Affinage

VEGFC

Vascular endothelial growth factor C · UniProt P49767

Length
419 aa
Mass
46.9 kDa
Annotated
2026-04-28
100 papers in source corpus 30 papers cited in narrative 30 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

VEGF-C is a secreted lymphangiogenic and angiogenic growth factor that undergoes obligate stepwise proteolytic processing — by proprotein convertases (furin, PC5, PC7) and serine proteases (thrombin, plasmin) — to generate mature forms with progressively higher affinity for VEGFR-3 (Kd ~135 pM) and, for the fully processed form, VEGFR-2 (Kd ~410 pM); processing also exposes a cryptic neuropilin-2-binding motif whose structural basis has been defined by crystallography (PMID:9233800, PMID:12782675, PMID:31562136, PMID:25752543). Mature VEGF-C additionally engages integrin α9β1 and heparan sulfate as co-receptors that facilitate VEGFR-3 signaling, and signals through PI3K/AKT and Src pathways to drive lymphangiogenesis, blood vascular angiogenesis, intestinal lacteal maintenance and dietary lipid absorption, fetal erythropoiesis, osteoclast-mediated bone resorption, podocyte survival, and CD8+ T cell proliferation (PMID:15590642, PMID:21343305, PMID:26459520, PMID:27343251, PMID:18359770, PMID:16525158, PMID:34194927). VEGF-C transcription is driven by NF-κB, SIX1, LEDGF/p75, FOXO-1, Hes1, and YAP/TAZ, while under hypoxia its translation switches to an IRES-dependent mechanism, and post-transcriptionally the OTUD3/ZFP36 axis targets VEGF-C mRNA for degradation (PMID:18359770, PMID:22466647, PMID:19934313, PMID:24388748, PMID:34853315, PMID:32796823). Meningeal lymphatic growth induced by VEGF-C enhances cerebrospinal fluid drainage and confers neuroprotection against ischemic stroke in mice (PMID:38442272).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 1997 High

    Establishing that VEGF-C bioactivity requires stepwise proteolytic maturation resolved how a single precursor generates forms with differential receptor selectivity — only the fully processed mature form activates VEGFR-2, while intermediates activate VEGFR-3 alone.

    Evidence Recombinant VEGF-C processing in yeast, receptor-binding/phosphorylation assays, endothelial proliferation/migration/permeability assays

    PMID:9233800

    Open questions at the time
    • Identity of the endogenous processing proteases was unknown
    • Structural basis for receptor selectivity of different processed forms unresolved
    • In vivo significance of differential receptor activation not tested
  2. 2003 High

    Identification of furin, PC5, and PC7 as the proprotein convertases that cleave proVEGF-C at the HSIIRR motif — and demonstration that mutating this site abolishes in vivo angiogenesis and lymphangiogenesis — established that PC-mediated processing is the gateway to VEGF-C bioactivity.

    Evidence Enzymatic cleavage assays in furin-deficient cells, site-directed mutagenesis, tumor implantation in nude mice

    PMID:12782675

    Open questions at the time
    • Whether additional proteases contribute to VEGF-C activation in vivo remained open
    • Tissue-specific regulation of PC access to proVEGF-C unknown
  3. 2000 High

    Demonstrating that VEGF-C signals through both VEGFR-3 and VEGFR-2 during embryonic vasculogenesis and hematopoiesis, with VEGFR-3 acting as a sink to regulate VEGF-C availability for VEGFR-2, established the dual-receptor signaling logic governing VEGF-C function in development.

    Evidence VEGFR-3-deficient embryo cultures, soluble VEGFR-3-Fc rescue, hematopoietic colony assays

    PMID:11090062

    Open questions at the time
    • Downstream intracellular pathways distinguishing VEGFR-2 vs VEGFR-3 signaling in hematopoiesis unresolved
    • Relative contribution of each receptor in different tissues unknown
  4. 2004 High

    Discovery of integrin α9β1 as a direct VEGF-C receptor that signals independently of VEGFR-2/VEGFR-3 expanded the receptor repertoire beyond tyrosine kinases and explained VEGF-C effects in VEGFR-negative cells.

    Evidence Solid-phase binding with purified integrin, adhesion/migration assays with α9β1-transfected cells, ERK/paxillin signaling in VEGFR-lacking cells

    PMID:15590642

    Open questions at the time
    • Physiological context where α9β1 is the dominant VEGF-C receptor not defined
    • Structural basis for VEGF-C/α9β1 interaction unknown
  5. 2006 High

    Identification of neuropilin-2 as a VEGF-C co-receptor that co-internalizes with VEGFR-3 upon ligand stimulation established NRP2 as a component of the active lymphangiogenic signaling complex, and demonstration of VEGF-C's autocrine survival role in podocytes broadened its functions beyond vascular contexts.

    Evidence Binding assays, co-IP, co-internalization imaging for NRP2/VEGFR-3; siRNA, kinase inhibitors, and apoptosis assays in podocytes

    PMID:16525158 PMID:16816121

    Open questions at the time
    • Structural mechanism of NRP2/VEGF-C interaction not yet resolved
    • Whether NRP2 modulates VEGFR-3 signaling quantitatively or qualitatively unknown
  6. 2008 High

    Showing that RANKL induces VEGF-C expression via NF-κB in osteoclasts, which then signals autocrinally through VEGFR-3/Src to enhance bone resorption, established the first non-vascular autocrine loop for VEGF-C and linked it to skeletal homeostasis.

    Evidence NF-κBp50/p52 double-knockout osteoclasts, VEGFR3:Fc blocking, Src-knockout osteoclasts, pit resorption assays

    PMID:18359770

    Open questions at the time
    • Whether VEGF-C/VEGFR-3 signaling in osteoclasts is relevant in non-pathological bone remodeling unclear
    • Downstream effectors beyond Src not mapped
  7. 2009 Medium

    Dissection of transcriptional regulators — LEDGF/p75 binding the VEGF-C promoter downstream of gonadotropins, and FOXO-1 mediating androgen withdrawal-induced VEGF-C — revealed context-dependent transcriptional control linking hormonal cues to lymphangiogenic output.

    Evidence ChIP for LEDGF/p75 at VEGF-C promoter, siRNA, GnRH antagonist; RalA activation assays, FOXO-1 knockdown in prostate cancer cells

    PMID:16964283 PMID:19934313

    Open questions at the time
    • Whether LEDGF/p75 and FOXO-1 cooperate or operate in distinct cellular contexts not tested
    • Full promoter architecture and enhancer landscape of VEGF-C uncharacterized
  8. 2011 High

    Demonstrating that heparan sulfate on lymphatic endothelial cells is required for VEGF-C binding to VEGFR-3 and for downstream ERK1/2 activation added a glycosaminoglycan co-receptor requirement to the VEGF-C signaling model.

    Evidence Heparinase treatment, Ndst1 siRNA knockdown, VEGFR-3 phosphorylation assays, sprouting assays in collagen matrices

    PMID:21343305

    Open questions at the time
    • Specific heparan sulfate modifications (sulfation patterns) that mediate VEGF-C interaction unknown
    • Whether heparan sulfate requirement is shared across all VEGF-C target cell types not tested
  9. 2012 Medium

    SIX1 was identified as a direct transcriptional activator of VEGF-C that drives tumor lymphangiogenesis and lymphatic metastasis, providing a molecular link between a developmental transcription factor and tumor-associated lymphatic remodeling.

    Evidence SIX1 overexpression/knockdown in breast cancer cells, VEGF-C rescue, xenograft lymphangiogenesis quantification

    PMID:22466647

    Open questions at the time
    • Whether SIX1 binds the VEGF-C promoter directly (ChIP) was not shown in this study
    • Relevance to non-neoplastic lymphangiogenesis not established
  10. 2014 High

    Discovery that hypoxia switches VEGF-C translation from cap-dependent to IRES-dependent (independent of HIF-1α) explained how VEGF-C protein production is sustained in severely hypoxic microenvironments such as tumor-draining lymph nodes.

    Evidence IRES reporter assays, 4E-BP1 phosphorylation analysis, HIF-1α knockdown, comparison of VEGF-C in primary tumors vs lymph node metastases

    PMID:24388748

    Open questions at the time
    • IRES trans-acting factors that mediate VEGF-C IRES activity unidentified
    • Whether IRES-dependent translation is relevant in non-tumor hypoxia not tested
  11. 2015 High

    The crystal structure of the VEGF-C C-terminus bound to the NRP2-b1 domain revealed that proteolytic maturation exposes a cryptic NRP2-binding motif, providing the structural basis for how processing controls co-receptor engagement and offering a template for soluble NRP2-based inhibitors.

    Evidence X-ray crystallography, binding assays, cell-based signaling assays with soluble s9Nrp2 inhibitor

    PMID:25752543

    Open questions at the time
    • Full ternary complex of VEGF-C/NRP2/VEGFR-3 not structurally resolved
    • Whether the s9Nrp2 decoy has therapeutic utility in vivo not established
  12. 2015 High

    Conditional Vegfc deletion in adult mice causing lacteal atrophy and defective lipid absorption proved that VEGF-C is continuously required for intestinal lymphatic maintenance, not only developmental lymphangiogenesis.

    Evidence Conditional Vegfc knockout in adult mice, histology, fecal fat measurements, high-fat diet challenge

    PMID:26459520

    Open questions at the time
    • The specific VEGFR (VEGFR-2 vs VEGFR-3) mediating lacteal maintenance not genetically dissected
    • Whether VEGF-C from smooth muscle cells is the sole source or other cells contribute not excluded
  13. 2016 High

    Demonstrating that embryonic Vegfc deletion blocks the transition from primitive to definitive erythropoiesis — via reduced α4-integrin on progenitors impairing fetal liver colonization — revealed an unexpected hematopoietic role for VEGF-C beyond vascular development.

    Evidence Conditional Vegfc deletion at E7.5, flow cytometry, colony assays, α4-integrin expression analysis

    PMID:27343251

    Open questions at the time
    • Whether VEGF-C regulates α4-integrin directly or indirectly unresolved
    • The receptor mediating this effect on erythro-myeloid progenitors not definitively identified
  14. 2019 High

    Identification of thrombin and plasmin as VEGF-C-activating proteases, and demonstration that platelets drive wound lymphangiogenesis via VEGF-C, established a molecular link between hemostasis and lymphatic repair.

    Evidence In vitro cleavage assays, platelet-specific genetic deletion, tail-wounding lymphangiogenesis quantification in mice

    PMID:31562136

    Open questions at the time
    • Relative contributions of thrombin vs plasmin vs furin/PCs in wound healing not quantified
    • Whether platelet-derived VEGF-C is pre-stored or de novo synthesized not resolved
  15. 2019 Medium

    ChIP-seq identification of Hes1 as a direct transcriptional activator of VEGF-C, coupled with the finding that VEGF-C attenuates TLR signaling by suppressing WDFY1, revealed an immunomodulatory arm of VEGF-C function.

    Evidence Genome-wide Hes1 ChIP-seq, Hes1 knockout mice, WDFY1 signaling analysis, viral infection and lupus nephritis models

    PMID:31015298

    Open questions at the time
    • Mechanism by which VEGF-C inhibits WDFY1 not fully elucidated
    • Whether this pathway operates in non-immune cell types unknown
  16. 2020 High

    Multiple 2020 studies converged on tissue-specific regulatory axes: YAP/TAZ in intestinal stromal cells drives VEGF-C for lacteal maintenance; S1PR1 in lymphatic endothelium antagonizes VEGF-C/VEGFR-3 to enforce vascular quiescence; and EV-mediated VEGF-C transport and COUP-TFII-dependent repression operate in endometriosis — collectively revealing that VEGF-C bioavailability is tuned by mechanosensitive, inflammatory, and vesicular mechanisms.

    Evidence Conditional YAP/TAZ models with scRNA-seq; conditional S1pr1 knockout with Vegfr3 genetic rescue; EV isolation and COUP-TFII knockdown in endometriosis models

    PMID:32544090 PMID:32796823 PMID:33004630

    Open questions at the time
    • Whether YAP/TAZ regulation of VEGF-C extends to other organs not tested
    • Mechanotransduction pathway connecting shear stress to S1PR1-mediated VEGFR-3 suppression incompletely defined
    • COUP-TFII regulation confirmed in one disease context only
  17. 2021 High

    Discovery of the OTUD3/ZFP36 axis — where OTUD3 stabilizes ZFP36 to promote VEGF-C mRNA decay — established the first post-transcriptional regulatory circuit controlling VEGF-C abundance, and its disruption by nicotine explained increased lymphatic metastasis.

    Evidence Co-IP, ubiquitination assays, RNA immunoprecipitation, RNA pulldown, mRNA stability assays, in vivo metastasis models

    PMID:34853315

    Open questions at the time
    • Whether other ARE-binding proteins besides ZFP36 target VEGF-C mRNA not examined
    • Generalizability beyond nicotine-exposed tumor context unknown
  18. 2021 Medium

    Demonstration that VEGF-C promotes CD8+ T cell proliferation via VEGFR-3/PI3K/AKT/Cyclin D1 expanded VEGF-C biology into adaptive immunity, showing it is not exclusively a vascular growth factor.

    Evidence MSC-CD8+ T cell co-culture, conditional VEGFR3 knockout in T cells, PI3K/AKT signaling, GvHD model

    PMID:34194927

    Open questions at the time
    • Whether VEGF-C/VEGFR-3 signaling on T cells operates during normal immune responses not established
    • Interaction with other T cell co-stimulatory pathways not addressed
  19. 2024 Medium

    AAV-mediated VEGF-C overexpression in the CNS promoted meningeal lymphatic growth and enhanced CSF drainage, reducing ischemic stroke injury — an effect abolished by lymphatic cauterization — establishing VEGF-C-driven meningeal lymphangiogenesis as neuroprotective.

    Evidence AAV-mVEGF-C intracerebrospinal delivery, lymphatic cauterization, snRNA-seq, CSF drainage assays, stroke model with MRI and behavioral outcomes

    PMID:38442272

    Open questions at the time
    • Whether endogenous meningeal VEGF-C plays a role in stroke outcome unknown
    • Neuroprotective pathways downstream of enhanced drainage not mechanistically defined
    • Translational relevance to human stroke not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major open questions include: the full ternary structure of VEGF-C/NRP2/VEGFR-3, how tissue-specific protease availability quantitatively tunes the VEGF-C activity gradient in vivo, the complete enhancer/promoter logic integrating the many identified transcription factors, and whether the immunomodulatory and hematopoietic functions of VEGF-C are clinically targetable independently of its lymphangiogenic role.
  • No ternary receptor complex structure available
  • Quantitative in vivo protease contribution mapping lacking
  • Integration of multiple transcriptional inputs at the VEGF-C locus not modeled

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 8 GO:0008289 lipid binding 1
Localization
GO:0005576 extracellular region 4 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-162582 Signal Transduction 10 R-HSA-392499 Metabolism of proteins 3 R-HSA-1266738 Developmental Biology 2 R-HSA-168256 Immune System 2 R-HSA-109582 Hemostasis 1
Partners
FLT4FURINITGA9KDRNRP2ZFP36

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 Stepwise proteolytic processing of the VEGF-C precursor generates several forms with progressively increased activity toward VEGFR-3; only the fully processed (mature) form can activate VEGFR-2. Mature VEGF-C binds VEGFR-3 (Kd=135 pM) and VEGFR-2 (Kd=410 pM), increases vascular permeability, and promotes endothelial cell migration and proliferation. Unlike other PDGF/VEGF family members, mature VEGF-C forms predominantly non-covalent homodimers. Recombinant protein production in yeast, receptor-binding assays, receptor phosphorylation assays, endothelial cell proliferation/migration assays, vascular permeability assay The EMBO journal High 9233800
2003 The proprotein convertases furin, PC5, and PC7 cleave proVEGF-C at the dibasic motif HSIIRR↓SL to generate mature VEGF-C. Mutation of this cleavage site (HSIIRR→HSIISS) blocks processing and abolishes VEGF-C-induced angiogenesis, lymphangiogenesis, and tumor growth in vivo, demonstrating that proteolytic processing by PCs is required for VEGF-C bioactivity. Cotransfection in furin-deficient LoVo cells, in vitro fluorogenic peptide cleavage assay, site-directed mutagenesis of cleavage site, subcutaneous tumor implantation in nude mice The Journal of clinical investigation High 12782675
2006 VEGF-C and VEGF-D directly bind neuropilin-2 (NP2) in a heparin-independent manner (VEGF-C) or heparin-dependent manner (VEGF-D). Upon VEGF-C or VEGF-D stimulation, NP2 co-internalizes with VEGFR-3 into endocytic vesicles of lymphatic endothelial cells, and NP2 co-precipitates with VEGFR-3, indicating NP2 participates in an active signaling complex with VEGFR-3. In vitro binding studies, domain-mapping experiments, co-internalization imaging, co-immunoprecipitation FASEB journal High 16816121
2004 VEGF-C (and VEGF-D) are direct ligands for the integrin α9β1. Cells expressing α9β1 adhere to and migrate on VEGF-C in a concentration-dependent, antibody-blockable manner; recombinant VEGF-C binds purified α9β1 integrin in a dose- and cation-dependent solid-phase assay; in cells lacking cognate VEGF receptors, VEGF-C induces α9β1-dependent ERK and paxillin phosphorylation. Cell adhesion and migration assays with α9β1-transfected cells, function-blocking antibody, solid-phase binding with purified integrin, signaling assays The Journal of biological chemistry High 15590642
2015 Crystal structure of the VEGF-C C-terminus in complex with the ligand-binding domains (b1) of neuropilin-2 reveals that a cryptic Nrp2-binding motif is exposed only upon C-terminal proteolytic maturation of VEGF-C. The endogenous secreted splice form s9Nrp2 forms a stable dimer that potently inhibits VEGF-C/Nrp2 binding and downstream cellular signaling. X-ray crystallography, biochemical binding assays, cell-based signaling assays Structure High 25752543
2000 VEGF-C signals through both VEGFR-2 and VEGFR-3 during vasculogenesis and hematopoiesis. In VEGFR-3-deficient embryos, excess VEGF-C signals through VEGFR-2 and disturbs vasculogenesis and hematopoiesis; trapping VEGF-C with VEGFR-3-Fc in these embryos rescues vascular bed formation and partially rescues hematopoiesis, indicating that VEGFR-3 binding regulates the available pool of VEGF-C for VEGFR-2 signaling. Para-aortic splanchnopleural mesoderm coculture with stromal cells, soluble receptor competitor proteins, VEGFR-3 knockout embryos, rescue experiments Blood High 11090062
2008 RANKL stimulates osteoclasts and their precursors to express and secrete VEGF-C through an NF-κB-dependent mechanism (reduced in NF-κBp50/p52 double-knockout cells or with NF-κB inhibitor). VEGF-C then acts as an autocrine factor via VEGFR-3 on osteoclasts: it stimulates Src phosphorylation and enhances bone resorption, an effect blocked by VEGFR3:Fc or in Src-knockout osteoclasts. Real-time RT-PCR, Western blot, immunostaining, osteoclastogenesis and pit resorption assays, NF-κB inhibition, knockout osteoclasts, receptor-blocking fusion protein The Journal of biological chemistry High 18359770
2015 VEGF-C is required for maintenance of intestinal lymphatic vessels (lacteals) in adult mice; conditional Vegfc deletion leads to lacteal atrophy, defective dietary lipid absorption, and increased fecal excretion of cholesterol and fatty acids. VEGF-C is expressed by a subset of smooth muscle cells adjacent to the lacteals. Deletion also causes resistance to high-fat diet-induced obesity. Conditional Vegfc gene deletion in adult mice, histology, lipid absorption assays, fecal fat measurement, high-fat diet challenge EMBO molecular medicine High 26459520
2016 VEGF-C plays a critical role in the transition from primitive to definitive (fetal liver) erythropoiesis. Vegfc deletion at E7.5 causes defective fetal erythropoiesis: anemia, lack of enucleated red blood cells, and reduced macrophage and erythroid cell numbers in fetal liver due to decreased proliferation and increased apoptosis. VEGF-C loss reduces α4-integrin expression on erythro-myeloid progenitors, impairing their colonization of the fetal liver. Conditional Vegfc gene deletion in mouse embryos, flow cytometry, colony assays, α4-integrin expression analysis Blood High 27343251
2019 VEGF-C (and VEGF-D) are cleaved and activated by thrombin and plasmin, serine proteases generated during hemostasis and wound healing. Platelets accelerate lymphatic growth after injury in vivo in a VEGF-C-dependent manner (but not VEGF-D-dependent), establishing a molecular link between hemostasis/platelet activation and lymphangiogenesis. In vitro cleavage assays with thrombin and plasmin, tail-wounding assay in mice, genetic studies with platelet-specific deletion, lymphangiogenesis quantification Blood High 31562136
2011 VEGF-C binds to heparan sulfate on lymphatic endothelial cells; heparin interference or heparinase treatment reduces VEGF-C-induced ERK1/2 and VEGFR-3 phosphorylation. Silencing of lymphatic Ndst1 (a heparan sulfate biosynthetic enzyme) inhibits VEGF-C-mediated ERK1/2 activation, abrogates cell-surface VEGFR-3-dependent VEGF-C binding, and reduces cell growth, migration, and collagen matrix sprouting in response to VEGF-C. Heparan sulfate binding assays, heparinase treatment, siRNA knockdown of Ndst1, phosphorylation assays, scratch migration assays, ex vivo sprouting in collagen matrix The Journal of biological chemistry High 21343305
2012 FGF-2 and VEGF-C collaboratively promote lymphangiogenesis; VEGFR-3-mediated signaling is required for lymphatic tip cell formation in both FGF-2- and VEGF-C-induced lymphangiogenesis. A VEGFR-3-specific neutralizing antibody markedly inhibits FGF-2-induced lymphangiogenesis, placing VEGFR-3 downstream of FGF-2/FGFR-1 for tip cell formation. Mouse cornea lymphangiogenesis assay, VEGFR-3-neutralizing antibody, in vivo coimplantation, tumor metastasis models Proceedings of the National Academy of Sciences of the United States of America Medium 22967508
2006 COX-2 promotes VEGF-C synthesis in breast cancer cells via prostaglandin E2 (PGE2) signaling through EP1 and EP4 receptors; EP1 and EP4 antagonists inhibit VEGF-C production. VEGF-C secretion also requires Her-2/neu, Src, and p38 MAPK kinase activities, as inhibitors of these kinases block VEGF-C secretion. COX-2 siRNA knockdown, COX inhibitors, EP receptor antagonists, kinase inhibitors, ELISA for VEGF-C secretion, LYVE-1 immunostaining in breast cancer tissues British journal of cancer Medium 16570043
2012 The transcription factor SIX1 directly induces transcription of VEGF-C; SIX1-induced VEGF-C is required for peritumoral and intratumoral lymphangiogenesis and lymphatic metastasis of breast cancer cells in immunocompromised mice. SIX1 overexpression and knockdown in human breast cancer cells, mouse xenograft models, lymphangiogenesis quantification, VEGF-C rescue experiments The Journal of clinical investigation Medium 22466647
2014 Hypoxia reduces VEGF-C transcription and cap-dependent translation via upregulation of hypophosphorylated 4E-BP1, but induces VEGF-C translation through an internal ribosome entry site (IRES)-dependent, HIF-1α-independent mechanism. IRES-dependent VEGF-C translation is higher in metastasizing tumor cells within lymph nodes (severely hypoxic) than in primary tumors. IRES reporter assays, 4E-BP1 phosphorylation analysis, HIF-1α knockdown, cap-dependent vs. IRES-dependent translation assays, in vivo tumor/lymph node comparison Cell reports High 24388748
2009 Androgens regulate VEGF-C expression: androgen deprivation in LNCaP prostate cancer cells activates the small GTPase RalA (via elevated reactive oxygen species), and RalA activation leads to VEGF-C upregulation. The FOXO-1 transcription factor (activated by SIRT-1 downstream of reduced IGF-IR signaling) also mediates VEGF-C transcriptional upregulation upon androgen withdrawal. RalA activation assays, ROS measurement, RalA dominant-negative/knockdown, FOXO-1 siRNA, VEGF-C mRNA/protein measurement Oncogene Medium 16964283
2021 Nicotine downregulates the deubiquitinase OTUD3, which normally stabilizes the mRNA-binding protein ZFP36 by inhibiting FBXW7-mediated K48-linked polyubiquitination. ZFP36 binds the VEGF-C 3'-UTR and recruits an RNA-degrading complex to induce VEGF-C mRNA decay; loss of OTUD3/ZFP36 leads to VEGF-C mRNA stabilization and increased VEGF-C production, promoting lymphatic metastasis. Co-immunoprecipitation, ubiquitination assays, RNA immunoprecipitation, RNA pulldown, mRNA stability assays, in vivo metastasis models Nature communications High 34853315
2020 VEGF-C is transported by extracellular vesicles (EVs) from endometriotic cells to lymphatic endothelial cells where it enhances lymphangiogenic capacity. The orphan nuclear receptor COUP-TFII negatively regulates VEGF-C expression; proinflammatory cytokines suppress COUP-TFII, thereby inducing VEGF-C overexpression. Extracellular vesicle isolation and functional assays, COUP-TFII knockdown, cytokine treatment, autotransplanted mouse model of endometriosis, lenvatinib treatment Proceedings of the National Academy of Sciences of the United States of America Medium 33004630
2020 PIK3CA(H1047R)-driven lymphatic malformations grow in a VEGF-C-dependent manner; combined inhibition of VEGF-C (blocking VEGF-C/VEGFR3 signaling) and mTOR (downstream of PI3K) with rapamycin promotes regression of microcystic lymphatic malformations, whereas neither treatment alone is sufficient. Mouse model of PIK3CA(H1047R)-driven lymphatic malformations, VEGF-C inhibition, rapamycin treatment, epistasis by combined pharmacological blockade Nature communications Medium 32513927
2020 In intestinal villi, YAP/TAZ activity in PDGFRβ+ interstitial stromal cells drives VEGF-C secretion to maintain lacteal integrity and dietary fat uptake. Mechanical or osmotic stress regulates YAP/TAZ-dependent VEGF-C secretion in these cells; single-cell RNA sequencing identified distinct fibroblast subtypes near lacteals that upregulate Vegfc upon YAP/TAZ activation. Conditional YAP/TAZ hyperactivation or depletion in PDGFRβ+ cells, single-cell RNA sequencing, VEGF-C ELISA, lacteal morphology and fat uptake assays, mechanical/osmotic stress experiments Nature communications High 32796823
2009 VEGF-C regulates capillary stabilization through paracrine induction of PDGF-B expression. In ischemic hindlimb, VEGFR-3 blockade not only diminishes lymphangiogenesis but also causes capillary dilation with mural cell dissociation; VEGF-C and PDGF-B expression are mutually dependent (blocking either reduces expression of the other), placing VEGF-C upstream of PDGF-B-mediated vessel stabilization. VEGFR-3 neutralizing antibody in ischemic hindlimb model, FGF-2 adenoviral gene transfer, real-time RT-PCR, histology, limb salvage/blood flow assessment American journal of physiology. Heart and circulatory physiology Medium 19734356
2006 VEGF-C promotes podocyte survival through an autocrine mechanism: ablation of VEGF-C or treatment with a VEGFR-2/-3 tyrosine kinase inhibitor reduces podocyte survival, and VEGF-C activates antiapoptotic PI3K/AKT and suppresses p38MAPK via VEGFR-2 (SU-5416 at VEGFR-1-specific concentration blocks VEGF-C survival effect, suggesting a VEGFR-1-containing complex may be involved). VEGF-C siRNA knockdown in human conditionally immortalized podocytes, cytotoxicity assays, kinase inhibitors (MAZ51, SU-5416), phosphorylation assays, intracellular calcium measurements, immunoprecipitation American journal of physiology. Renal physiology Medium 16525158
2018 VEGF-C activates autocrine VEGFR-2 signaling in glioblastoma cells to promote cell survival and tumor growth; VEGF-C/VEGFR-2 interaction was detected by proximity ligation assay in surgical specimens. Targeting VEGF-C (but not bevacizumab, which targets VEGF-A) impairs glioblastoma tumor growth in vivo. RNA interference, proximity ligation assay, immunohistochemistry, patient-derived xenograft lines in vitro and in vivo Neuro-oncology Medium 29939339
2020 VEGF-C secreted by EMT breast cancer cells activates non-canonical GLI signaling in neighboring epithelial breast cancer cells via NRP2 (a VEGF-C receptor), promoting their proliferation, migration, invasion, and metastasis. This paracrine VEGF-C/NRP2/GLI axis can be disrupted by VEGF-C inhibition in EMT cells or NRP2 knockdown in epithelial cells. VEGF-C knockdown, NRP2 knockdown, GLI signaling assays, in vivo metastasis models, conditioned medium experiments Oncogene Medium 33299122
2020 S1PR1 in lymphatic endothelial cells antagonizes laminar shear stress-induced VEGF-C/VEGFR3 signaling to promote lymphatic vascular quiescence. S1pr1 loss in LECs induces lymphatic hypersprouting and hyperbranching that can be rescued by reducing Vegfr3 gene dosage in vivo, placing S1PR1 as a negative regulator upstream of VEGF-C/VEGFR3-driven sprouting. Conditional S1pr1 knockout in LECs, Vegfr3 genetic rescue, laminar shear stress assays, signaling assays, in vivo vascular phenotyping JCI insight High 32544090
2009 Gonadotropins (LH, FSH) induce VEGF-C expression in ovarian cancer cells via LEDGF/p75, which binds a stress-response element in the VEGF-C promoter (confirmed by chromatin immunoprecipitation); FSH augments LEDGF/p75 binding to the VEGF-C promoter. LEDGF siRNA, GnRH antagonist, or mutation of the stress-response element suppresses gonadotropin-induced VEGF-C expression. Chromatin immunoprecipitation, LEDGF siRNA, GnRH antagonist (cetrorelix), promoter mutation, ovariectomy mouse model, VEGF-C mRNA and promoter activity assays Cancer research Medium 19934313
2021 VEGF-C, induced in mesenchymal stromal cells by steroids and TNFα, promotes CD8+ T cell proliferation via VEGFR-3 expressed on CD8+ T cells; VEGF-C augments PI3K/AKT signaling and downstream Cyclin D1 expression in CD8+ T cells. Blockade or genetic ablation of VEGFR3 in CD8+ T cells abolishes the VEGF-C-mediated immune-promoting effect. MSC-CD8+ T cell co-culture, VEGFR3 blockade antibody, conditional VEGFR3 knockout in T cells, PI3K/AKT signaling assays, in vivo GvHD model Advanced science Medium 34194927
2019 Hes1, a transcription factor, directly binds and positively activates VEGF-C gene expression (genome-wide Hes1 occupancy analysis); elevated VEGF-C produced downstream of Hes1 attenuates TLR upstream signaling by inhibiting the adaptor WDFY1, thereby suppressing type I IFN production. Genome-wide ChIP-seq for Hes1 occupancy, Hes1 knockout mice, VEGF-C expression analysis, WDFY1 signaling assays, viral infection and lupus nephritis models The Journal of experimental medicine Medium 31015298
2014 SIX1 cooperates with TGFβ/SMAD2/3 signaling to enhance VEGF-C expression in cervical cancer cells; SIX1 augments TGFβ-induced SMAD2/3 activation, and together they produce much higher VEGF-C than either alone. Increased VEGF-C from SIX1-expressing tumor cells promotes lymphatic endothelial cell migration and tube formation and counteracts TGFβ's direct inhibitory effects on LECs. SIX1 overexpression/knockdown, TGFβ treatment, SMAD2/3 phosphorylation assays, VEGF-C promoter/expression assays, LEC migration and tube formation assays, in vivo lymphangiogenesis Cancer research Medium 25142796
2024 Intracerebrospinal AAV-mediated VEGF-C overexpression enhances CSF drainage to deep cervical lymph nodes by promoting meningeal lymphatic vessel growth, upregulates neuroprotective signaling pathways, and reduces ischemic stroke injury in mice. Neuroprotective effects are lost upon cauterization of afferent lymphatics to the deep cervical lymph nodes, demonstrating that the effect is mediated through enhanced lymphatic drainage. AAV-mVEGF-C intracerebrospinal delivery, lymphatic cauterization, single-nucleus RNA sequencing, CSF drainage assays, ischemic stroke model (MRI, behavioral tests) The Journal of experimental medicine Medium 38442272

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1997 Proteolytic processing regulates receptor specificity and activity of VEGF-C. The EMBO journal 637 9233800
1999 VEGFR-3 and its ligand VEGF-C are associated with angiogenesis in breast cancer. The American journal of pathology 478 10329591
2012 VEGF-C promotes immune tolerance in B16 melanomas and cross-presentation of tumor antigen by lymph node lymphatics. Cell reports 288 22832193
2006 Functional interaction of VEGF-C and VEGF-D with neuropilin receptors. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 237 16816121
2003 VEGF-C gene therapy augments postnatal lymphangiogenesis and ameliorates secondary lymphedema. The Journal of clinical investigation 211 12618526
2002 Therapeutic lymphangiogenesis with human recombinant VEGF-C. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 200 12397087
2006 Secondary lymphedema in the mouse tail: Lymphatic hyperplasia, VEGF-C upregulation, and the protective role of MMP-9. Microvascular research 189 16876204
2012 Collaborative interplay between FGF-2 and VEGF-C promotes lymphangiogenesis and metastasis. Proceedings of the National Academy of Sciences of the United States of America 178 22967508
2001 VEGF-A, VEGF-C, and VEGF-D in colorectal cancer progression. Neoplasia (New York, N.Y.) 177 11687953
2003 The secretory proprotein convertases furin, PC5, and PC7 activate VEGF-C to induce tumorigenesis. The Journal of clinical investigation 175 12782675
2015 VEGF-C is required for intestinal lymphatic vessel maintenance and lipid absorption. EMBO molecular medicine 172 26459520
2001 Clinicopathological significance of vascular endothelial growth factor (VEGF)-C in human esophageal squamous cell carcinomas. International journal of cancer 166 11477575
2004 The lymphangiogenic vascular endothelial growth factors VEGF-C and -D are ligands for the integrin alpha9beta1. The Journal of biological chemistry 158 15590642
2006 COX-2-mediated stimulation of the lymphangiogenic factor VEGF-C in human breast cancer. British journal of cancer 141 16570043
1999 Current biology of VEGF-B and VEGF-C. Current opinion in biotechnology 133 10600689
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