ArticleTransplantation2015
Vascular endothelial growth factor c/vascular endothelial growth factor receptor 3 signaling regulates chemokine gradients and lymphocyte migration from tissues to lymphatics.
Article in Transplantation, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 25 citations in OpenAlex.
- Bidirectional crosstalk between obesity and the lymphatic system: a novel pathway in obesity pathogenesis and treatment.International journal of obesity (2005) · 2026Review
- Integrated transcriptomic analysis reveals lymphaticZoological research · 2026Article
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- Targeting lymphatic function in cardiovascular-kidney-metabolic syndrome: preclinical methods to analyze lymphatic function and therapeutic opportunities.Frontiers in cardiovascular medicine · 2024Review
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- Engineering approaches to investigate the roles of lymphatics vessels in rheumatoid arthritis.Microcirculation (New York, N.Y. : 1994) · 2023Review
- miR-31-5p-Modified RAW 264.7 Macrophages Affect Profibrotic Phenotype of Lymphatic Endothelial Cells In Vitro.International journal of molecular sciences · 2022Article
- Single-Cell RNA Sequencing Reveals Heterogeneity and Functional Diversity of Lymphatic Endothelial Cells.International journal of molecular sciences · 2021Review
- Review
- Lymphatic Proliferation Ameliorates Pulmonary Fibrosis after Lung Injury.The American journal of pathology · 2020Article
- Extracellular vesicle-associated VEGF-C promotes lymphangiogenesis and immune cells infiltration in endometriosis.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Induced dural lymphangiogenesis facilities soluble amyloid-beta clearance from brain in a transgenic mouse model of Alzheimer's disease.Neural regeneration research · 2018Article
- Targeting lymphatic function as a novel therapeutic intervention for rheumatoid arthritis.Nature reviews. Rheumatology · 2018Review
- A robust in vitro model for trans-lymphatic endothelial migration.Scientific reports · 2017Article
- Obesity but not high-fat diet impairs lymphatic function.International journal of obesity (2005) · 2016Article
- Dermal lymphatic dilation in a mouse model of alopecia areata.Experimental and molecular pathology · 2016Article
- Skewed Lung CCR4 to CCR6 CD4Frontiers in immunology · 2016Article
- Serum biomarkers VEGF-C and IL-6 are associated with severe human Peripheral Artery Stenosis.Journal of inflammation (London, England) · 2015Article
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
backgroundCirculation of leukocytes via blood, tissue and lymph is integral to adaptive immunity. Afferent lymphatics form CCL21 gradients to guide dendritic cells and T cells to lymphatics and then to draining lymph nodes (dLN). Vascular endothelial growth factor C and vascular endothelial growth factor receptor 3 (VEGFR-3) are the major lymphatic growth factor and receptor. We hypothesized these molecules also regulate chemokine gradients and lymphatic migration.
methodsCD4 T cells were injected into the foot pad or ear pinnae, and migration to afferent lymphatics and dLN quantified by flow cytometry or whole mount immunohistochemistry. Vascular endothelial growth factor receptor 3 or its signaling or downstream actions were modified with blocking monoclonal antibodies (mAbs) or other reagents.
resultsAnti-VEGFR-3 prevented migration of CD4 T cells into lymphatic lumen and significantly decreased the number that migrated to dLN. Anti-VEGFR-3 abolished CCL21 gradients around lymphatics, although CCL21 production was not inhibited. Heparan sulfate (HS), critical to establish CCL21 gradients, was down-regulated around lymphatics by anti-VEGFR-3 and this was dependent on heparanase-mediated degradation. Moreover, a Phosphoinositide 3-kinase (PI3K)α inhibitor disrupted HS and CCL21 gradients, whereas a PI3K activator prevented the effects of anti-VEGFR-3. During contact hypersensitivity, VEGFR-3, CCL21, and HS expression were all attenuated, and anti-heparanase or PI3K activator reversed these effects.
conclusionsVascular endothelial growth factor C/VEGFR-3 signaling through PI3Kα regulates the activity of heparanase, which modifies HS and CCL21 gradients around lymphatics. The functional and physical linkages of these molecules regulate lymphatic migration from tissues to dLN. These represent new therapeutic targets to influence immunity and inflammation.
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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.