ArticleThe Journal of clinical investigation2018
Epsin deficiency promotes lymphangiogenesis through regulation of VEGFR3 degradation in diabetes.
Article in The Journal of clinical investigation, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers.
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43 citing papers in PubMed, 61 citations in OpenAlex.
- Single-cell transcriptomic profiling reveals PDK4 upregulation and impaired VEGF-C/VEGFR3 signaling in cardiac lymphatic endothelial cells in diabetic cardiomyopathy.Molecular medicine (Cambridge, Mass.) · 2026Article
- Endocytic Adaptor Proteins in Vascular Diseases: Critical Role of Intracellular Trafficking in Regulating Pathobiology of Vascular Disorders.Cardiology discovery · 2026Review
- APOA1 binding protein promotes lymphatic cell fate and lymphangiogenesis by relieving caveolae-mediated inhibition of VEGFR3 signaling.Nature communications · 2025Article
- Endothelial FOXM1 and Dab2 promote diabetic wound healing.JCI insight · 2025Article
- Regulation of VEGFR3 signaling in lymphatic endothelial cells.Frontiers in cell and developmental biology · 2025Review
- Lymphatic vessel: origin, heterogeneity, biological functions, and therapeutic targets.Signal transduction and targeted therapy · 2024Review
- Epsin Endocytic Adaptor Proteins in Angiogenic and Lymphangiogenic Signaling.Cold Spring Harbor perspectives in medicine · 2024Review
- Targeting lymphatic function in cardiovascular-kidney-metabolic syndrome: preclinical methods to analyze lymphatic function and therapeutic opportunities.Frontiers in cardiovascular medicine · 2024Review
- A 3D biomimetic model of lymphatics reveals cell-cell junction tightening and lymphedema via a cytokine-induced ROCK2/JAM-A complex.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Targeting Synovial Lymphatic Function as a Novel Therapeutic Intervention for Age-Related Osteoarthritis in Mice.Arthritis & rheumatology (Hoboken, N.J.) · 2023Article
- Epsin1-mediated exosomal sorting of Dll4 modulates the tubular-macrophage crosstalk in diabetic nephropathy.Molecular therapy : the journal of the American Society of Gene Therapy · 2023Article
- Modeling lymphangiogenesis: Pairing in vitro and in vivo metrics.Microcirculation (New York, N.Y. : 1994) · 2023Review
- Promoting Lymphangiogenesis and Lymphatic Growth and Remodeling to Treat Cardiovascular and Metabolic Diseases.Arteriosclerosis, thrombosis, and vascular biology · 2023Review
- Hydrogen sulfide donor activates AKT-eNOS signaling and promotes lymphatic vessel formation.PloS one · 2023Article
- KAmerican journal of physiology. Cell physiology · 2022Review
- The role of lymphangiogenesis in cardiovascular diseases and heart transplantation.Heart failure reviews · 2022Review
- Lymphatic Vascular Permeability.Cold Spring Harbor perspectives in medicine · 2022Review
- Review
- Diabetes and Its Cardiovascular Complications: Comprehensive Network and Systematic Analyses.Frontiers in cardiovascular medicine · 2022Review
- Epsins Negatively Regulate Aortic Endothelial Cell Function by Augmenting Inflammatory Signaling.Cells · 2021Article
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26 authors at 7 institutions in 2 countries.
Funding
Abstract
Impaired lymphangiogenesis is a complication of chronic complex diseases, including diabetes. VEGF-C/VEGFR3 signaling promotes lymphangiogenesis, but how this pathway is affected in diabetes remains poorly understood. We previously demonstrated that loss of epsins 1 and 2 in lymphatic endothelial cells (LECs) prevented VEGF-C-induced VEGFR3 from endocytosis and degradation. Here, we report that diabetes attenuated VEGF-C-induced lymphangiogenesis in corneal micropocket and Matrigel plug assays in WT mice but not in mice with inducible lymphatic-specific deficiency of epsins 1 and 2 (LEC-iDKO). Consistently, LECs isolated from diabetic LEC-iDKO mice elevated in vitro proliferation, migration, and tube formation in response to VEGF-C over diabetic WT mice. Mechanistically, ROS produced in diabetes induced c-Src-dependent but VEGF-C-independent VEGFR3 phosphorylation, and upregulated epsins through the activation of transcription factor AP-1. Augmented epsins bound to and promoted degradation of newly synthesized VEGFR3 in the Golgi, resulting in reduced availability of VEGFR3 at the cell surface. Preclinically, the loss of lymphatic-specific epsins alleviated insufficient lymphangiogenesis and accelerated the resolution of tail edema in diabetic mice. Collectively, our studies indicate that inhibiting expression of epsins in diabetes protects VEGFR3 against degradation and ameliorates diabetes-triggered inhibition of lymphangiogenesis, thereby providing a novel potential therapeutic strategy to treat diabetic complications.
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