ArticleHuman molecular genetics2016
Haploinsufficiency of Klippel-Trenaunay syndrome gene Aggf1 inhibits developmental and pathological angiogenesis by inactivating PI3K and AKT and disrupts vascular integrity by activating VE-cadherin.
Article in Human molecular genetics, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 49 citations in OpenAlex.
- Empagliflozin-pretreated mesenchymal stem cell-derived extracellular vesicles facilitate cardiac repair via AGGF1.Journal of nanobiotechnology · 2026Article
- AGGF1-primed endothelial progenitor cells alleviate ischaemia-reperfusion injury in diabetic hearts.Scientific reports · 2025Article
- Endothelial AGGF1 promotes retinal angiogenesis by coordinating TNFSF12/FN14 signalling.Nature communications · 2025Article
- Review
- Klippel-Trenaunay Syndrome, Segmental/Focal Overgrowth Malformations: A Review.Children (Basel, Switzerland) · 2023Review
- AGGF1 therapy inhibits thoracic aortic aneurysms by enhancing integrin α7-mediated inhibition of TGF-β1 maturation and ERK1/2 signaling.Nature communications · 2023Article
- Protein therapy of skeletal muscle atrophy and mechanism by angiogenic factor AGGF1.Journal of cachexia, sarcopenia and muscle · 2023Article
- Endothelial G protein stimulatory α-subunit is a critical regulator of post-ischemic angiogenesis.Frontiers in cardiovascular medicine · 2022Article
- FHA domain of AGGF1 is essential for its nucleocytoplasmic transport and angiogenesis.Science China. Life sciences · 2021Article
- AGGF1 Shows the α5β1 Integrin to Be AnotherArteriosclerosis, thrombosis, and vascular biology · 2021Article
- Receptor and Molecular Mechanism of AGGF1 Signaling in Endothelial Cell Functions and Angiogenesis.Arteriosclerosis, thrombosis, and vascular biology · 2021Article
- A literature review of microvascular proliferation in arteriovenous malformations of skin and soft tissue.Journal of clinical and translational research · 2021Review
- The combined prevalence of classified rare rheumatic diseases is almost double that of ankylosing spondylitis.Orphanet journal of rare diseases · 2021Article
- QPCT regulation by CTCF leads to sunitinib resistance in renal cell carcinoma by promoting angiogenesis.International journal of oncology · 2021Article
- AGGF1 inhibits the expression of inflammatory mediators and promotes angiogenesis in dental pulp cells.Clinical oral investigations · 2021Article
- Angiogenic factor AGGF1 acts as a tumor suppressor by modulating p53 post-transcriptional modifications and stability via MDM2.Cancer letters · 2021Article
- A Review of Multiple Venous Malformations of the Upper Limb: Classification, Genetics, and Pathogenesis.Plastic and reconstructive surgery. Global open · 2021Article
- Genetic syndromes with vascular malformations - update on molecular background and diagnostics.Archives of medical science : AMS · 2021Article
- The Relationship Between UBE2C and AGGF1 Overexpression and Tumor Angiogenesis in Non-Small Cell Lung Cancer.Cancer management and research · 2021Article
- CircRNA-Mediated Regulation of Angiogenesis: A New Chapter in Cancer Biology.Frontiers in oncology · 2021Review
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Authors and funding
13 authors at 2 institutions in 2 countries.
Funding
Abstract
Aggf1 is the first gene identified for Klippel-Trenaunay syndrome (KTS), and encodes an angiogenic factor. However, the in vivo roles of Aggf1 are incompletely defined. Here we demonstrate that Aggf1 is essential for both physiological angiogenesis and pathological tumour angiogenesis in vivo. Two lines of Aggf1 knockout (KO) mice showed a particularly severe phenotype as no homozygous embryos were observed and heterozygous mice also showed embryonic lethality (haploinsufficient lethality) observed only for Vegfa and Dll4. Aggf1+/- KO caused defective angiogenesis in yolk sacs and embryos. Survived adult heterozygous mice exhibit frequent haemorrhages and increased vascular permeability due to increased phosphorylation and reduced membrane localization of VE-cadherin. AGGF1 inhibits VE-cadherin phosphorylation, increases plasma membrane VE-cadherin in ECs and in mice, blocks vascular permeability induced by ischaemia-reperfusion (IR), restores depressed cardiac function and contraction, reduces infarct sizes, cardiac fibrosis and necrosis, haemorrhages, edema, and macrophage density associated with IR. Mechanistically, AGGF1 promotes angiogenesis by activating catalytic p110α subunit and p85α regulatory subunit of PI3K, leading to activation of AKT, GSK3β and p70S6K. AKT activation is significantly reduced in heterozygous KO mice and isolated KO ECs, which can be rescued by exogenous AGGF1. ECs from KO mice show reduced capillary angiogenesis, which is rescued by AGGF1 and AKT. Tumour growth/angiogenesis is reduced in heterozygous mice, which was associated with reduced activation of p110α, p85α and AKT. Together with recent identification of somatic mutations in p110α (encoded by PIK3CA), our data establish a potential mechanistic link between AGGF1 and PIK3CA, the two genes identified for KTS.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.