ArticleCell communication and signaling : CCS2020
AKT/FOXO1 axis links cross-talking of endothelial cell and pericyte in TIE2-mutated venous malformations.
Article in Cell communication and signaling : CCS, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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12 citing papers in PubMed, 21 citations in OpenAlex.
- Review
- A high-sensitivity TIE2-GRB2 BRET platform for functional and pharmacologic profiling of pathogenic variants associated with venous malformations.Angiogenesis · 2026Article
- A human endothelial and adipose stem cell-based co-culture model for venous malformations.Angiogenesis · 2026Article
- Bleomycin ElectroScleroTherapy (BEST): mechanistic parallels to electrochemotherapy, experimental models, and unresolved questions.Radiology and oncology · 2026Review
- Venous Malformations: Unraveling Latest Mechanisms and Bridging Gaps in Targeted Therapy Development.International journal of biological sciences · 2025Review
- EndothelialInternational journal of medical sciences · 2025Article
- What the Interventional Radiologist Needs to Know about the Genetics of Vascular Anomalies.Seminars in interventional radiology · 2024Review
- Association Between theInternational journal of general medicine · 2024Article
- Role of UDP-glucose ceramide glucosyltransferase in venous malformation.Frontiers in cell and developmental biology · 2023Article
- A histological study of vascular wall resident stem cells in venous malformations.Cell and tissue research · 2022Article
- The Genetic Architecture of Vascular Anomalies: Current Data and Future Therapeutic Perspectives Correlated with Molecular Mechanisms.International journal of molecular sciences · 2022Review
- Article
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8 authors at 2 institutions in 1 country.
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Abstract
backgroundVenous malformations (VMs), most of which associated with activating mutations in the endothelial cells (ECs) tyrosine kinase receptor TIE2, are characterized by dilated and immature veins with scarce smooth muscle cells (SMCs) coverage. However, the underlying mechanism of interaction between ECs and SMCs responsible for VMs has not been fully understood.
methodsHere, we screened 5 patients with TIE2-L914F mutation who were diagnosed with VMs by SNP sequencing, and we compared the expression of platelet-derived growth factor beta (PDGFB) and α-SMA in TIE2 mutant veins and normal veins by immunohistochemistry. In vitro, we generated TIE2-L914F-expressing human umbilical vein endothelial cells (HUVECs) and performed BrdU, CCK-8, transwell and tube formation experiments on none-transfected and transfected ECs. Then we investigated the effects of rapamycin (RAPA) on cellular characteristics. Next we established a co-culture system and investigated the role of AKT/FOXO1/PDGFB in regulating cross-talking of mutant ECs and SMCs.
resultsVMs with TIE2-L914F mutation showed lower expression of PDGFB and α-SMA than normal veins. TIE2 mutant ECs revealed enhanced cell viability and motility, and decreased tube formation, whereas these phenotypes could be reversed by rapamycin. Mechanically, RAPA ameliorated the physiological function of mutant ECs by inhibiting AKT-mTOR pathway, but also facilitated the nuclear location of FOXO1 and the expression of PDGFB in mutant ECs, and then improved paracrine interactions between ECs and SMCs. Moreover, TIE2 mutant ECs strongly accelerated the transition of SMCs from contractile phenotype to synthetic phenotype, whereas RAPA could prevent the phenotype transition of SMCs.
conclusionsOur data demonstrate a previously unknown mechanistic linkage of AKT-mTOR/FOXO1 pathway between mutant ECs and SMCs in modulating venous dysmorphogenesis, and AKT/FOXO1 axis might be a potential therapeutic target for the recovery of TIE2-mutation causing VMs. Video Abstract.
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