Low Molecular Weight Hyaluronan Induces Lymphangiogenesis through LYVE-1-Mediated Signaling Pathways

Hyaluronan (HA), a large nonsulfated glycosaminogycan in the extracellular matrix, whose degraded fragments termed as low molecular weight hyaluronan (LMW-HA), has been reported as an important regulator of angiogenesis. However, little is known about the influence of LMW-HA on lymphangiogenesis. In this study, we try to explore the in vitro effects of LMW-HA on lymphangiogenesis and identify the underlying molecular mechanisms. Our results showed that LMW-HA stimulation significantly increased lymphatic endothelial cells (LECs) proliferation, migration and tube formation. Further experiments demonstrated that LMW-HA altered actin cytoskeleton rearrangement and increased the formation of intense stress fibers, lamellipodia and filopodia. Mechanistically, LMW-HA stimulation resulted in rapid tyrosine phosphorylation of protein kinase C α/βII (PKCα/βII) and extracellular-regulated kinase 1/2 (ERK1/2). Lymphalic vessel endotheilial hyaluronan receptor 1 (LYVE-1), a homologue of CD44, is the main cell surface receptor for HA in LECs. Blocking the binding interaction of LMW-HA with LYVE-1 using neutralizing anti-LYVE-1 antibodies significantly inhibited LECs proliferation, migration, tube formation and signal transduction induced by LMW-HA, suggesting that LMW-HA may play a critical role in the processes required for lymphangiogenesis through interactions with its receptor LYVE-1 and triggering intracellular signal cascades.

• Publication year

  2014

• Venue

  PLoS ONE

• Publication date

  2014-03-25

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1371/journal.pone.0092857PMID 24667755PMCID 3965470
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• CRSBP‐1/LYVE‐1 ligands stimulate contraction of the CRSBP‐1‐associated ER network in lymphatic endothelial cells

  2012influential reference
• LYVE-1 enhances the adhesion of HS-578T cells to COS-7 cells via hyaluronan.

  2011cited by this paper
• Role of Receptor for Hyaluronic Acid-mediated Motility (RHAMM) in Low Molecular Weight Hyaluronan (LMWHA)-mediated Fibrosarcoma Cell Adhesion

  2011cited by this paper
• Lymphangiogenesis and cancer metastasis.

  2011cited by this paper
• Low molecular weight heparin inhibits melanoma cell adhesion and migration through a PKCa/JNK signaling pathway inducing actin cytoskeleton changes.

  2011cited by this paper
• CRSBP-1/LYVE-1 ligands disrupt lymphatic intercellular adhesion by inducing tyrosine phosphorylation and internalization of VE-cadherin

  2011cited by this paper
• Lymphangiogenesis and cancer metastasis

  2009cited by this paper
• A Mechanism of Sialylation Functionally Silences the Hyaluronan Receptor LYVE-1 in Lymphatic Endothelium*

  2009cited by this paper
• Abrogating drug resistance in malignant peripheral nerve sheath tumors by disrupting hyaluronan-CD44 interactions with small hyaluronan oligosaccharides.

  2009cited by this paper
• The sphingosine 1-phosphate receptor 1 causes tissue retention by inhibiting the entry of peripheral tissue T lymphocytes into afferent lymphatics

  2008cited by this paper
• Macrophages define the invasive microenvironment in breast cancer

  2008cited by this paper
• Hyaluronan-dependent pericellular matrix.

  2007cited by this paper
• Hyaluronan in tissue injury and repair.

  2007cited by this paper
• Hyaluronan fragments: an information-rich system.

  2006cited by this paper
• Preparation and characterization of hyaluronan oligosaccharides for angiogenesis study.

  2006cited by this paper
• Hyaluronan promotes tumor lymphangiogenesis and intralymphantic tumor growth in xenografts.

  2005cited by this paper
• Hyaluronan, angiogenesis and malignant disease

  2004cited by this paper
• LDL transcytosis by protein membrane diffusion.

  2004cited by this paper
• Lymphatic vasculature: development, molecular regulation and role in tumor metastasis and inflammation.

  2004cited by this paper
• The role of the CD44 transmembrane and cytoplasmic domains in co-ordinating adhesive and signalling events

  2003cited by this paper
• Hyaluronan-CD44s signaling regulates matrix metalloproteinase-2 secretion in a human lung carcinoma cell line QG90.

  2002cited by this paper
• Hyaluronan promotes the malignant phenotype.

  2002cited by this paper
• Angiogenic Oligosaccharides of Hyaluronan Induce Multiple Signaling Pathways Affecting Vascular Endothelial Cell Mitogenic and Wound Healing Responses*

  2002cited by this paper
• Inhibition of prostate tumor cell hyaluronan synthesis impairs subcutaneous growth and vascularization in immunocompromised mice.

  2002cited by this paper
• Hyaluronan-Cell Interactions in Cancer and Vascular Disease*

  2002cited by this paper
• Signaling Properties of Hyaluronan Receptors*

  2002cited by this paper
• Hyaluronan and Homeostasis: A Balancing Act*

  2002cited by this paper
• VEGF‐C induced lymphangiogenesis is associated with lymph node metastasis in orthotopic MCF‐7 tumors

  2002cited by this paper
• Hyaluronan and its catabolic products in tissue injury and repair.

  2002cited by this paper
• Abnormal accumulation of hyaluronan matrix diminishes contact inhibition of cell growth and promotes cell migration

  2002cited by this paper
• Structural characterization of the mouse Foxf1a gene.

  2001cited by this paper
• Vascular endothelial growth factor‐C‐mediated lymphangiogenesis promotes tumour metastasis

  2001cited by this paper
• Hyaluronan synthase 3 overexpression promotes the growth of TSU prostate cancer cells.

  2001cited by this paper
• Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis

  2001cited by this paper
• Stromal and Epithelial Expression of Tumor Markers Hyaluronic Acid and HYAL1 Hyaluronidase in Prostate Cancer*

  2001cited by this paper
• LYVE-1, the lymphatic system and tumor lymphangiogenesis.

  2001cited by this paper
• LYVE-1, a New Homologue of the CD44 Glycoprotein, Is a Lymph-specific Receptor for Hyaluronan

  1999cited by this paper
• Hyaluronan stimulates tumor cell migration by modulating the fibrin fiber architecture.

  1999cited by this paper
• Src can regulate carboxy terminal interactions with AFAP-110, which influence self-association, cell localization and actin filament integrity

  1998cited by this paper
• Angiogenic oligosaccharides of hyaluronan induce protein tyrosine kinase activity in endothelial cells and activate a cytoplasmic signal transduction pathway resulting in proliferation.

  1998influential reference
• Early‐response gene signalling is induced by angiogenic oligosaccharides of hyaluronan in endothelial cells. Inhibition by non‐angiogenic, high‐molecular‐weight hyaluronan

  1997cited by this paper
• Opposing Effects of ERK and JNK-p38 MAP Kinases on Apoptosis

  1995cited by this paper
• Hyaluronate receptors: key players in growth, differentiation, migration and tumor progression.

  1994cited by this paper
• Astrocyte and microglial motility in vitro is functionally dependent on the hyaluronan receptor RHAMM

  1994cited by this paper
• CD44 is the principal cell surface receptor for hyaluronate.

  1990cited by this paper
• A mouse lymphoid endothelial cell line immortalized by simian virus 40 binds lymphocytes and retains functional characteristics of normal endothelial cells.

  1990cited by this paper
• Sera of children with renal tumours contain low‐molecular‐mass hyaluronic acid

  1989influential reference
• The effect of hyaluronate and its oligosaccharides on endothelial cell proliferation and monolayer integrity.

  1989cited by this paper

• Dysregulated hyaluronan metabolism drives inflammation and angiogenesis in proliferative diabetic retinopathy.

  2026cites this paper
• Interaction-driven classification of hyaluronic acid products

  2025cites this paper
• Fatty acid metabolite promotes lymphatic identity in stem cell-derived endothelial cells

  2025cites this paper
• A novel approach for reliable differentiation of lymphatic endothelial progenitor cells in vitro

  2025cites this paper
• An overview of the multi-dimensional mechanisms of exercise-regulated hormones and growth factors in cardiac physiological adaptation

  2025cites this paper
• Limited Proteolysis as a Regulator of Lymphatic Vessel Function and Architecture

  2025cites this paper
• Innate and Adaptive Immune Responses to Clinical Hyaluronic Acid Fillers

  2025cites this paper
• CRISPR/Cas9-mediated Knockout of LYVE1 In Human Tongue Cancer Cells Reveals Transcriptomic Changes in Metastasis-associated Pathways

  2025cites this paper
• Design strategies for hyaluronic acid-based drug delivery systems in cancer immunotherapy.

  2025cites this paper
• Bioactivated scaffolds promote angiogenesis and lymphangiogenesis for dermal regeneration in vivo

  2025cites this paper
• Identification of Endocrine Disrupting Chemicals Targeting NTD-related Hub Genes During Pregnancy via In Silico Analysis.

  2025cites this paper
• Design of a composite wound dressing: Combining an electrospun fleece with a free-standing multilayer film

  2024cites this paper
• Complexed hyaluronic acid-based nanoparticles in cancer therapy and diagnosis: Research trends by natural language processing

  2024cites this paper
• IL-17A/CEBPβ/OPN/LYVE-1 axis inhibits anti-tumor immunity by promoting tumor-associated tissue-resident macrophages.

  2024cites this paper
• Methods for determining the structure and physicochemical properties of hyaluronic acid and its derivatives: A review.

  2024cites this paper
• Hyaluronan‐protein interactions: Lilliput revisited

  2024cites this paper
• Role of Hyaluronic acid and its chemical derivatives in immunity during homeostasis, cancer and tissue regeneration

  2024cites this paper
• Dual Targeted Nanoparticles Encapsulating Cantharidin for Treatment of Hepatocellular Carcinoma and Lymphatic Metastasis

  2024cites this paper
• Hyaluronic Acid Interacting Molecules Mediated Crosstalk between Cancer Cells and Microenvironment from Primary Tumour to Distant Metastasis

  2024cites this paper
• Role of lymphatic endothelium specific hyaluronan receptor 1 in virus infection and associated diseases

  2024cites this paper
• Gelatin-based hydrogel functionalized with taurine moieties for in vivo skin tissue regeneration

  2023cites this paper
• Arsenic Trioxide Decreases Lymphangiogenesis by Inducing Apoptotic Pathways and Inhibition of Important Endothelial Cell Receptors

  2023cites this paper
• CD6 triggers actomyosin cytoskeleton remodeling after binding to its receptor complex.

  2023cites this paper
• Synthetic hyaluronic acid coating preserves the phenotypes of lymphatic endothelial cells

  2023cites this paper
• Angiogenesis—An Emerging Role in Organ Fibrosis

  2023cites this paper
• Extracellular matrix molecules associated with lymphatic vessels in health and disease.

  2023cites this paper
• Hyaluronic acid: More than a carrier, having an overpowering extracellular and intracellular impact on cancer.

  2023cites this paper
• Breaking a Vicious Circle: Lymphangiogenesis as a New Therapeutic Target in Wound Healing

  2023influential citation
• Lymphangiogenesis Guidance Mechanisms and Therapeutic Implications in Pathological States of the Cornea

  2023cites this paper
• Adipose tissue-derived microvascular fragments promote lymphangiogenesis in a murine lymphedema model

  2022cites this paper
• The peripheral lymphatic system is impaired by the loss of neuronal control associated with chronic spinal cord injury.

  2022cites this paper
• Synthetic hydrogels engineered to promote collecting lymphatic vessel sprouting.

  2022cites this paper
• Methods for Isolating and Analyzing Physiological Hyaluronan: A Review.

  2022cites this paper
• Hyaluronan Receptors as Mediators and Modulators of the Tumor Microenvironment

  2022cites this paper
• Kuoxin Decoction promotes lymphangiogenesis in zebrafish and in vitro based on network analysis

  2022influential citation
• Tumour cells express functional lymphatic endothelium-specific hyaluronan receptor in vitro and in vivo: Lymphatic mimicry promotes oral oncogenesis?

  2021cites this paper
• Matrix stiffness primes lymphatic tube formation directed by vascular endothelial growth factor‐C

  2021cites this paper
• Use of photosynthetic transgenic cyanobacteria to promote lymphangiogenesis in scaffolds for dermal regeneration.

  2021cites this paper
• Effects of TNFα receptor TNF-Rp55- or TNF-Rp75- deficiency on corneal neovascularization and lymphangiogenesis in the mouse

  2021cites this paper
• Hyaluronic Acid Carrier-Based Photodynamic Therapy for Head and Neck Squamous Cell Carcinoma.

  2021cites this paper
• Natural Presentation of Glycosaminoglycans in Synthetic Matrices for 3D Angiogenesis Models

  2021cites this paper
• Collagen- and hyaluronic acid-based hydrogels and their biomedical applications.

  2021cites this paper
• Hyaluronan and Its Receptors: Key Mediators of Immune Cell Entry and Trafficking in the Lymphatic System

  2021cites this paper
• Lung Inflammatory Response to Environmental Dust Exposure in Mice Suggests a Link to Regional Respiratory Disease Risk

  2021cites this paper
• Stromal regulation of tufmor-associated lymphatics.

  2020cites this paper
• Intracellular hyaluronan: Importance for cellular functions.

  2020cites this paper
• Revisiting the hallmarks of cancer: the role of hyaluronan.

  2020cites this paper
• Lymphatic Type 1 Interferon Responses Are Critical for Control of Systemic Reovirus Dissemination

  2020cites this paper
• Role of Cardiac Lymphatics in Myocardial Edema and Fibrosis: JACC Review Topic of the Week.

  2020cites this paper
• Lymph nodes are innervated by a unique population of sensory neurons with immunomodulatory potential.

  2020cites this paper
• Caractérisation des mécanismes responsables des effets variables du récepteur des lipoprotéines de faible densité sur l’intégrité des cellules endothéliales lymphatiques

  2020cites this paper
• Arterial Lymphatics in Atherosclerosis: Old Questions, New Insights, and Remaining Challenges

  2019cites this paper
• Sensory Neurons Innervate Peripheral Lymph Nodes and Locally Regulate Gene Expression in Postsynaptic Endothelium, Stromal Cells, and Innate Leukocytes

  2019cites this paper
• Serum sLYVE-1 is not associated with coronary disease but with renal dysfunction: a retrospective study

  2019cites this paper
• Colorectal cancer‐associated ~ 6 kDa hyaluronan serves as a novel biomarker for cancer progression and metastasis

  2019cites this paper
• Hyaluronan Derived From the Limbus is a Key Regulator of Corneal Lymphangiogenesis

  2019cites this paper
• In vitro inflammatory and immune response to uncrosslinked hyaluronic acid (HA) and HA fillers

  2018cites this paper
• Heparan sulfate proteoglycan deficiency up‐regulates the intracellular production of nitric oxide in Chinese hamster ovary cell lines

  2018influential citation
• Co-treatment of tumor cells with hyaluronan plus doxorubicin affects endothelial cell behavior independently of VEGF expression

  2018cites this paper
• Roles of the TGF-β–VEGF-C Pathway in Fibrosis-Related Lymphangiogenesis

  2018influential citation
• In Situ Drug Delivery to Breast Cancer-Associated Extracellular Matrix.

  2018cites this paper
• Inhibition of tumor formation and metastasis by a monoclonal antibody against lymphatic vessel endothelial hyaluronan receptor 1

  2018cites this paper
• Dynamic Hyaluronan drives liver endothelial cells towards angiogenesis

  2018cites this paper
• Lymphatics-associated genes are downregulated at transcription level in non-small cell lung cancer.

  2018cites this paper
• Hyaluronan in the lymphatics: The key role of the hyaluronan receptor LYVE-1 in leucocyte trafficking.

  2018cites this paper
• Animal Models of Secondary Lymphedema: New Approaches in the Search for Therapeutic Options

  2017cites this paper
• The shedded ectodomain of Lyve-1 expressed on M2-like tumor-associated macrophages inhibits melanoma cell proliferation

  2017cites this paper
• Impact of immobilizing of low molecular weight hyaluronic acid within gelatin-based hydrogel through enzymatic reaction on behavior of enclosed endothelial cells.

  2017cites this paper
• Therapeutic effects of hyaluronidase on acquired lymphedema using a newly developed mouse limb model

  2017cites this paper
• TGFβ counteracts LYVE-1-mediated induction of lymphangiogenesis by small hyaluronan oligosaccharides

  2017cites this paper
• A LYVE-1/CRSBP-1 Mutation in Inherited Primary Lymphedema.

  2017cites this paper
• Correlation between lymphatic endothelial markers and lymph node status or N-staging of colorectal cancer

  2017cites this paper
• Recapitulating the Size and Cargo of Tumor Exosomes in a Tissue-Engineered Model

  2016cites this paper
• Binding of Hyaluronan to the Native Lymphatic Vessel Endothelial Receptor LYVE-1 Is Critically Dependent on Receptor Clustering and Hyaluronan Organization*

  2016cites this paper
• Pathway-related molecules of VEGFC/D-VEGFR3/NRP2 axis in tumor lymphangiogenesis and lymphatic metastasis.

  2016cites this paper
• Lymphatic vascular endothelial hyaluronan receptor-1 immunoexpression in placenta of HIV infected pre-eclamptic women.

  2016cites this paper
• Hyaluronic acid in digestive cancers

  2016cites this paper
• The expression profile of angiogenic genes in critical limb ischemia popliteal arteries.

  2016cites this paper
• Downregulation of long non-coding RNA ANRIL suppresses lymphangiogenesis and lymphatic metastasis in colorectal cancer

  2016cites this paper
• The role of lymphangiogenesis and angiogenesis in tumor metastasis

  2016cites this paper
• Thymocytes in Lyve1-CRE/S1pr1f/f Mice Accumulate in the Thymus due to Cell-Intrinsic Loss of Sphingosine-1-Phosphate Receptor Expression

  2016cites this paper
• MT1-MMP sheds LYVE-1 on lymphatic endothelial cells and suppresses VEGF-C production to inhibit lymphangiogenesis

  2016cites this paper
• TGF-β1 Is Present at High Levels in Wound Fluid from Breast Cancer Patients Immediately Post-Surgery, and Is Not Increased by Intraoperative Radiation Therapy (IORT)

  2016cites this paper
• Matricryptins Network with Matricellular Receptors at the Surface of Endothelial and Tumor Cells

  2016cites this paper
• Controlled Immobilization Strategies to Probe Short Hyaluronan-Protein Interactions

  2016cites this paper
• Hyaluronan fragments as mediators of inflammation in allergic pulmonary disease.

  2015cites this paper
• A novel role of low molecular weight hyaluronan in breast cancer metastasis

  2015cites this paper
• The cooperative role of S1P3 with LYVE-1 in LMW-HA-induced lymphangiogenesis.

  2015cites this paper
• Glycosaminoglycans and Glycomimetics in the Central Nervous System

  2015cites this paper
• Hyaluronan-induced VEGF-C promotes fibrosis-induced lymphangiogenesis via Toll-like receptor 4-dependent signal pathway.

  2015cites this paper
• Hyaluronan synthase 3 (HAS3) overexpression downregulates MV3 melanoma cell proliferation, migration and adhesion.

  2015cites this paper
• Identification et vectorisation de combinaisons de traitements pour la thérapie des tumeurs pulmonaires résistantes aux inhibiteurs de tyrosine kinase de l'EGFR

  2015cites this paper
• Lymphatic Vascular Regeneration: The Next Step in Tissue Engineering

  2015cites this paper
• Lymphangiogenesis and Lesion Heterogeneity in Interstitial Lung Diseases

  2015cites this paper
• Update June 2014

  2014cites this paper
• Flow cytometry-based isolation of dermal lymphatic endothelial cells from newborn rats.

  2014cites this paper
• Hyaluroan-regulated lymphatic permeability through S1P receptors is crucial for cancer metastasis

  2014cites this paper
• Metabolically Driven Differentiation of Human 1 Pluripotent Stem Cells to Generate Robust and 2 Functional Lymphatic Endothelial Cells

  year unknowncites this paper