ArticleAngiogenesis2022
Unique functions for Notch4 in murine embryonic lymphangiogenesis.
Article in Angiogenesis, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 28 citations in OpenAlex.
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- Esaxerenone Attenuates Aldosterone-Induced Renal Fibrosis by Suppressing Fibroblast-to-Lymphatic Endothelial-like Cell Transdifferentiation.International journal of molecular sciences · 2026Article
- Lymphatic Endothelial Cells and Organ-Associated Lymphangiogenesis in Tumor Microenvironment.Cells · 2025Review
- Advances in sweat gland organoids: construction, molecular mechanisms, and challenges.Stem cell research & therapy · 2025Review
- Cancer Stem Cells in Melanoma: Drivers of Tumor Plasticity and Emerging Therapeutic Strategies.International journal of molecular sciences · 2025Review
- Regulation of VEGFR3 signaling in lymphatic endothelial cells.Frontiers in cell and developmental biology · 2025Review
- Identification of potential diagnostic markers and molecular mechanisms of asthma and ulcerative colitis based on bioinformatics and machine learning.Frontiers in molecular biosciences · 2025Article
- Global trends and emerging insights in BRAF and MEK inhibitor resistance in melanoma: a bibliometric analysis.Frontiers in molecular biosciences · 2025Article
- The role of potential oxidative biomarkers in the prognosis of intracerebral hemorrhage and the exploration antioxidants as possible preventive and treatment options.Frontiers in molecular biosciences · 2025Review
- Lymphatic System Development and Function.Current cardiology reports · 2024Review
- Lymphatic vessel: origin, heterogeneity, biological functions, and therapeutic targets.Signal transduction and targeted therapy · 2024Review
- Pathological angiogenesis: mechanisms and therapeutic strategies.Angiogenesis · 2023Review
- VEGFR3 is required for button junction formation in lymphatic vessels.Cell reports · 2023Article
- Research progress in the cardiac lymphatic system and myocardial repair after myocardial infarction.Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences · 2023Article
- Notch1 and Notch4 core binding domain peptibodies exhibit distinct ligand-binding and anti-angiogenic properties.Angiogenesis · 2023Article
- The Role of a Lung Vascular Endothelium Enriched Gene TMEM100.Biomedicines · 2023Review
- Lymphangiogenesis Guidance Mechanisms and Therapeutic Implications in Pathological States of the Cornea.Cells · 2023Review
- Notch4 participates in mesenchymal stem cell-induced differentiation in 3D-printed matrix and is implicated in eccrine sweat gland morphogenesis.Burns & trauma · 2023Article
- Inactivation ofCancer research communications · 2022Article
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Authors and funding
14 authors at 4 institutions in 3 countries.
Funding
Abstract
In mice, embryonic dermal lymphatic development is well understood and used to study gene functions in lymphangiogenesis. Notch signaling is an evolutionarily conserved pathway that modulates cell fate decisions, which has been shown to both inhibit and promote dermal lymphangiogenesis. Here, we demonstrate distinct roles for Notch4 signaling versus canonical Notch signaling in embryonic dermal lymphangiogenesis. Actively growing embryonic dermal lymphatics expressed NOTCH1, NOTCH4, and DLL4 which correlated with Notch activity. In lymphatic endothelial cells (LECs), DLL4 activation of Notch induced a subset of Notch effectors and lymphatic genes, which were distinctly regulated by Notch1 and Notch4 activation. Treatment of LECs with VEGF-A or VEGF-C upregulated Dll4 transcripts and differentially and temporally regulated the expression of Notch1 and Hes/Hey genes. Mice nullizygous for Notch4 had an increase in the closure of the lymphangiogenic fronts which correlated with reduced vessel caliber in the maturing lymphatic plexus at E14.5 and reduced branching at E16.5. Activation of Notch4 suppressed LEC migration in a wounding assay significantly more than Notch1, suggesting a dominant role for Notch4 in regulating LEC migration. Unlike Notch4 nulls, inhibition of canonical Notch signaling by expressing a dominant negative form of MAML1 (DNMAML) in Prox1+ LECs led to increased lymphatic density consistent with an increase in LEC proliferation, described for the loss of LEC Notch1. Moreover, loss of Notch4 did not affect LEC canonical Notch signaling. Thus, we propose that Notch4 signaling and canonical Notch signaling have distinct functions in the coordination of embryonic dermal lymphangiogenesis.
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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.