Affinage

VEGFC

Vascular endothelial growth factor C · UniProt P49767

Length
419 aa
Mass
46.9 kDa
Annotated
2026-06-11
100 papers in source corpus 31 papers cited in narrative 31 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

VEGF-C is a secreted lymphangiogenic growth factor that drives the proliferation of lymphatic endothelial cells and the formation of new lymphatic vessels, an activity not shared by VEGF-A or PlGF (PMID:9245515). It is synthesized as an inactive precursor and activated by stepwise proteolytic processing: progressive cleavage releases the VEGF homology domain and generates forms with increasing potency, with partially processed material preferentially activating VEGFR-3 and only fully mature VEGF-C engaging VEGFR-2 (PMID:9233800, PMID:9012504). Plasmin, and during hemostasis also thrombin, performs this maturation by removing N- and C-terminal propeptides to enhance receptor binding and cross-linking (PMID:12963694, PMID:31562136). Proteolysis additionally exposes a cryptic C-terminal motif that binds the b1 domain of neuropilin-2 (NRP2), which co-internalizes with and co-precipitates with VEGFR-3 to form an active signaling complex on lymphatic endothelial cells (PMID:16816121, PMID:25752543). VEGF-C is stored in platelet alpha-granules and released upon platelet activation, coupling hemostasis to wound lymphangiogenesis (PMID:9684805, PMID:31562136). Beyond development, VEGF-C is required in adult tissues to maintain intestinal lacteals and dietary lipid absorption (PMID:26459520), to support fetal liver erythropoiesis (PMID:27343251), and to preserve the bone marrow perivascular niche and hematopoietic recovery (PMID:32842144); engineered VEGF-C delivery enhances meningeal lymphatic CSF drainage and is neuroprotective after stroke (PMID:38442272). VEGF-C transcription is controlled by C/EBP-δ acting with HIF-1α in lymphatic endothelium (PMID:21666710), by Smad3 and AKT downstream of TGF-β1 (PMID:31409309), and by Hes1 (PMID:31015298), while its mRNA is degraded through an OTUD3–ZFP36–3'-UTR decay axis (PMID:34853315). In disease, VEGF-C supports autocrine VEGFR-2-driven survival in glioblastoma (PMID:29939339) and acts through NRP2 to non-canonically activate GLI signaling in breast cancer paracrine metastasis (PMID:33299122).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 1996 High

    Establishing that a secreted factor preferentially activates the lymphatic-associated receptor VEGFR-3 and is expressed near sites of lymphatic sprouting set up VEGF-C as a candidate lymphatic morphogen.

    Evidence Recombinant protein receptor autophosphorylation assays plus in situ hybridization in mouse embryos

    PMID:9012504

    Open questions at the time
    • Did not establish whether VEGF-C is required for lymphatic development in vivo
    • Processing requirements for receptor selectivity not yet defined
  2. 1997 High

    Defining stepwise proteolytic processing as the switch governing receptor selectivity answered how a single ligand can engage VEGFR-3 versus VEGFR-2, and direct lymphangiogenesis assays established VEGF-C as the first lymphangiogenic growth factor.

    Evidence Recombinant protein binding/autophosphorylation kinetics and in vivo chorioallantoic membrane lymphangiogenesis assay with growth factor controls

    PMID:9233800 PMID:9245515

    Open questions at the time
    • Identity of the activating protease(s) not yet determined
    • Structural basis of receptor engagement not resolved
  3. 2003 High

    Identifying plasmin as a protease that cleaves both propeptides connected VEGF-C activation to a defined enzymatic event rather than an unknown maturation step.

    Evidence In vitro protease cleavage and receptor binding/cross-linking assays comparing full-length and processed VEGF-C

    PMID:12963694

    Open questions at the time
    • Did not address physiological context in which plasmin activation occurs
    • Other contributing proteases not excluded
  4. 2006 High

    Showing direct VEGF-C binding to neuropilin-2 and NRP2 co-internalization with VEGFR-3 placed NRP2 as a partner within an active lymphatic signaling complex rather than a passive co-receptor.

    Evidence In vitro binding, domain mapping, co-immunoprecipitation, and co-internalization imaging in lymphatic endothelial cells

    PMID:16816121

    Open questions at the time
    • Structural determinant of the VEGF-C/NRP2 interaction not resolved
    • Functional consequence of complex internalization for signaling output not quantified
  5. 2015 High

    A crystal structure of the VEGF-C C-terminus bound to NRP2 explained how proteolysis unmasks a cryptic NRP2-binding motif and how a secreted splice form can antagonize it.

    Evidence X-ray crystallography with in vitro binding and cellular signaling assays

    PMID:25752543

    Open questions at the time
    • In vivo role of the s9Nrp2 antagonist not established
    • Structure does not capture the full VEGFR-3/NRP2 ternary complex
  6. 2019 High

    Demonstrating that platelet-stored VEGF-C is activated by hemostatic proteases and is the dominant driver of wound lymphangiogenesis linked clotting directly to lymphatic regeneration.

    Evidence In vitro thrombin/plasmin cleavage assays plus platelet-specific Vegfc deletion in tail-wounding and full-thickness excision mouse models

    PMID:31562136 PMID:36766814 PMID:9684805

    Open questions at the time
    • Relative contributions of thrombin versus plasmin in vivo not quantified
    • Mechanism linking inflammation resolution to VEGF-C-driven lymphatics incomplete
  7. 2016 High

    Conditional and temporally controlled Vegfc deletion revealed non-lymphangiogenic adult and developmental roles—maintaining intestinal lacteals and enabling fetal liver erythropoiesis—broadening VEGF-C beyond a purely lymphatic factor.

    Evidence Conditional Vegfc knockout in adult and embryonic mice with cellular, lipid-absorption, and hematopoietic readouts

    PMID:26459520 PMID:27343251

    Open questions at the time
    • Receptor and cellular target mediating the erythropoietic effect not fully defined
    • Whether lacteal maintenance and erythropoiesis share a common mechanism unknown
  8. 2020 High

    Loss- and gain-of-function studies established VEGF-C as a maintenance factor for the bone marrow perivascular niche, with exogenous delivery accelerating hematopoietic recovery.

    Evidence Endothelial- and LepR+-specific Vegfc deletion plus AAV-VEGF-C rescue in an irradiation/transplant model

    PMID:32842144

    Open questions at the time
    • Direct receptor mediating niche maintenance not pinned down
    • Identity of induced hematopoietic regenerative factors only partially defined
  9. 2021 High

    Reconstitution of an OTUD3–ZFP36 axis acting on the VEGF-C 3'-UTR identified a post-transcriptional control layer governing VEGF-C abundance and lymphatic metastasis.

    Evidence Co-IP, ubiquitination and RNA decay assays, 3'-UTR binding assays, and an in vivo metastasis model

    PMID:21666710 PMID:31015298 PMID:31409309 PMID:34853315

    Open questions at the time
    • Generality of this decay axis across non-cancer tissues not established
    • Interplay between transcriptional and post-transcriptional control not integrated
  10. 2024 High

    AAV-driven VEGF-C overexpression coupled with lymphatic cauterization epistasis demonstrated that VEGF-C-enhanced meningeal lymphatic drainage is neuroprotective after stroke, extending its physiology to the CNS.

    Evidence Intra-CSF AAV-VEGF-C, single-nuclei RNA-seq, CSF drainage assays, and stroke model with afferent lymphatic cauterization

    PMID:38442272

    Open questions at the time
    • Endogenous VEGF-C requirement for meningeal lymphatics not tested by loss-of-function
    • Direct molecular link between drainage and BDNF/microglial changes incomplete

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the distinct VEGF-C receptor/co-receptor configurations (VEGFR-3, VEGFR-2, VEGFR-1, NRP2) are selected in different cell types to produce lymphangiogenic versus autocrine survival versus non-canonical GLI outputs remains unresolved.
  • Cell-context determinants of receptor choice not defined
  • Conflicting receptor usage in podocytes (VEGFR-1 vs VEGFR-2) unreconciled
  • Mechanism of NRP2-to-GLI signal transduction unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 4 GO:0060089 molecular transducer activity 3
Localization
GO:0005576 extracellular region 3 GO:0031410 cytoplasmic vesicle 2
Pathway
R-HSA-1266738 Developmental Biology 3 R-HSA-162582 Signal Transduction 3 R-HSA-1500931 Cell-Cell communication 2
Partners
F2FLT4KDRNRP2PLG
Complex memberships
VEGFR-3/NRP2 signaling complex

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 Stepwise proteolytic processing of the VEGF-C precursor generates forms with progressively increased activity toward VEGFR-3; only fully processed mature VEGF-C can activate VEGFR-2. Mature VEGF-C binds VEGFR-3 (Kd ~135 pM) and VEGFR-2 (Kd ~410 pM), activates both receptors, increases vascular permeability, and stimulates 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 autophosphorylation assays, vascular permeability assays, endothelial cell migration and proliferation assays, biochemical characterization of processing intermediates The EMBO journal High 9233800
1996 Mouse VEGF-C is secreted as VEGFR-3 (Flt4)-binding polypeptides of 30–32 kDa and 22–23 kDa that preferentially stimulate VEGFR-3 autophosphorylation over VEGFR-2. In situ hybridization shows VEGF-C mRNA in mesenchymal cells near regions where lymphatic vessels sprout from embryonic veins, consistent with a paracrine role in lymphatic vessel development. Recombinant protein production, receptor autophosphorylation assay (VEGFR-3 vs VEGFR-2), in situ hybridization in mouse embryos Development (Cambridge, England) High 9012504
1997 VEGF-C is the first identified lymphangiogenic growth factor; it induces proliferation of lymphatic endothelial cells and formation of new lymphatic sinuses in the avian chorioallantoic membrane (CAM). VEGF, by contrast, is angiogenic but not lymphangiogenic in this model, and PlGF has neither activity. In vivo CAM assay with microinjection, immunohistochemistry, in situ hybridization for VEGFR-2 and VEGFR-3 Developmental biology High 9245515
2003 The serine protease plasmin cleaves both NH2- and COOH-terminal propeptides from the VEGF homology domain of VEGF-C (and VEGF-D), generating a mature form with greatly enhanced binding and cross-linking of VEGFR-2 and VEGFR-3 compared to full-length material. Plasmin thereby activates VEGF-C. In vitro protease cleavage assay, receptor binding and cross-linking assays with full-length versus plasmin-processed VEGF-C The Journal of experimental medicine High 12963694
2006 VEGF-C and VEGF-D directly interact with neuropilin-2 (NP2): VEGF-C binds NP2 in a heparin-independent manner while VEGF-D binding is heparin-dependent. The domains of VEGF-C and NP2 required for this interaction were mapped. NP2 co-internalizes with VEGFR-3 into endocytic vesicles of lymphatic endothelial cells upon VEGF-C or VEGF-D stimulation, and NP2 co-precipitates with VEGFR-3, indicating that NP2 participates in an active signaling complex with VEGFR-3. In vitro binding studies, domain mapping, co-immunoprecipitation, co-internalization imaging in lymphatic endothelial cells FASEB journal High 16816121
2015 Proteolytic maturation of VEGF-C releases a cryptic Nrp2-binding motif at the C-terminus, allowing specific engagement with the b1 domain of Nrp2. Crystal structure of the VEGF-C C-terminus in complex with Nrp2 ligand-binding domains was determined. The endogenous secreted splice form s9Nrp2 forms a stable dimer and potently inhibits VEGF-C/Nrp2 binding and downstream cellular signaling. X-ray crystallography, in vitro binding assays, cellular signaling assays Structure (London, England : 1993) High 25752543
1998 VEGF-C protein is stored in platelet alpha-granules and is released from platelets upon activation, together with beta-thromboglobulin. VEGF-C mRNA in peripheral blood is restricted to platelets and T cells. VEGF-C mRNA detection in blood cell fractions, VEGF-C protein release assay from activated platelets, co-release with beta-thromboglobulin as alpha-granule marker Thrombosis and haemostasis Medium 9684805
2019 VEGF-C is cleaved and activated by thrombin and plasmin generated during hemostasis. Platelets accelerate lymphatic growth after injury in vivo, and this platelet-enhanced lymphangiogenesis depends on platelet-derived VEGF-C (but not VEGF-D). VEGF-C, but not VEGF-D, is also the dominant factor for lymphangiogenesis after full-thickness skin excision. In vitro protease cleavage assays, tail-wounding mouse model, genetic studies with platelet-specific VEGF-C deletion, full-thickness excision wound model Blood High 31562136
2015 VEGF-C is required for maintenance of intestinal lymphatic vessels (lacteals) in adult mice. VEGF-C is expressed by smooth muscle cells adjacent to lacteals. Deletion of Vegfc in adult mice causes gradual atrophy of intestinal lymphatics, leading to defective lipid absorption, increased fecal excretion of dietary cholesterol and fatty acids, and resistance to diet-induced obesity. Conditional Vegfc gene deletion in adult mice, immunohistochemistry for lymphatic markers, lipid absorption assays, dietary challenge experiments EMBO molecular medicine High 26459520
2000 VEGF-C signaling via VEGFR-2 works synergistically with VEGF-A to enhance vascular bed formation. VEGF-C binding to VEGFR-3 sequesters VEGF-C away from VEGFR-2, thereby regulating VEGFR-2 signaling. In VEGFR-3-deficient embryos, excess VEGF-C signals through VEGFR-2, causing disturbed vasculogenesis and suppressed hematopoiesis. Para-aortic splanchnopleural mesoderm (P-Sp) coculture with OP9 stromal cells, soluble receptor competitive inhibition, VEGFR-3-deficient embryo explants Blood Medium 11090062
2012 FGF-2-induced lymphangiogenesis requires VEGFR-3 signaling; a VEGFR-3-neutralizing antibody markedly inhibits FGF-2-induced lymphangiogenesis. VEGFR-3-mediated signaling is a prerequisite for lymphatic tip cell formation in both FGF-2- and VEGF-C-induced lymphangiogenesis. FGFR-1 expressed in lymphatic endothelial cells is the receptor mediating FGF-2-induced lymphangiogenesis. Mouse corneal lymphangiogenesis assay, VEGFR-3 neutralizing antibody epistasis, tumor co-implantation model, in vitro lymphatic endothelial cell assays Proceedings of the National Academy of Sciences of the United States of America Medium 22967508
2014 Hypoxia reduces VEGF-C cap-dependent translation via upregulation of hypophosphorylated 4E-BP1, but induces VEGF-C translation through an internal ribosome entry site (IRES)-dependent mechanism that is independent of HIF-1α. This IRES-dependent VEGF-C translation is higher in lymph node metastases than in primary tumors. IRES reporter assays, 4E-BP1 manipulation, HIF-1α knockdown, comparison of primary tumor vs. lymph node metastasis samples Cell reports Medium 24388748
2009 VEGF-C regulates capillary stabilization by controlling PDGF-B expression via VEGFR-3 in a paracrine mode during neovascularization. Blockade of VEGFR-3 inhibited FGF-2-mediated limb salvage and caused capillary dilation with mural cell dissociation, and VEGF-C and PDGF-B were mutually dependent (blocking VEGFR-3 decreased PDGF-B expression, and blocking PDGF-BB decreased VEGF-C expression). Murine ischemic hindlimb model, VEGFR-3 neutralizing antibody AFL-4, PDGF-BB blocking antibody, immunohistochemistry American journal of physiology. Heart and circulatory physiology Medium 19734356
2016 VEGF-C is required for the transition to fetal liver erythropoiesis. Embryonic Vegfc deletion causes defective fetal erythropoiesis with anemia and absence of enucleated red blood cells, reduced macrophages and erythroid cells in fetal liver due to decreased proliferation and increased apoptosis, decreased α4-integrin on erythro-myeloid progenitors (EMPs), and impaired EMP colonization of the fetal liver. Vegfc deletion from E10.5 onward or in adults does not affect definitive hematopoiesis. Conditional Vegfc deletion at E7.5, flow cytometry, immunohistochemistry, blood cell analysis, integrin expression assays Blood High 27343251
2020 VEGF-C maintains the integrity of the bone marrow perivascular niche. Global and conditional deletion of Vegfc from endothelial or LepR+ cells disrupts the BM perivascular niche and delays hematopoietic recovery after irradiation by decreasing endothelial proliferation and LepR+ cell regeneration. Exogenous AAV-delivered VEGF-C improves hematopoietic recovery by accelerating endothelial and LepR+ cell regeneration and increasing expression of hematopoietic regenerative factors. Conditional Vegfc gene deletion from endothelial and LepR+ cells, irradiation/transplantation model, AAV-mediated VEGF-C delivery, immunohistochemistry, flow cytometry Blood High 32842144
2018 VEGF-C acts as both a paracrine and autocrine pro-survival cytokine in glioblastoma, activating VEGFR-2 in an autocrine manner to promote tumor cell survival and sustain VEGFR2 activation that is bevacizumab-resistant. Targeting VEGF-C expression in vivo impairs tumor growth more effectively than bevacizumab treatment. RNA interference, exogenous ligand treatment, proximity ligation assay for VEGF-C/VEGFR2 interaction in tumor specimens, patient-derived xenograft in vivo experiments, matched pre/post-bevacizumab treatment cohort analysis Neuro-oncology Medium 29939339
2020 VEGF-C secreted by breast cancer cells that have undergone EMT promotes paracrine non-canonical GLI signaling activation in neighboring epithelial breast cancer cells via NRP2. Inhibiting VEGF-C in EMT cells or knocking down NRP2 in epithelial cancer cells disrupts the aggressive phenotypes (proliferation, migration, invasion, metastasis) imparted by EMT cells. VEGF-C knockdown in EMT cells, NRP2 knockdown in epithelial cells, co-culture systems, in vivo metastasis models, TCGA/GEO dataset correlation Oncogene Medium 33299122
2011 C/EBP-δ transcription factor regulates VEGF-C and VEGFR-3 expression specifically in lymphatic endothelial cells (LECs). Genetic deletion of C/EBP-δ in mice dramatically reduces VEGF-C and VEGFR-3 in LECs, reduces lymphangiogenesis and pulmonary metastases. Forced VEGF-C expression (but not recombinant VEGF-C protein) rescues C/EBP-δ knockdown-induced LEC apoptosis, demonstrating autocrine VEGF-C signaling is essential for LEC survival. C/EBP-δ-induced VEGF-C expression requires HIF-1α. C/EBP-δ knockout mice, forced expression/knockdown in cultured LECs, HIF-1α blocking, rescue experiments with VEGF-C plasmid vs. recombinant protein Oncogene Medium 21666710
2009 Autocrine VEGF-C (along with VEGF-A) in human podocytes is important for podocyte survival via VEGFR-2-mediated activation of PI3K/AKT (anti-apoptotic) and suppression of p38MAPK (pro-apoptotic). Exogenous VEGF-C can reverse the effect of VEGF-A neutralization, indicating functional overlap and complementarity between autocrine VEGF-A and VEGF-C in podocytes. siRNA knockdown of VEGF-A and VEGF-C in human podocytes, bevacizumab treatment, VEGFR-2/-3 tyrosine kinase inhibitor, phospho-AKT and p38MAPK western blotting, apoptosis assays American journal of physiology. Renal physiology Medium 19828679
2006 VEGF-C acts as an autocrine survival factor in cultured human podocytes via VEGFR-1 (not VEGFR-3, as VEGF-C did not autophosphorylate VEGFR-3 in these cells despite doing so in HMVECs). VEGF-C reduces intracellular calcium and cytotoxicity, reduces MAPK phosphorylation, and has no effect on Akt phosphorylation in podocytes. VEGF-C treatment of conditionally immortalized human podocytes, VEGFR-3 kinase inhibitor (MAZ51), SU-5416 (VEGFR-1-specific concentrations), immunoprecipitation for VEGFR-3 autophosphorylation, calcium imaging, cytotoxicity assays American journal of physiology. Renal physiology Medium 16525158
2018 VEGF-C drives bone lymphatic vessel formation via VEGFR-3 (but not VEGFR-2) signaling, as inhibition of VEGFR-3 but not VEGFR-2 prevented formation of bone lymphatics in Osx-tTA;TetO-Vegfc mice. VEGF-C overexpression in bone also promotes bone loss via increased osteoclast numbers, which is attenuated by an osteoclast inhibitor. Double-transgenic mouse model (Osx-tTA;TetO-Vegfc), VEGFR-selective antibody blockade, radiological and histological bone analysis, osteoclast inhibitor treatment eLife Medium 29620526
2021 OTUD3 deubiquitinase stabilizes ZFP36 by inhibiting FBXW7-mediated K48-linked polyubiquitination of ZFP36. ZFP36 binds the VEGF-C 3'-UTR and recruits the RNA-degrading complex to induce rapid VEGF-C mRNA decay. Nicotine downregulates OTUD3, leading to ZFP36 destabilization and increased VEGF-C production and lymphatic metastasis. Co-immunoprecipitation of OTUD3-ZFP36 interaction, ubiquitination assays, RNA decay assays, ZFP36-VEGF-C 3'-UTR binding assays, OTUD3 knockdown/overexpression in cancer cells, in vivo metastasis model Nature communications High 34853315
2020 Functional VEGF-C is transported by extracellular vesicles (EVs) from endometriotic cells to lymphatic endothelial cells, enhancing their lymphangiogenic ability. VEGF-C expression in endometriotic cells is negatively regulated by COUP-TFII, and proinflammatory cytokines increase VEGF-C by suppressing COUP-TFII levels. EV isolation and functional transfer assay, COUP-TFII knockdown/overexpression, cytokine treatment, autotransplanted mouse endometriosis model, lenvatinib (VEGFR inhibitor) treatment Proceedings of the National Academy of Sciences of the United States of America Medium 33004630
2009 TGF-β1 induces VEGF-C expression in gastric cancer cells via Smad-dependent pathway: phospho-Smad3 in the nucleus directly binds to the VEGFC promoter. Additionally, a Smad-independent AKT pathway also activates VEGF-C expression in response to TGF-β1 in a cell-line-dependent manner. Western blot for Smad2/3 phosphorylation, EMSA (electrophoretic mobility shift assay) for Smad3 binding to VEGFC promoter, AKT pathway inhibition, TGF-β1 inhibitor treatment, lymphatic tube forming assay, xenograft mouse model BMC cancer Medium 31409309
2002 Cyclic pressure (60/20 mmHg sinusoidal) selectively induces VEGF-C transcription in human umbilical vein endothelial cells, and VEGF-C mediates the cyclic pressure-induced endothelial cell proliferation response. Affymetrix GeneChip transcriptional profiling, cyclic pressure apparatus, VEGF-C-mediated proliferation assay Physiological genomics Medium 12388793
2005 Androgen ablation in LNCaP prostate cancer cells upregulates VEGF-C transcription. The mechanism involves downregulation of the IGF-IR pathway, with FOXO-1 (activated by SIRT-1) identified as the downstream transcriptional mediator of VEGF-C upregulation. Androgen withdrawal in LNCaP cells, FOXO-1 manipulation, SIRT-1 involvement analysis, VEGF-C mRNA measurement Oncogene Low 15897888
2019 Hes1 transcription factor directly binds and positively regulates VEGF-C gene expression (a rare positive target of Hes1). VEGF-C upregulation by Hes1 contributes to attenuation of TLR upstream signaling by reducing WDFY1 expression, thereby suppressing type I IFN production. Genome-wide Hes1 occupancy (ChIP), VEGF-C expression analysis after Hes1 manipulation, Hes1-deficient mice, antiviral and autoimmune phenotype analysis The Journal of experimental medicine Medium 31015298
2006 VEGF-A upregulates VEGF-C mRNA expression and secretion in human retinal pigment epithelial (RPE) cells, and VEGF-A also stimulates VEGFR-3 mRNA expression. VEGF-C acts synergistically with VEGF-A to promote in vitro tube formation by choroidal endothelial cells. RT-PCR, western blotting, ELISA, Matrigel tube formation assay in choroidal endothelial cells, VEGF-A treatment of RPE cells The British journal of ophthalmology Medium 16687456
2014 RhoGDI2 upregulates VEGF-C expression in gastric cancer cells, positively correlating with VEGF-C in human gastric tumor tissues. VEGF-C depletion suppresses RhoGDI2-induced gastric cancer metastasis and restores sensitivity to cisplatin-induced apoptosis. RhoGDI2 positively regulates Rac1 activity, and Rac1 inhibition suppresses RhoGDI2-induced VEGF-C expression. VEGF-C depletion (siRNA) in RhoGDI2-overexpressing cells, Rac1 inhibition, in vitro invasion assays, in vivo tumor metastasis models, immunohistochemistry of human tumor tissues International journal of cancer Medium 24585459
2024 VEGF-C overexpression (via AAV-mVEGF-C) in mouse brain increases CSF drainage to deep cervical lymph nodes by enhancing meningeal lymphatic vessel growth. VEGF-C prophylaxis reduces ischemic stroke injury and inflammation through a mechanism dependent on lymphatic drainage (neuroprotection was lost upon cauterization of deep cervical lymph node afferent lymphatics) and is associated with increased BDNF signaling and mitigated microglia-mediated inflammation. Intracerebrospinal AAV injection, single nuclei RNA sequencing, CSF drainage assay, mouse ischemic stroke model, cauterization of afferent lymphatics (epistasis), motor performance testing, immunohistochemistry The Journal of experimental medicine High 38442272
2019 VEGF-C/VEGFR3 signaling is required for wound lymphangiogenesis and anti-VEGF-C lymphangiogenesis blockade mediates a pro-inflammatory wound microenvironment and delayed wound closure. Targeted delivery of VEGF-C (F8-VEGF-C antibody fusion) to EDA-fibronectin-expressing remodeling tissue promotes wound healing, induces lymphangiogenesis, and reduces tissue inflammation in diabetic mice. Transgenic mice with increased/absent lymphatic vessels, VEGF-C/VEGFR3 pathway blocking, F8-VEGF-C fusion protein in db/db diabetic wound model, wound closure measurements, immunohistochemistry Cells Medium 36766814

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 640 9233800
1996 VEGF-C receptor binding and pattern of expression with VEGFR-3 suggests a role in lymphatic vascular development. Development (Cambridge, England) 521 9012504
1999 VEGFR-3 and its ligand VEGF-C are associated with angiogenesis in breast cancer. The American journal of pathology 478 10329591
1997 VEGF and VEGF-C: specific induction of angiogenesis and lymphangiogenesis in the differentiated avian chorioallantoic membrane. Developmental biology 418 9245515
1998 Vascular endothelial growth factors VEGF-B and VEGF-C are expressed in human tumors. The American journal of pathology 285 9665470
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
1998 Peripheral blood platelets express VEGF-C and VEGF which are released during platelet activation. Thrombosis and haemostasis 224 9684805
2003 VEGF-C gene therapy augments postnatal lymphangiogenesis and ameliorates secondary lymphedema. The Journal of clinical investigation 213 12618526
2002 Therapeutic lymphangiogenesis with human recombinant VEGF-C. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 201 12397087
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 180 22967508
2001 VEGF-A, VEGF-C, and VEGF-D in colorectal cancer progression. Neoplasia (New York, N.Y.) 178 11687953
2015 VEGF-C is required for intestinal lymphatic vessel maintenance and lipid absorption. EMBO molecular medicine 173 26459520
2003 Plasmin activates the lymphangiogenic growth factors VEGF-C and VEGF-D. The Journal of experimental medicine 167 12963694
1999 Current biology of VEGF-B and VEGF-C. Current opinion in biotechnology 133 10600689
2000 VEGF-C signaling pathways through VEGFR-2 and VEGFR-3 in vasculoangiogenesis and hematopoiesis. Blood 117 11090062
2011 PI3K/Akt and MAPK/ERK1/2 signaling pathways are involved in IGF-1-induced VEGF-C upregulation in breast cancer. Journal of cancer research and clinical oncology 115 21904903
2000 Intravascular adenovirus-mediated VEGF-C gene transfer reduces neointima formation in balloon-denuded rabbit aorta. Circulation 108 11056103
2014 Hypoxia induces VEGF-C expression in metastatic tumor cells via a HIF-1α-independent translation-mediated mechanism. Cell reports 106 24388748
2001 Novel VEGF family members: VEGF-B, VEGF-C and VEGF-D. The international journal of biochemistry & cell biology 102 11312110
2009 Activated forms of VEGF-C and VEGF-D provide improved vascular function in skeletal muscle. Circulation research 91 19443835
2008 Lymphatic spread is related to VEGF-C expression and D2-40-positive myofibroblasts in intrahepatic cholangiocarcinoma. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 90 18192971
2020 Blockade of VEGF-C signaling inhibits lymphatic malformations driven by oncogenic PIK3CA mutation. Nature communications 85 32513927
1997 Expression of FLT4 and its ligand VEGF-C in acute myeloid leukemia. Leukemia 84 9264375
2011 Therapeutic lymphangiogenesis using stem cell and VEGF-C hydrogel. Biomaterials 80 21421266
2020 MiR-182-5p inhibits colon cancer tumorigenesis, angiogenesis, and lymphangiogenesis by directly downregulating VEGF-C. Cancer letters 78 32473243
2020 VEGF-C mediates tumor growth and metastasis through promoting EMT-epithelial breast cancer cell crosstalk. Oncogene 78 33299122
2008 Coexpression of VEGF-C and COX-2 and its association with lymphangiogenesis in human breast cancer. BMC cancer 76 18190720
2013 VEGF-C and VEGF-D blockade inhibits inflammatory skin carcinogenesis. Cancer research 72 23695550
2011 C/EBP-δ regulates VEGF-C autocrine signaling in lymphangiogenesis and metastasis of lung cancer through HIF-1α. Oncogene 67 21666710
2006 Expression and localization of VEGF-C and VEGFR-3 in glioblastomas and haemangioblastomas. The Journal of pathology 67 16523449
2024 VEGF-C prophylaxis favors lymphatic drainage and modulates neuroinflammation in a stroke model. The Journal of experimental medicine 66 38442272
2018 VEGF-C sustains VEGFR2 activation under bevacizumab therapy and promotes glioblastoma maintenance. Neuro-oncology 65 29939339
2007 VEGF-C induced angiogenesis preferentially occurs at a distance from lymphangiogenesis. Cardiovascular research 64 18065770
2018 VEGF-C promotes the development of lymphatics in bone and bone loss. eLife 63 29620526
2013 Inhibition of VEGF-C modulates distal lymphatic remodeling and secondary metastasis. PloS one 63 23874750
2017 An Important Role of VEGF-C in Promoting Lymphedema Development. The Journal of investigative dermatology 61 28526302
2020 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 60 33004630
2003 Evaluation of VEGF and VEGF-C expression in gastric cancer cells producing alpha-fetoprotein. Journal of gastroenterology 58 12825129
2013 VEGF-C, VEGF-A and related angiogenesis factors as biomarkers of allograft vasculopathy in cardiac transplant recipients. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation 57 23260712
2009 The balance of autocrine VEGF-A and VEGF-C determines podocyte survival. American journal of physiology. Renal physiology 57 19828679
2020 VEGF-C protects the integrity of the bone marrow perivascular niche in mice. Blood 55 32842144
2005 Role of VEGF-C and VEGF-D in lymphangiogenesis in gastric cancer. International journal of clinical oncology 55 16247658
2005 Upregulation of VEGF-C by androgen depletion: the involvement of IGF-IR-FOXO pathway. Oncogene 52 15897888
2021 Nicotine-mediated OTUD3 downregulation inhibits VEGF-C mRNA decay to promote lymphatic metastasis of human esophageal cancer. Nature communications 51 34853315
2020 Increased levels of VEGF-C and macrophage infiltration in lipedema patients without changes in lymphatic vascular morphology. Scientific reports 51 32616854
2019 Hemostasis stimulates lymphangiogenesis through release and activation of VEGFC. Blood 51 31562136
2013 Acidic pH via NF-κB favours VEGF-C expression in human melanoma cells. Clinical & experimental metastasis 51 23784694
2004 Expression and significance of VEGF-C and FLT-4 in gastric cancer. World journal of gastroenterology 48 14760756
2012 The expression and clinical significance of pSTAT3, VEGF and VEGF-C in pancreatic adenocarcinoma. Neoplasma 47 22082308
2015 Structural basis for VEGF-C binding to neuropilin-2 and sequestration by a soluble splice form. Structure (London, England : 1993) 46 25752543
2014 VEGF-C mediates RhoGDI2-induced gastric cancer cell metastasis and cisplatin resistance. International journal of cancer 46 24585459
2013 Tumor resistance to anti-VEGF therapy through up-regulation of VEGF-C expression. Cancer letters 46 24333721
2016 Leptin promotes VEGF-C production and induces lymphangiogenesis by suppressing miR-27b in human chondrosarcoma cells. Scientific reports 45 27345723
2007 VEGF-C is associated with lymphatic status and invasion in oral cancer. Journal of clinical pathology 45 17351086
2009 Therapeutic responses to exogenous VEGF-C administration in experimental lymphedema: immunohistochemical and molecular characterization. Lymphatic research and biology 44 19302023
2006 VEGF-C promotes survival in podocytes. American journal of physiology. Renal physiology 44 16525158
2001 Expression of VEGF-C and activation of its receptors VEGFR-2 and VEGFR-3 in trophoblast. Histology and histopathology 44 11332691
2019 VEGF-C induced by TGF- β1 signaling in gastric cancer enhances tumor-induced lymphangiogenesis. BMC cancer 41 31409309
2011 VEGF-C promotes the development of esophageal cancer via regulating CNTN-1 expression. Cytokine 41 21482472
2011 COX-2 expression is correlated with VEGF-C, lymphangiogenesis and lymph node metastasis in human cervical cancer. Microvascular research 41 21600223
2017 dNK cells facilitate the interaction between trophoblastic and endothelial cells via VEGF-C and HGF. Immunology and cell biology 40 28653669
2009 VEGF-C regulates lymphangiogenesis and capillary stability by regulation of PDGF-B. American journal of physiology. Heart and circulatory physiology 40 19734356
2018 Antibody-mediated delivery of VEGF-C potently reduces chronic skin inflammation. JCI insight 37 30518687
2018 VEGF-C and Mortality in Patients With Suspected or Known Coronary Artery Disease. Journal of the American Heart Association 37 30554564
2016 Critical requirement of VEGF-C in transition to fetal erythropoiesis. Blood 37 27343251
2011 Metastasis-associated protein 1 induces VEGF-C and facilitates lymphangiogenesis in colorectal cancer. World journal of gastroenterology 37 21448429
2016 CCL5 promotes VEGF-C production and induces lymphangiogenesis by suppressing miR-507 in human chondrosarcoma cells. Oncotarget 36 27166194
2007 VEGF-C and VEGF-A synergistically enhance lymph node metastasis of gastric cancer. Biological & pharmaceutical bulletin 36 17409493
2011 Lymphatic microvessel density, VEGF-C, and VEGFR-3 expression in different molecular types of breast cancer. Anticancer research 35 21617236
2006 VEGF-C and COX-2 expression in papillary thyroid cancer. Endocrine-related cancer 35 16728574
2018 VEGF-C attenuates renal damage in salt-sensitive hypertension. Journal of cellular physiology 34 30378108
2002 VEGF-C mediates cyclic pressure-induced endothelial cell proliferation. Physiological genomics 34 12388793
2024 DHCR7 promotes lymph node metastasis in cervical cancer through cholesterol reprogramming-mediated activation of the KANK4/PI3K/AKT axis and VEGF-C secretion. Cancer letters 33 38211648
2006 Expression of vascular endothelial growth factor (VEGF)-C and -D in gastric carcinoma. International journal of clinical oncology 33 16508727
2014 Radiation-induced VEGF-C expression and endothelial cell proliferation in lung cancer. Strahlentherapie und Onkologie : Organ der Deutschen Rontgengesellschaft ... [et al] 32 24989178
2007 VEGF-C expression in squamous cell carcinoma and adenocarcinoma of the esophagus. World journal of surgery 32 17354029
2022 ADSCs stimulated by VEGF-C alleviate intestinal inflammation via dual mechanisms of enhancing lymphatic drainage by a VEGF-C/VEGFR-3-dependent mechanism and inhibiting the NF-κB pathway by the secretome. Stem cell research & therapy 31 36064450
2019 VEGF-C Induces Alternative Activation of Microglia to Promote Recovery from Traumatic Brain Injury. Journal of Alzheimer's disease : JAD 27 30958378
2016 Predictive role of the overexpression for CXCR4, C-Met, and VEGF-C among breast cancer patients: A meta-analysis. Breast (Edinburgh, Scotland) 27 27214240
2004 Quantification of vascular endothelial growth factor-C (VEGF-C) by a novel ELISA. Journal of immunological methods 27 14980429
2023 Promotion of Lymphangiogenesis by Targeted Delivery of VEGF-C Improves Diabetic Wound Healing. Cells 26 36766814
2017 Foxp3 is correlated with VEGF-C expression and lymphangiogenesis in cervical cancer. World journal of surgical oncology 26 28923073
2006 VEGF-A regulates the expression of VEGF-C in human retinal pigment epithelial cells. The British journal of ophthalmology 26 16687456
2017 Association of CXCR4, CCR7, VEGF-C and VEGF-D expression with lymph node metastasis in patients with cervical cancer. European journal of obstetrics, gynecology, and reproductive biology 25 28535405
2015 Ischemic tolerance is associated with VEGF-C and VEGFR-3 signaling in the mouse hippocampus. Neuroscience 24 25637798
2019 Long Noncoding RNA ASLNC07322 Functions in VEGF-C Expression Regulated by Smad4 during Colon Cancer Metastasis. Molecular therapy. Nucleic acids 23 31739210
2017 Expressions and clinical significance of COX-2, VEGF-C, and EFGR in endometrial carcinoma. Archives of gynecology and obstetrics 23 28474124
2012 Serum VEGF and VEGF-C values before surgery and after postoperative treatment in gastric cancer. Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico 23 22855190
2007 Expression of VEGF-C, VEGF-D and their receptor VEGFR-3 in diffuse large B-cell lymphomas. Leukemia & lymphoma 23 17926187
2015 Hyaluronan-induced VEGF-C promotes fibrosis-induced lymphangiogenesis via Toll-like receptor 4-dependent signal pathway. Biochemical and biophysical research communications 22 26362177
2013 Impact of VEGF-C gene polymorphisms and environmental factors on oral cancer susceptibility in Taiwan. PloS one 22 23593187
2012 Survivin regulates the expression of VEGF-C in lymphatic metastasis of breast cancer. Diagnostic pathology 22 22607367
2007 Distinct roles of VEGF-A and VEGF-C in tumour metastasis of gastric carcinoma. Oncology reports 22 17203176
2006 Vascular endothelial growth factor-C (VEGF-C) expression in normal human tissues. Lymphatic research and biology 22 16808669
2016 Elevated Expression of VEGF-C and Its Receptors, VEGFR-2 and VEGFR-3, in Patients with Mesial Temporal Lobe Epilepsy. Journal of molecular neuroscience : MN 21 26798047
2010 VEGF-C contributes to head and neck squamous cell carcinoma growth and motility. Oral oncology 21 20227330
2019 Hes1 attenuates type I IFN responses via VEGF-C and WDFY1. The Journal of experimental medicine 20 31015298
2018 VEGFR2 and VEGF-C Suppresses the Epithelial-Mesenchymal Transition Via YAP in Retinal Pigment Epithelial Cells. Current molecular medicine 20 30289073
2017 VEGF-C expression attributes the risk for lymphatic metastases to ovarian cancer patients. Oncotarget 20 28591727
2009 Lentivirus-mediated small interfering RNA targeting VEGF-C inhibited tumor lymphangiogenesis and growth in breast carcinoma. Anatomical record (Hoboken, N.J. : 2007) 20 19382240

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