ArticleThe Journal of clinical investigation2021
Foxo1 deletion promotes the growth of new lymphatic valves.
Article in The Journal of clinical investigation, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
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Who cites it
37 citing papers in PubMed, 54 citations in OpenAlex.
- Lymphatic Malformations With Activating KRAS Mutations Impair Lymphatic Valve Development Through Matrix Metalloproteinases.Arteriosclerosis, thrombosis, and vascular biology · 2026Article
- Lysophosphatidic acid-mediated NF-κB activation promotes FOXC2 expression essential for lymphatic valve development.The Journal of clinical investigation · 2026Article
- The role of the cardiac lymphatic system in heart failure "reverse remodeling": from developmental signals to druggable targets.Frontiers in immunology · 2026Review
- Hierarchical Requirement for Endothelial Cell Connexins Cx37, Cx47, Cx43, and Cx45 in Lymphatic Valve Function.Function (Oxford, England) · 2025Article
- S1PR1 regulates lymphatic valve development and tertiary lymphoid organ formation in the ileum.The Journal of experimental medicine · 2025Article
- TIE1-dependent lymphatic vascular remodeling is mediated by its second tyrosine kinase domain.Development (Cambridge, England) · 2025Article
- IL-19 Is a Novel Lymphangiocrine Factor Inducing Lymphangiogenesis and Lymphatic Junctional Regulation.Arteriosclerosis, thrombosis, and vascular biology · 2025Article
- Meningeal lymphatic drainage: novel insights into central nervous system disease.Signal transduction and targeted therapy · 2025Review
- Emerging role of exosomes during the pathogenesis of viral hepatitis, non-alcoholic steatohepatitis and alcoholic hepatitis.Human cell · 2024Review
- EPHB4-RASA1 Inhibition of PIEZO1 Ras Activation Drives Lymphatic Valvulogenesis.Circulation research · 2024Article
- Connexin-45 is expressed in mouse lymphatic endothelium and required for lymphatic valve function.JCI insight · 2024Article
- The mechanosensory channel PIEZO1 functions upstream of angiopoietin/TIE/FOXO1 signaling in lymphatic development.The Journal of clinical investigation · 2024Article
- Multiple cis-regulatory elements control prox1a expression in distinct lymphatic vascular beds.Development (Cambridge, England) · 2024Article
- Central conducting lymphatic anomaly: from bench to bedside.The Journal of clinical investigation · 2024Review
- Profibrotic VEGFR3-Dependent Lymphatic Vessel Growth in Autoimmune Valvular Carditis.Arteriosclerosis, thrombosis, and vascular biology · 2024Article
- Role of Sensory Nerves in Pulmonary Fibrosis.International journal of molecular sciences · 2024Review
- Lymphatic System and the Kidney: From Lymphangiogenesis to Renal Inflammation and Fibrosis Development.International journal of molecular sciences · 2024Review
- Zmiz1 is a novel regulator of lymphatic endothelial cell gene expression and function.PloS one · 2024Article
- Developmental progression of lymphatic valve morphology and function.Frontiers in cell and developmental biology · 2024Article
- An EPHB4-RASA1 signaling complex inhibits shear stress-induced Ras-MAPK activation in lymphatic endothelial cells to promote the development of lymphatic vessel valves.bioRxiv : the preprint server for biology · 2023Article
Corrections and comments
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Authors and funding
6 authors at 3 institutions in 1 country.
Funding
Abstract
Patients with congenital lymphedema suffer from tissue swelling in part due to mutations in genes regulating lymphatic valve development. Lymphatic valve leaflets grow and are maintained throughout life in response to oscillatory shear stress (OSS), which regulates gene transcription in lymphatic endothelial cells (LECs). Here, we identified the first transcription factor, Foxo1, that repressed lymphatic valve formation by inhibiting the expression of valve-forming genes. We showed that both embryonic and postnatal ablation of Foxo1 in LECs induced additional valve formation in postnatal and adult mice in multiple tissues. Our quantitative analyses revealed that after deletion, the total number of valves in the mesentery was significantly (P < 0.01) increased in the Foxo1LEC-KO mice compared with Foxo1fl/fl controls. In addition, our quantitative real-time PCR (RT-PCR) data from cultured LECs showed that many valve-forming genes were significantly (P < 0.01) upregulated upon knockdown of FOXO1. To confirm our findings in vivo, rescue experiments showed that Foxc2+/- mice, a model of lymphedema-distichiasis, had 50% fewer lymphatic valves and that the remaining valves exhibited backleak. Both valve number and function were completely restored to control levels upon Foxo1 deletion. These findings established FOXO1 as a clinically relevant target to stimulate de novo lymphatic valve formation and rescue defective valves in congenital lymphedema.
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