score in German Holstein cattle. Journal of dairy science 1 23726425
2026 Adipocyte-driven STAT3-ANGPT2-PTGIS axis promotes cutaneous metastasis in breast cancer and represents a targetable pathway. NPJ precision oncology 0 41651922
2026 Endothelial miR-7052 Safeguards Blood-Brain Barrier Integrity During Endotoxemia by Co-repressing ANGPT2 and PDE5A. Molecular neurobiology 0 41677948
2026 Hypoxia-Induced KDM3A Binding With AP-1 Promotes Angiogenesis by Mediating ANGPT2 in the Development of Small Bowel Angiodysplasia. Journal of gastroenterology and hepatology 0 41705573
2026 ANGPT2/Tie2 Enhances H3K18la-Mediated Macrophage M2 Polarization to Promote Endothelial Cell Proliferation in the Chronically Ischaemic Brain. CNS neuroscience & therapeutics 0 41968454
2026 Association Between the ANGPT2 rs2442598 Polymorphism and Diabetic Nephropathy in Slovenian Patients with Type 2 Diabetes Mellitus. Genes 0 42074491
2026 Targeting H3K27me3 methyltransferase EZH2 restrains ANGPT2 signaling in choroidal neovascularization. Experimental eye research 0 42176839
2025 Associations of ANGPT2 expression and its variants (rs1868554 and rs7825407) with multiple myeloma risk and outcome. Frontiers in oncology 0 40115011
2025 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. Stem cell research & therapy 0 40155988
2025 Human cytomegalovirus UL82 promotes colorectal cancer cell proliferation through inhibiting the ubiquitination of OGDH via ANGPT2. Tumour virus research 0 40571161
2025 Identification Of ANGPT2, FLT3, IGF1, and SPP1 associated with glycolysis and PI3K/Akt signaling pathway in hepatocellular carcinoma. Gene 0 40675517
2025 The role of ANGPT2 in pathogenesis of preeclampsia. Placenta 0 41138551
2025 Association of ANGPT2 and NOS3 Gene Variants With Esophageal Variceal Progression in HCV-Induced Cirrhosis. Journal of medical virology 0 41186068
2025 Endothelial ANGPT2 impairs cardiomyocyte calcium homeostasis via ITGB3 receptor in murine sepsis-related cardiomyopathy. Biochimica et biophysica acta. Molecular cell research 0 41192563

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