Affinage

VEGFA

Vascular endothelial growth factor A, long form · UniProt P15692

Round 2 corrected
Length
395 aa
Mass
43.6 kDa
Annotated
2026-04-28
130 papers in source corpus 45 papers cited in narrative 45 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

VEGF-A is a secreted, disulfide-linked dimeric glycoprotein that serves as the master regulator of vasculogenesis, angiogenesis, and vascular permeability, acting through the endothelial receptor tyrosine kinases VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk-1), with VEGFR-2 functioning as the principal mitogenic and chemotactic signaling receptor via PLC-γ, ERK1/2, Akt/eNOS, and CREB pathways, while VEGFR-1 binds VEGF-A with higher affinity but primarily signals through Fyn/Yes kinases (PMID:7929439, PMID:20067582, PMID:12459464). Alternative splicing of a single eight-exon gene generates isoforms (VEGF121, VEGF165, VEGF189, VEGF206, VEGF111, VEGF165b) with distinct heparin-binding, matrix-association, and secretion properties that specify vascular patterning outcomes—matrix-bound isoforms drive thin branched vessels while MMP-cleaved soluble forms promote vessel dilation—and the co-receptor neuropilin-1 selectively enhances VEGF165/VEGFR-2 signaling (PMID:1791831, PMID:15911882, PMID:9529250). Transcription is directly regulated by HIF-1α (via PI3K/MAPK-driven translation), Stat3, and PPARγ/GPR120 binding to the VEGF-A promoter (PMID:11960372, PMID:12149254, PMID:25697344). Beyond its vascular roles, VEGF-A exerts direct VEGFR-2-dependent neuroprotection in retinal ganglion cells and motoneurons, promotes CD8+ T cell exhaustion by upregulating PD-1 and other checkpoint receptors in the tumor microenvironment, and is a genetic modifier of amyotrophic lateral sclerosis risk (PMID:23416159, PMID:25601652, PMID:12847526).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1989 High

    The molecular identity of an endothelial-selective angiogenic factor was established: two independent groups purified and cloned VEGF-A as a secreted heparin-binding glycoprotein structurally related to PDGF, resolving the molecular basis of vascular permeability factor activity and endothelial mitogenesis.

    Evidence Protein purification, cDNA cloning, transfection/expression in 293 cells, endothelial mitogenesis and Miles permeability assays

    PMID:2479986 PMID:2479987

    Open questions at the time
    • Receptor identity unknown
    • In vivo developmental requirement unestablished
    • Mechanism of endothelial selectivity undefined
  2. 1991 High

    The genomic architecture and isoform diversity of VEGF-A were defined: alternative splicing of eight exons produces at least four isoforms with distinct secretion, matrix-binding, and bioactivity profiles, explaining how a single gene generates diverse angiogenic signals.

    Evidence Genomic sequencing, RT-PCR isoform cloning, transient transfection, endothelial mitogenesis and permeability assays

    PMID:1711045 PMID:1791831

    Open questions at the time
    • Physiological significance of individual isoforms in vivo unknown
    • Mechanism of differential matrix association undefined
    • Transcriptional regulation beyond Sp1/AP-1 unexplored
  3. 1992 High

    The receptors mediating VEGF-A signaling were identified: Flt-1 (VEGFR-1) and KDR (VEGFR-2) were each shown to be high-affinity VEGF-A-binding receptor tyrosine kinases by heterologous expression, establishing a two-receptor signaling system.

    Evidence cDNA expression in COS cells and CMT-3 cells, radioligand binding, affinity cross-linking, Xenopus oocyte calcium release

    PMID:1312256 PMID:1417831

    Open questions at the time
    • Relative signaling contributions of the two receptors unknown
    • In vivo requirement of each receptor for angiogenesis undemonstrated
    • Downstream signaling cascades uncharacterized
  4. 1994 High

    The functional division between VEGFR-1 and VEGFR-2 was resolved: VEGFR-2 mediates mitogenesis, chemotaxis, actin reorganization, and PLC-γ activation, whereas VEGFR-1 binds with higher affinity but signals weakly through Fyn/Yes kinases, establishing VEGFR-2 as the principal angiogenic signaling receptor.

    Evidence Stable transfection in porcine aortic endothelial cells, comparative radioligand binding, autophosphorylation, chemotaxis, mitogenesis, PI3K and PLC-γ assays

    PMID:7929439

    Open questions at the time
    • Downstream second-messenger cascades beyond PLC-γ unresolved
    • VEGFR-1 decoy versus active signaling role debated
    • Co-receptor contributions unknown
  5. 1998 High

    Neuropilin-1 was identified as an isoform-selective co-receptor that binds VEGF165 (but not VEGF121), enhances its binding to VEGFR-2, and augments chemotaxis, explaining how heparin-binding isoforms achieve preferential signaling.

    Evidence Expression cloning from tumor cells, competitive binding assays, co-expression with KDR, chemotaxis and mitogenesis inhibition assays

    PMID:9529250

    Open questions at the time
    • Structural basis of isoform selectivity at atomic resolution unknown
    • In vivo necessity of Nrp1 for VEGF165 signaling undemonstrated at this stage
    • Nrp1 signaling-competent vs. presentation-only role unresolved
  6. 2000 High

    In vivo loss-of-function in zebrafish demonstrated that VEGF-A is absolutely required for intersegmental vessel formation but dispensable for initial axial vasculature, establishing its role as a sprouting angiogenesis factor rather than a general vasculogenesis factor.

    Evidence Morpholino knockdown in zebrafish with in situ hybridization for endothelial markers (fli-1, flk-1)

    PMID:11119306

    Open questions at the time
    • Mammalian conditional loss-of-function required to confirm
    • Isoform-specific requirements in vivo unknown
    • Whether axial vasculature uses compensatory ligands unclear
  7. 2002 High

    Key transcriptional and post-receptor signaling mechanisms were defined: Stat3 directly binds the VEGF-A promoter to drive expression, HIF-1α upregulates VEGF-A via PI3K/MAPK-driven translational synthesis, and Akt/eNOS was established as the pathway mediating VEGF-A-induced vascular permeability in vivo.

    Evidence ChIP and promoter mutagenesis for Stat3; pharmacological inhibitors and constitutively active MEK2 for HIF-1α; adenoviral gain/loss-of-function Akt with eNOS inhibitor L-NAME in Miles assay

    PMID:11960372 PMID:12149254 PMID:12459464

    Open questions at the time
    • Integration of multiple transcriptional inputs at the promoter unclear
    • Whether Akt-eNOS pathway is endothelial-cell-autonomous in vivo unresolved
    • Other HIF-independent transcriptional mechanisms not comprehensively mapped
  8. 2003 High

    VEGF-A was shown to control angiogenic patterning through spatial presentation: gradient-sensing drives tip cell filopodial migration while concentration drives stalk cell proliferation, both via VEGFR-2; separately, VEGF-A promoter haplotypes reducing expression were linked to ALS risk and VEGF-A treatment rescued motoneuron degeneration, revealing a direct neuroprotective role.

    Evidence Retinal wholemount imaging with VEGF isoform-specific mouse models for vascular patterning; human genetic meta-analysis, SOD1(G93A) mouse cross, and spinal cord ischemia rescue for ALS

    PMID:12810700 PMID:12847526

    Open questions at the time
    • Molecular basis of gradient sensing vs. concentration sensing in tip vs. stalk cells unknown
    • Whether VEGF-A neuroprotection is VEGFR-2-dependent in motoneurons required confirmation
    • Mechanism linking reduced VEGF to motoneuron-specific vulnerability unclear
  9. 2005 High

    Extracellular proteolytic processing was shown to determine vascular morphology: MMP cleavage of matrix-bound VEGF-A releases soluble fragments that promote vessel dilation, whereas MMP-resistant matrix-bound VEGF drives thin branched neovessels, despite equivalent VEGFR-2 phosphorylation.

    Evidence MMP cleavage site mapping, recombinant MMP-cleaved and MMP-resistant VEGF mutants, VEGFR-2 phosphorylation assays, tumor implantation vascular morphometry

    PMID:15911882

    Open questions at the time
    • Which specific MMPs are physiologically relevant in different tissues unclear
    • How identical VEGFR-2 phosphorylation produces different morphological outcomes mechanistically unresolved
    • Plasmin vs. MMP cleavage hierarchy in vivo unknown
  10. 2007 High

    A genotoxic-stress-induced isoform VEGF111 was identified that is protease-resistant and diffusible yet fully activates VEGFR-2/ERK and promotes vascular networks, expanding the functional isoform repertoire and revealing stress-responsive splicing regulation.

    Evidence RT-PCR after UV-B/genotoxic drug exposure, VEGFR-2 and ERK1/2 activation assays, endothelial tube formation, xenograft models

    PMID:18086921

    Open questions at the time
    • Splicing factors mediating VEGF111 inclusion unknown
    • Physiological relevance in wound healing or tumor biology undemonstrated
    • Whether VEGF111 binds neuropilin-1 untested
  11. 2010 High

    The neuroprotective signaling pathway was fully delineated: VEGF-A protects neurons and endothelial cells via VEGFR-2→ERK→CREB(Ser-133) phosphorylation, as demonstrated by CREB dominant-negative mutant blockade of protection in both cell types.

    Evidence Rat pup hypoxia-ischemia model, oxygen-glucose deprivation in neurons and endothelial cells, VEGFR-2/ERK inhibitors, CREB S133A mutant transfection

    PMID:20067582

    Open questions at the time
    • CREB target genes mediating survival not identified
    • Whether this pathway operates in adult neurodegeneration models unconfirmed
    • Contribution of non-neuronal cells in vivo not excluded
  12. 2012 High

    Cell-type-specific VEGF-A functions were expanded: astrocyte-derived VEGF-A drives blood-brain barrier breakdown via eNOS; VEGF-A recruits MMP-9-high proangiogenic neutrophils critical for tissue revascularization; and the Nrp1-VEGF165 binding interface was structurally mapped as distinct from semaphorin binding.

    Evidence Conditional astrocytic Vegfa knockout with eNOS inhibitor cavtratin in EAE model; syngeneic islet transplantation in VEGF-A and MMP-9 knockout mice; Nrp1 binding domain mutagenesis and competition assays

    PMID:22653056 PMID:22966168 PMID:23145112

    Open questions at the time
    • Whether eNOS-mediated BBB disruption is universal across neuroinflammatory conditions unknown
    • Signals specifying MMP-9-high neutrophil subset identity not defined
    • High-resolution co-crystal of Nrp1-VEGF165 complex still lacking
  13. 2013 High

    Direct VEGFR-2-dependent neuroprotection was confirmed in retinal ganglion cells via PI3K/Akt, and SRPK1-regulated alternative splicing was shown to control the balance between pro-angiogenic VEGF-Axxxa and anti-/weakly-angiogenic VEGF-Axxxb isoforms with functional consequences for nociception.

    Evidence Isolated RGC culture with VEGFR-2 and PI3K inhibitors plus glaucoma model; nerve injury pain models with SRPK1 inhibition and isoform-specific qPCR

    PMID:23416159 PMID:25151644

    Open questions at the time
    • SRPK1-substrate phosphorylation events driving splicing switch molecularly uncharacterized
    • Whether VEGF-Axxxb isoforms signal through distinct receptor complexes unresolved
    • Whether RGC neuroprotection is clinically exploitable alongside anti-VEGF therapy unknown
  14. 2015 High

    VEGF-A was shown to promote CD8+ T cell exhaustion in the tumor microenvironment by upregulating PD-1, Tim-3, and other inhibitory checkpoint receptors, a process reversible by anti-VEGF/VEGFR agents, establishing a direct immunosuppressive function.

    Evidence Tumor microenvironment analysis, anti-VEGF-A/VEGFR treatment, flow cytometry for checkpoint receptors, functional T cell assays

    PMID:25601652

    Open questions at the time
    • Whether VEGF-A acts directly on T cells or indirectly via APCs unresolved
    • Receptor (VEGFR-1 vs. VEGFR-2) mediating T cell exhaustion not identified
    • Mechanistic pathway from VEGF receptor activation to PD-1 transcription unknown
  15. 2016 Medium

    Isoform-specific VEGFR-2 trafficking was shown to determine signaling quality: different VEGF-A isoforms drive distinct endocytic routes and ubiquitylation patterns, with clathrin-dependent internalization specifically required for ERK1/2 signaling, providing a mechanism for isoform-specific biological outcomes.

    Evidence VEGFR-2 endocytosis tracking, clathrin inhibition, isoform-specific signaling and ubiquitylation assays in endothelial cells

    PMID:27044325

    Open questions at the time
    • Which endosomal compartments sustain ERK vs. Akt signaling undefined
    • In vivo relevance of isoform-specific trafficking undemonstrated
    • Adaptor proteins linking clathrin-VEGFR-2 to ERK not identified
  16. 2017 High

    The 4 Å crystal structure of the full-length VEGFR-1 ectodomain bound to VEGF-A revealed homotypic receptor contacts in Ig domains 4, 5, and 7 critical for ligand-induced dimerization, identifying potential allosteric therapeutic sites.

    Evidence X-ray crystallography, single-particle EM, mutagenesis-guided functional validation

    PMID:28111021

    Open questions at the time
    • Equivalent full-length VEGFR-2 ectodomain structure with VEGF-A not yet solved
    • Whether allosteric inhibitors targeting Ig4/5/7 contacts are pharmacologically tractable untested
    • Dynamics of receptor activation at the membrane unresolved
  17. 2021 High

    Endothelial insulin receptors were identified as required cofactors for VEGF-A→ERK signaling by enabling VEGFR-2 internalization, while leaving Akt/eNOS signaling intact, revealing a metabolic gatekeeper of angiogenic versus permeability signaling arms.

    Evidence Endothelium-restricted Insr haploinsufficiency mice, hindlimb ischemia and retinal angiogenesis models, VEGFR-2 internalization assay, phospho-ERK and phospho-Akt western blots in HUVECs

    PMID:34037749

    Open questions at the time
    • Physical interaction mechanism between insulin receptor and VEGFR-2 trafficking machinery undefined
    • Whether insulin resistance in diabetes impairs VEGF-A angiogenic signaling via this mechanism untested clinically
    • Tissue specificity of insulin receptor requirement for VEGF signaling unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: how identical VEGFR-2 phosphorylation by matrix-bound versus soluble VEGF-A generates distinct vascular morphologies; the molecular basis of VEGF-A's direct immunosuppressive signaling in T cells (receptor identity and downstream pathway); high-resolution structural characterization of the full VEGFR-2 ectodomain in complex with VEGF-A; and integration of the multiple transcriptional inputs (HIF-1α, Stat3, PPARγ, NF-κB) at the VEGF-A promoter in physiological contexts.
  • Mechanistic basis of spatial-presentation-dependent morphological outcomes unknown
  • VEGF-A receptor and signaling pathway on CD8+ T cells unidentified
  • Full-length VEGFR-2/VEGF-A co-crystal structure unavailable
  • Promoter-level integration of combinatorial transcription factor inputs uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 5 GO:0098772 molecular function regulator activity 2
Localization
GO:0005576 extracellular region 4 GO:0031012 extracellular matrix 2
Pathway
R-HSA-162582 Signal Transduction 7 R-HSA-1266738 Developmental Biology 4 R-HSA-109582 Hemostasis 3 R-HSA-1474244 Extracellular matrix organization 2 R-HSA-168256 Immune System 2
Partners
FLT1HIF1AKDRMMP9MMRN2NOS3NRP1STAT3

Evidence

Reading pass · 45 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1989 VEGF-A (then called VEGF) was identified as a secreted, heparin-binding glycoprotein mitogen specific for vascular endothelial cells, capable of inducing angiogenesis in vivo. cDNA cloning revealed structural relatedness to PDGF A and B chains, and transfection of 293 cells with VEGF cDNA confirmed secretion of an active endothelial cell mitogen. Protein purification, cDNA cloning, transfection/expression assay, in vivo angiogenesis assay Science High 2479986
1989 Vascular permeability factor (VPF/VEGF-A) was identified as a 40-kDa disulfide-linked dimeric glycoprotein with sequence similarity to PDGF-B, retaining all eight cysteines of PDGF-B, functioning as an endothelial cell mitogen and vascular permeability-inducing factor. cDNA sequencing, protein biochemistry, endothelial cell growth assay, Miles vascular permeability assay Science High 2479987
1991 The human VEGF-A gene is split across eight exons and generates at least four isoforms (VEGF121, VEGF165, VEGF189, VEGF206) through alternative mRNA splicing; VEGF189 and VEGF206 are predominantly cell-associated while VEGF121 and VEGF165 are efficiently secreted, and only VEGF121 and VEGF165 display endothelial cell mitogenic activity despite all four having vascular permeability activity. PCR, cDNA cloning, genomic DNA sequencing, transient transfection, endothelial cell mitogenesis assay, vascular permeability assay Molecular endocrinology High 1791831
1991 VEGF-A is encoded by a single gene whose promoter contains Sp1-binding sites and AP-1/AP-2 binding sites; phorbol ester treatment elevates VEGF mRNA levels in vascular smooth muscle cells, identifying the gene's transcriptional regulatory elements. Northern blot, PCR, cDNA cloning, genomic sequencing, promoter analysis The Journal of biological chemistry High 1711045
1992 VEGF-A binds with high affinity to the receptor tyrosine kinase Flt-1 (VEGFR-1); expression of flt cDNA in COS cells confers specific VEGF-A binding, and expression in Xenopus oocytes triggers calcium release in response to VEGF-A, establishing Flt-1 as a functional signaling receptor. cDNA expression, radioligand binding, Xenopus oocyte calcium release assay Science High 1312256
1992 KDR (VEGFR-2) was identified as a second high-affinity receptor for VEGF-A; expression of KDR cDNA in CMT-3 cells confers saturable 125I-VEGF binding (Kd ~75 pM) and affinity cross-linking labels proteins of 195 and 235 kDa. cDNA expression, radioligand binding, affinity cross-linking Biochemical and biophysical research communications High 1417831
1993 VEGF-A acts directly on endothelial cells via specific high-affinity tyrosine kinase receptors to activate phospholipase C and induce intracellular calcium transients; it is a potent permeability factor promoting extravasation of plasma fibrinogen and fibrin deposition, and is a selective endothelial cell mitogen in vitro. Receptor binding assays, PLC activation, intracellular calcium measurement, endothelial cell proliferation assay, fibrinogen extravasation assay Cancer metastasis reviews High 8281615
1993 Flk-1 (VEGFR-2/KDR) is the high-affinity VEGF-A receptor expressed specifically on endothelial cells throughout mouse development from blood island progenitors through vascular sprouts, establishing this receptor-ligand pair as a major regulator of vasculogenesis and angiogenesis. In situ hybridization, radioligand binding, cDNA expression Cell High 7681362
1994 KDR (VEGFR-2) and Flt-1 (VEGFR-1) transduce different signals in response to VEGF-A: KDR mediates cell morphology changes, actin reorganization, membrane ruffling, chemotaxis, and mitogenicity with efficient ligand-induced autophosphorylation; Flt-1 binds VEGF-A with higher affinity (Kd 16 pM vs 760 pM for KDR) but lacks these mitogenic and chemotactic responses and instead activates Fyn/Yes kinases. Stable transfection in porcine aortic endothelial cells, radioligand binding, kinase autophosphorylation assay, chemotaxis assay, mitogenesis assay, PI3K and PLC-γ assays The Journal of biological chemistry High 7929439
1998 Neuropilin-1 was identified as an isoform-specific receptor for VEGF-A: it binds VEGF165 but not VEGF121, and when co-expressed with KDR/VEGFR-2, enhances VEGF165 binding to KDR and VEGF165-mediated chemotaxis; inhibiting VEGF165 binding to neuropilin-1 blocks its binding to KDR and endothelial mitogenic activity. Expression cloning from tumor cells, binding assays, co-expression studies, chemotaxis assay, mitogenesis inhibition assay Cell High 9529250
2000 VEGF-A morphant zebrafish (morpholino knockdown) develop with nearly complete absence of intersegmental vasculature but retain axial vascular patterning, demonstrating that VEGF-A signaling is absolutely required for intersegmental vessel specification but not for initial establishment of axial vasculature. Morpholino antisense knockdown in zebrafish, in situ hybridization with endothelial markers (fli-1, flk-1), morphological analysis Yeast High 11119306
2002 Constitutively active Stat3 directly binds the VEGF-A promoter in vivo (shown by chromatin immunoprecipitation) and upregulates VEGF-A expression; mutation of the Stat3-binding site in the VEGF promoter abolishes Stat3- and v-Src-induced VEGF-A promoter activity, establishing Stat3 as a direct transcriptional regulator of VEGF-A. Chromatin immunoprecipitation, promoter mutagenesis, luciferase reporter assay, dominant-negative and antisense approaches Oncogene High 11960372
2002 IGF-1 induces VEGF-A expression in colon cancer cells via HIF-1α protein synthesis (not by blocking HIF-1α ubiquitination as hypoxia does), mediated through PI3K and MAP kinase signaling pathways that phosphorylate translational regulators 4E-BP1, p70 S6 kinase, and eIF-4E; constitutively active MEK2 alone is sufficient to induce HIF-1α and VEGF-A. HIF-1α western blot, VEGF mRNA northern blot, pharmacological inhibitors, constitutively active MEK2 expression, phosphorylation assays The Journal of biological chemistry High 12149254
2003 VEGF-A controls angiogenic sprouting in the postnatal retina by guiding filopodial extension from specialized tip endothelial cells (migration response) while stimulating proliferation in stalk cells; both responses are mediated by VEGFR-2, but tip cell migration depends on a VEGF-A gradient whereas stalk proliferation depends on VEGF-A concentration. Retinal wholemount imaging, genetic mouse models with altered VEGF-A isoform expression, VEGFR-2 antibody blocking, live imaging of tip cell filopodia The Journal of cell biology High 12810700
2004 VEGF-A binds VEGFR1 and VEGFR2 to drive hemangiogenesis; VEGF-A also promotes lymphangiogenesis indirectly by recruiting macrophages that then release VEGF-C/D; depletion of bone marrow-derived cells or macrophages inhibits both hemangiogenesis and lymphangiogenesis. VEGF Trap neutralization, VEGF-A isoform-specific transgenic mice, irradiation, clodronate liposome macrophage depletion, LYVE-1 lymphatic vessel staining in cornea model The Journal of clinical investigation High 15057311
2002 VEGF-A (VPF/VEGF) triggers an angiogenic cascade that includes increased microvascular permeability, deposition of a pro-angiogenic extracellular fibrin matrix, and subsequent formation of mother/daughter vessels through interaction with two high-affinity tyrosine kinase receptors selectively expressed on vascular endothelium. In vivo angiogenesis models, vascular permeability assays, histological analysis Seminars in perinatology Medium 10709865
2005 Matrix metalloproteinases (MMPs) cleave matrix-bound VEGF-A isoforms extracellularly, releasing soluble fragments; MMP-cleaved VEGF promotes capillary dilation of existing vessels, while MMP-resistant (matrix-bound) VEGF supports growth of thin, highly branched neovessels. All forms equally phosphorylate VEGFR-2, but the spatial presentation (matrix-bound vs. soluble) determines angiogenic outcome. MMP cleavage site mapping, recombinant MMP-cleaved and MMP-resistant VEGF generation, VEGFR-2 phosphorylation assays, tumor implantation models, vascular morphometric analysis The Journal of cell biology High 15911882
2002 Akt signaling is both necessary and sufficient for VEGF-A-induced vascular permeability in vivo: dominant-negative Akt blocks VEGF-induced permeability, while constitutively active Akt promotes permeability equivalently to VEGF protein; this Akt-mediated permeability is inhibited by the eNOS inhibitor L-NAME, placing eNOS downstream of Akt in the VEGF-A permeability pathway. Adenovirus-mediated gene transfer, Miles vascular permeability assay in guinea pigs, dominant-negative and constitutively active Akt constructs, eNOS inhibition with L-NAME FEBS letters High 12459464
2003 VEGF-A is a modifier of ALS: VEGF promoter haplotypes that reduce VEGF expression and IRES-mediated translation of a novel large-VEGF (L-VEGF) isoform are associated with 1.8-fold greater ALS risk; Vegfa(delta/delta) mice crossed with SOD1(G93A) die earlier with more severe motoneuron degeneration; Vegfa treatment protects against ischemic motoneuron death in mice. Human genetic meta-analysis, mouse cross-breeding, spinal cord ischemia model, VEGF protein treatment, IRES-mediated translation assays Nature genetics High 12847526
2003 Conditional hypomorphic reduction of VEGF-A in neural progenitors via Nestin-Cre decreases blood vessel branching and density in cortex and retina, causing retinal thinning and cortical disorganization; severe reduction causes cortical degeneration and neonatal lethality. Conditional inactivation of VEGFR-2 (Flk1) in neuronal lineages showed no abnormality, ruling out significant VEGF-A/Flk1 autocrine signaling in CNS development. Nestin-Cre conditional hypomorphic and knockout alleles, histology, BrdU proliferation assay, TUNEL apoptosis assay, conditional Flk1 knockout Developmental biology High 14550787
2006 Serine proteases (particularly plasmin) present in chronic wound microenvironments cleave VEGF165 at Arg110/Ala111, reducing its mitogenic activity; inactivation of the plasmin cleavage site increases angiogenic potency of VEGF165 in an impaired healing mouse model. Elevated soluble VEGFR-1 (sVEGFR-1) in non-healing wounds acts as a VEGF-A inhibitor and correlates inversely with wound closure. Protease cleavage mapping, site-directed mutagenesis of cleavage site, recombinant protein functional assays, impaired healing mouse model, wound fluid sVEGFR-1 measurement The Journal of investigative dermatology. Symposium proceedings High 17069014
2006 Podocytes have a functional autocrine VEGF-A system: differentiated podocytes express VEGFR-2 and secrete VEGF-A; exogenous VEGF165 induces VEGFR-2 phosphorylation, reduces apoptosis ~40%, upregulates podocin, and increases podocin/CD2AP interaction; anti-VEGFR-2 neutralizing antibody enhances apoptosis ~2-fold. RT-PCR, western blot, ELISA, VEGFR-2 phosphorylation assay, apoptosis assay, co-immunoprecipitation of VEGFR2 and nephrin from whole kidney lysates American journal of physiology. Renal physiology High 16597608
2007 A novel VEGF-A splice variant VEGF111, encoded by exons 1-4 and 8, is induced by UV-B and genotoxic drugs in many cell types and in vivo. VEGF111 activates VEGFR-2 and ERK1/2 in endothelial cells, is diffusible, resistant to proteolysis (due to skipping of exons with MMP cleavage sites and ECM-binding domains), and promotes vascular network formation comparable to VEGF121/165. RT-PCR, VEGFR-2 phosphorylation assay, ERK1/2 activation, endothelial mitogenesis/chemotaxis assay, embryonic stem cell differentiation tube formation, xenograft tumor models The Journal of cell biology High 18086921
2009 VEGF-A165 and HGF activate distinct but overlapping MAPK subsets with different kinetics; they synergistically activate ERK1/2 and p38 in endothelial cells. VEGFR-2 and c-met do not physically associate or transphosphorylate each other, indicating co-operation occurs at post-receptor signaling nodes. VEGF-A165 and HGF activate FAK with different kinetics and recruit phospho-FAK to different focal adhesion subsets; VEGF-A165 preferentially activates Rho while HGF activates Rac, producing structurally distinct vascular-like patterns. Co-immunoprecipitation (negative result), kinase activation assays (western blot for phospho-ERK1/2, p38, FAK), chemotaxis assay, actin cytoskeletal imaging, Rho/Rac inhibition Biology of the cell Medium 19281453
2010 VEGF-A overexpression in podocytes induces VEGFR-2 phosphorylation in podocytes themselves, and co-immunoprecipitation from whole kidney lysates confirms VEGFR2-nephrin interaction in vivo, demonstrating autocrine VEGF-A signaling through VEGFR2 in podocytes. Reversible VEGF164 overexpression causes proteinuria, GBM thickening, and podocyte effacement with downregulation of MMP-9 and nephrin. Doxycycline-inducible transgenic model, VEGFR-2 phosphorylation assay, co-immunoprecipitation (VEGFR2 and nephrin), transmission electron microscopy Kidney international High 20375978
2012 Astrocyte-derived VEGF-A drives blood-brain barrier disruption by activating endothelial eNOS as the principal downstream effector; inactivation of astrocytic Vegfa reduces BBB breakdown and lymphocyte infiltration; systemic administration of the selective eNOS inhibitor cavtratin abrogates VEGF-A-induced BBB disruption and protects against neurological deficit in an MS mouse model. Conditional Vegfa knockout in astrocytes, CNS endothelium eNOS knockdown, cavtratin pharmacological inhibition, EAE MS model, BBB permeability assay, lymphocyte infiltration quantification The Journal of clinical investigation High 22653056
2012 VEGF-A recruits a proangiogenic subset of CD11b+/Gr-1+/CXCR4hi neutrophils that express 10-fold higher amounts of MMP-9 than inflammatory stimulus-recruited neutrophils; MMP-9 from these neutrophils is required for islet revascularization, as shown by impaired revascularization in MMP-9-deficient mice. Syngeneic islet transplantation model, VEGF-A-deficient islets, flow cytometry, MMP-9 ELISA, MMP-9 knockout mice Blood High 22966168
2012 Neuropilin-1 binds VEGF-A165 specifically (not VEGF-A121) through residues in the b1 coagulation factor domain surrounding the invariant C-terminal arginine binding pocket; this binding mechanism is distinct from Sema3F binding, enabling engineering of soluble Nrp fragments that selectively sequester Sema3 in the presence of VEGF-A. Binding assays with Nrp1 mutants, competition assays, engineered soluble receptor fragments PloS one High 23145112
2013 VEGF-A acts directly on retinal ganglion cells via VEGFR-2 signaling through the PI3K/Akt pathway to promote neuronal survival; VEGF-A blockade significantly exacerbates RGC death in a hypertensive glaucoma model, demonstrating a direct neuroprotective function independent of vascular effects. Isolated RGC culture, VEGFR-2 and PI3K inhibition, staurosporine-induced death model, hypertensive glaucoma mouse model, VEGF-A blockade The American journal of pathology High 23416159
2013 VEGF-A165a sensitizes peripheral nociceptive neurons through VEGFR-2 and a TRPV1-dependent mechanism, enhancing nociceptive signaling; VEGF-A165b blocks this effect. After nerve injury, an SRPK1-dependent pre-mRNA splicing mechanism shifts the balance toward VEGF-Axxxa; pharmacological SRPK1 inhibition selectively reduces VEGF-Axxxa expression and reverses neuropathic pain. Rat/mouse pain behavioral assays, nerve injury models, VEGFR-2 and TRPV1 pharmacological inhibitors, SRPK1 inhibition, isoform-specific qPCR, exogenous VEGF-A165b treatment Neurobiology of disease High 25151644
2014 An antiangiogenic splice isoform VEGF-A165b is elevated in peripheral artery disease and impairs revascularization; conditions including leptin deficiency, diet-induced obesity, Sfrp5 knockout, and Wnt5a overexpression in myeloid cells upregulate VEGF-A165b; isoform-specific neutralizing antibody reverses impaired revascularization in metabolic dysfunction mouse models of PAD. Human PAD patient samples (ELISA), mouse hindlimb ischemia model, transgenic/knockout mouse models, isoform-specific neutralizing antibody Nature medicine High 25362254
2015 VEGF-A produced in the tumor microenvironment enhances expression of PD-1, Tim-3, and other inhibitory checkpoints on CD8+ T cells, promoting T cell exhaustion; this effect is reversible by anti-angiogenic agents targeting the VEGF-A/VEGFR axis. Tumor microenvironment analysis, anti-VEGF-A/VEGFR treatment, flow cytometry for checkpoint receptor expression on CD8+ T cells, functional T cell assays The Journal of experimental medicine High 25601652
2016 Different VEGF-A isoforms (VEGF-A165, VEGF-A121, VEGF-A145) promote distinct patterns of VEGFR-2 endocytosis into early endosomes and isoform-specific signal transduction; disruption of clathrin-dependent endocytosis blocks isoform-specific VEGFR-2 activation and causes substantial depletion of membrane-bound VEGFR-1 and VEGFR-2. Different isoforms also promote differential VEGFR-2 ubiquitylation and proteolysis. VEGFR-2 endocytosis tracking, clathrin inhibition, isoform-specific signaling assays, ubiquitylation assays, receptor degradation analysis Biology open Medium 27044325
2016 MULTIMERIN2 binds VEGF-A primarily via carbohydrate chains on the protein; this interaction impairs VEGFR-2 phosphorylation at Y1175 and Y1214, halts SAPK2/p38 activation, reduces VEGFR-2 availability at the plasma membrane, and inhibits endothelial cell motility and tumor angiogenesis. Co-immunoprecipitation, VEGFR-2 phosphorylation assay, endothelial motility assay, in vivo tumor angiogenesis model, deletion mutant analysis Oncotarget Medium 26655500
2017 The structure of the full-length VEGFR-1 extracellular domain in complex with VEGF-A was determined at 4 Å resolution, revealing molecular details of ligand-induced receptor dimerization: homotypic receptor contacts in immunoglobulin homology domains 4, 5, and 7 are critical for dimerization and represent potential allosteric therapeutic sites. X-ray crystallography, single-particle electron microscopy, molecular modeling, functional ligand binding and receptor activation assays Structure High 28111021
2010 VEGF-A165b and VEGF-A121b isoforms (the VEGFxxxb subfamily) activate VEGFR-2 and ERK1/2 but to a lesser extent than VEGF-A165; they stimulate endothelial cell proliferation and promote angiogenesis in vivo in xenograft models, demonstrating these are weakly angiogenic rather than anti-angiogenic isoforms. Recombinant protein production, VEGFR-2 and ERK1/2 activation assays, endothelial proliferation assay, in vivo xenograft angiogenesis assay Molecular cancer Medium 21194429
2010 VEGF-A-induced vascular permeability and angiogenic signaling downstream of VEGFR-2 involves the phospholipase C-γ (PLC-γ) and Akt cascades for endothelial proliferation and survival; cell density modulates VEGFR-2 protein levels (2-fold higher in confluent cells) and reduces receptor affinity for VEGF, with PLC-γ and Akt transducing upstream receptor differences downstream. Combined biological experiments (VEGFR-2 quantification, PLC-γ and Akt activation), mathematical modeling, theoretical analysis Blood Medium 22510875
2010 VEGF-A protects neurons and cerebral vascular endothelial cells against hypoxic-ischemic injury through VEGFR-2/ERK-mediated phosphorylation of CREB (Ser-133); inhibiting VEGFR-2 before VEGF-A reduced its in vivo protective effect, and a CREB S133A phosphorylation mutant blocked VEGF-A's protection in both neuron and endothelial cell types. Rat pup HI model, oxygen-glucose deprivation in H19-7 neurons and b.End3 endothelial cells, VEGFR-2 and ERK inhibitors, CREB phosphorylation assay, CREB S133A mutant transfection Journal of neurochemistry High 20067582
2013 Progesterone receptor (PR)-expressing decidual stromal cells secrete VEGF-A which drives decidual angiogenesis via VEGFR-2 signaling; P4-PR-regulated VEGF-A-VEGFR2 signaling, ligand-independent VEGFR3 signaling, and uterine NK cells coordinately regulate vascular sinus folding enlargement. Mouse uterine pregnancy model, conditional Vegfa and receptor knockouts, immunostaining, morphometric vascular analysis EMBO molecular medicine Medium 23853117
2013 Insulin directly stimulates VEGF-A mRNA and protein production in podocytes via the insulin receptor (IR); podocyte-specific IR knockout mice show impaired VEGF-A production before any podocyte structural damage, establishing insulin-IR signaling as an upstream regulator of VEGF-A in glomerular podocytes. In vitro podocyte culture (human and murine), shRNA IR knockdown, podocyte-specific IR knockout mice, VEGF-A mRNA and protein quantification American journal of physiology. Renal physiology High 23698113
2016 Increased VEGF-A in the lens induces age-related cataracts through ERK hyperactivation, increased oxidative damage, and higher NLRP3 inflammasome effector IL-1β expression; RPE-specific VEGF-A elevation causes choroidal neovascularization dependent on Flk1 (VEGFR-2) in RPE. Targeting NLRP3 inflammasome components or Il1r1 strongly inhibits VEGF-A-induced pathologies, placing NLRP3/IL-1β as shared effectors. Genetic mouse model with increased VEGF-A, RPE-specific Flk1 inactivation, Nlrp3 and Il1r1 genetic inactivation, ERK activation assay, oxidative stress markers, histopathology EMBO molecular medicine High 26912740
2021 Endothelial insulin receptors (Insr) are required for VEGF-A signaling to ERK1/2 and for VEGFR-2 internalization (which is specifically required for ERK1/2 signaling); Insr haploinsufficiency impairs sprouting angiogenesis and VEGF-A functional responses while leaving VEGF-A signaling to Akt and eNOS intact. Insr+/- mice, endothelium-restricted Insr haploinsufficiency, hindlimb ischemia model, neonatal retinal angiogenesis, shRNA Insr knockdown in HUVECs, VEGFR-2 internalization assay, phospho-ERK1/2 and phospho-Akt western blots Endocrinology High 34037749
2018 EPA upregulates VEGF-A production in adipocytes via synchronized activation of membrane receptor GPR120 and nuclear receptor PPARγ; GPR120 co-activation enhances EPA-induced PPARγ binding to the PPAR-response element in the VEGF-A promoter region, as demonstrated by chromatin immunoprecipitation assay. siRNA silencing of GPR120, PPARγ inhibitor GW9662, transfection of GPR120 and PPARγ in HEK293 cells, luciferase reporter assay, promoter deletion analysis, chromatin immunoprecipitation Molecular and cellular endocrinology High 25697344
2018 Molecular dynamics and docking modeling combined with circular dichroism spectroscopy reveals that the VEGF-A heparin-binding domain (HBD) forms HBD-heparin-HBD sandwich-like structures; conformational flexibility of the 12-amino acid interdomain linker regulates the mutual disposition of HBDs and affects VEGF-mediated signaling through VEGF/receptor/heparin interactions. Molecular docking, molecular dynamics simulation, circular dichroism spectroscopy Journal of molecular graphics & modelling Low 29738889
2014 VEGF-A transcriptional programs in endothelial cells are controlled by RNA polymerase II pausing; transition into productive elongation (not merely initiation) is the major mechanism activating virtually all VEGF-A-regulated genes. Chromatin interaction mapping (TCC) reveals that VEGF-A-responsive loci reside in large chromatin compartments enriched for super-enhancers. Genome-wide GRO-Seq (global run-on sequencing), tethered conformation capture (TCC), chromatin interaction mapping in HUVECs Nucleic acids research Medium 25352550

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1989 Vascular endothelial growth factor is a secreted angiogenic mitogen. Science (New York, N.Y.) 4338 2479986
2013 Discovery and refinement of loci associated with lipid levels. Nature genetics 2409 24097068
2003 VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia. The Journal of cell biology 2167 12810700
1998 Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor. Cell 2043 9529250
1992 The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor. Science (New York, N.Y.) 1851 1312256
1989 Vascular permeability factor, an endothelial cell mitogen related to PDGF. Science (New York, N.Y.) 1770 2479987
1993 High affinity VEGF binding and developmental expression suggest Flk-1 as a major regulator of vasculogenesis and angiogenesis. Cell 1717 7681362
1991 The human gene for vascular endothelial growth factor. Multiple protein forms are encoded through alternative exon splicing. The Journal of biological chemistry 1630 1711045
2018 Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges. Nature reviews. Clinical oncology 1586 29508855
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2008 Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes. Nature genetics 1435 18372903
1992 Identification of the KDR tyrosine kinase as a receptor for vascular endothelial cell growth factor. Biochemical and biophysical research communications 1366 1417831
1994 Different signal transduction properties of KDR and Flt1, two receptors for vascular endothelial growth factor. The Journal of biological chemistry 1298 7929439
2006 Substrate and functional diversity of lysine acetylation revealed by a proteomics survey. Molecular cell 1260 16916647
1991 The vascular endothelial growth factor family: identification of a fourth molecular species and characterization of alternative splicing of RNA. Molecular endocrinology (Baltimore, Md.) 1189 1791831
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2002 Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis. Oncogene 1014 11960372
2013 VEGF targets the tumour cell. Nature reviews. Cancer 1004 24263190
2015 VEGF-A modulates expression of inhibitory checkpoints on CD8+ T cells in tumors. The Journal of experimental medicine 943 25601652
2004 VEGF-A stimulates lymphangiogenesis and hemangiogenesis in inflammatory neovascularization via macrophage recruitment. The Journal of clinical investigation 890 15057311
1992 Vascular permeability factor (vascular endothelial growth factor) gene is expressed differentially in normal tissues, macrophages, and tumors. Molecular biology of the cell 882 1550962
2008 The role of vascular endothelial growth factor in wound healing. The Journal of surgical research 861 19027922
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2014 Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility. Nature genetics 834 24509480
1993 Vascular permeability factor (VPF, VEGF) in tumor biology. Cancer metastasis reviews 785 8281615
2010 Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution. Nature genetics 754 20935629
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2003 VEGF is a modifier of amyotrophic lateral sclerosis in mice and humans and protects motoneurons against ischemic death. Nature genetics 698 12847526
2010 New loci associated with kidney function and chronic kidney disease. Nature genetics 681 20383146
2002 Insulin-like growth factor 1 induces hypoxia-inducible factor 1-mediated vascular endothelial growth factor expression, which is dependent on MAP kinase and phosphatidylinositol 3-kinase signaling in colon cancer cells. The Journal of biological chemistry 681 12149254
2012 Genome-wide association analyses identify 18 new loci associated with serum urate concentrations. Nature genetics 657 23263486
2012 Astrocyte-derived VEGF-A drives blood-brain barrier disruption in CNS inflammatory disease. The Journal of clinical investigation 569 22653056
2005 Processing of VEGF-A by matrix metalloproteinases regulates bioavailability and vascular patterning in tumors. The Journal of cell biology 554 15911882
2018 Molecular Pharmacology of VEGF-A Isoforms: Binding and Signalling at VEGFR2. International journal of molecular sciences 381 29690653
2012 VEGF-A recruits a proangiogenic MMP-9-delivering neutrophil subset that induces angiogenesis in transplanted hypoxic tissue. Blood 306 22966168
2008 VEGF-A links angiogenesis and inflammation in inflammatory bowel disease pathogenesis. Gastroenterology 287 19013462
2012 Diverse roles for VEGF-A in the nervous system. Development (Cambridge, England) 229 22434866
2003 Cortical and retinal defects caused by dosage-dependent reductions in VEGF-A paracrine signaling. Developmental biology 226 14550787
2000 Distinct requirements for zebrafish angiogenesis revealed by a VEGF-A morphant. Yeast (Chichester, England) 206 11119306
2020 VEGF-A in Cardiomyocytes and Heart Diseases. International journal of molecular sciences 171 32722551
2013 VEGF-A is necessary and sufficient for retinal neuroprotection in models of experimental glaucoma. The American journal of pathology 160 23416159
2010 Overexpression of VEGF-A in podocytes of adult mice causes glomerular disease. Kidney international 160 20375978
2004 The role of VEGF-A in glomerular development and function. Current opinion in nephrology and hypertension 157 15090854
2014 An antiangiogenic isoform of VEGF-A contributes to impaired vascularization in peripheral artery disease. Nature medicine 156 25362254
2013 VEGF-A regulated by progesterone governs uterine angiogenesis and vascular remodelling during pregnancy. EMBO molecular medicine 148 23853117
2021 Direct and Indirect Modulation of T Cells by VEGF-A Counteracted by Anti-Angiogenic Treatment. Frontiers in immunology 142 33854498
2009 Cross-talk between the VEGF-A and HGF signalling pathways in endothelial cells. Biology of the cell 139 19281453
2017 MicroRNA-140-5p inhibits invasion and angiogenesis through targeting VEGF-A in breast cancer. Cancer gene therapy 135 28752859
2014 Brown adipose tissue derived VEGF-A modulates cold tolerance and energy expenditure. Molecular metabolism 129 24944907
2000 VPF/VEGF and the angiogenic response. Seminars in perinatology 125 10709865
2009 Molecular diversity of VEGF-A as a regulator of its biological activity. Microcirculation (New York, N.Y. : 1994) 112 19521900
2006 Autocrine VEGF-A system in podocytes regulates podocin and its interaction with CD2AP. American journal of physiology. Renal physiology 102 16597608
2003 Temporal and spatial regulation of VEGF-A controls vascular patterning in the embryonic lung. Developmental biology 99 14651929
2006 Molecular mechanisms of VEGF-A action during tissue repair. The journal of investigative dermatology. Symposium proceedings 96 17069014
2018 Modified VEGF-A mRNA induces sustained multifaceted microvascular response and accelerates diabetic wound healing. Scientific reports 87 30504800
2017 Structure of the Full-length VEGFR-1 Extracellular Domain in Complex with VEGF-A. Structure (London, England : 1993) 86 28111021
2015 Induction of Vasculogenic Mimicry Overrides VEGF-A Silencing and Enriches Stem-like Cancer Cells in Melanoma. Cancer research 77 25769726
2007 Newly identified biologically active and proteolysis-resistant VEGF-A isoform VEGF111 is induced by genotoxic agents. The Journal of cell biology 74 18086921
2021 Exploring the Intracrine Functions of VEGF-A. Biomolecules 70 33478167
2014 Regulation of alternative VEGF-A mRNA splicing is a therapeutic target for analgesia. Neurobiology of disease 70 25151644
2019 miR-126-3p down-regulation contributes to dabrafenib acquired resistance in melanoma by up-regulating ADAM9 and VEGF-A. Journal of experimental & clinical cancer research : CR 68 31227006
2017 WISP-1 positively regulates angiogenesis by controlling VEGF-A expression in human osteosarcoma. Cell death & disease 68 28406476
2018 Clostridium difficile toxins induce VEGF-A and vascular permeability to promote disease pathogenesis. Nature microbiology 66 30510170
2013 Antagonism of PDGF-BB suppresses subretinal neovascularization and enhances the effects of blocking VEGF-A. Angiogenesis 65 24154861
2012 Identification of ZNF217, hnRNP-K, VEGF-A and IPO7 as targets for microRNAs that are downregulated in prostate carcinoma. International journal of cancer 65 22815235
2015 Nanoparticle Delivered VEGF-A siRNA Enhances Photodynamic Therapy for Head and Neck Cancer Treatment. Molecular therapy : the journal of the American Society of Gene Therapy 64 26373346
2003 Adenovirus-mediated VEGF-A gene transfer induces bone formation in vivo. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 64 12692089
2015 Eicosapentaenoic acid upregulates VEGF-A through both GPR120 and PPARγ mediated pathways in 3T3-L1 adipocytes. Molecular and cellular endocrinology 60 25697344
2010 Targeting NF-κB in infantile hemangioma-derived stem cells reduces VEGF-A expression. Angiogenesis 59 20872175
2010 VEGF₁₂₁b and VEGF₁₆₅b are weakly angiogenic isoforms of VEGF-A. Molecular cancer 58 21194429
2009 Regulation of VEGF-A in uveal melanoma. Investigative ophthalmology & visual science 58 20042655
2019 VEGF-A and blood vessels: a beta cell perspective. Diabetologia 57 31414144
2022 How VEGF-A and its splice variants affect breast cancer development - clinical implications. Cellular oncology (Dordrecht, Netherlands) 56 35303290
2007 Inhibition of VEGF-A prevents the angiogenic switch and results in increased survival of Apc+/min mice. Proceedings of the National Academy of Sciences of the United States of America 56 17553957
2005 Gene targeting of VEGF-A in thymus epithelium disrupts thymus blood vessel architecture. Proceedings of the National Academy of Sciences of the United States of America 56 16027358
2002 Akt signaling mediates VEGF/VPF vascular permeability in vivo. FEBS letters 55 12459464
2013 Insulin directly stimulates VEGF-A production in the glomerular podocyte. American journal of physiology. Renal physiology 53 23698113
2013 The effects of VEGF-A on atherosclerosis, lipoprotein profile, and lipoprotein lipase in hyperlipidaemic mouse models. Cardiovascular research 53 23756254
2019 MiR-126 Modulates Angiogenesis in Breast Cancer by Targeting VEGF-A -mRNA. Asian Pacific journal of cancer prevention : APJCP 52 30678431
2001 Distinct regulation of genes by bFGF and VEGF-A in endothelial cells. Angiogenesis 51 12197476
2016 VEGF-A isoforms program differential VEGFR2 signal transduction, trafficking and proteolysis. Biology open 48 27044325
2016 Expressions of VEGF-A and VEGFR-2 in placentae from GDM pregnancies. Reproductive biology and endocrinology : RB&E 48 27645229
2022 Efficient delivery of VEGF-A mRNA for promoting diabetic wound healing via ionizable lipid nanoparticles. International journal of pharmaceutics 47 36586634
2014 hERG1 channels regulate VEGF-A secretion in human gastric cancer: clinicopathological correlations and therapeutical implications. Clinical cancer research : an official journal of the American Association for Cancer Research 46 24449824
2016 Increased VEGF-A promotes multiple distinct aging diseases of the eye through shared pathomechanisms. EMBO molecular medicine 43 26912740
2012 Endothelins reciprocally regulate VEGF-A and angiopoietin-1 production in cultured rat astrocytes: implications on astrocytic proliferation. Glia 43 22927341
2004 Regulation of the endogenous VEGF-A gene by exogenous designed regulatory proteins. Proceedings of the National Academy of Sciences of the United States of America 43 15475575
2021 VEGFR-2 redirected CAR-T cells are functionally impaired by soluble VEGF-A competition for receptor binding. Journal for immunotherapy of cancer 42 34389616
2016 Decrease of VEGF-A in myeloid cells attenuates glioma progression and prolongs survival in an experimental glioma model. Neuro-oncology 42 26951383
2010 Role of VEGF-A in pancreatic beta cells. Endocrine journal 42 20179357
2004 VEGF-A angiogenesis induces a stable neovasculature in adult murine brain. Journal of neuropathology and experimental neurology 41 15330339
2018 Biomarker potential of IL-6 and VEGF-A in ascitic fluid of epithelial ovarian cancer patients. Clinica chimica acta; international journal of clinical chemistry 40 29572186
2014 Control of VEGF-A transcriptional programs by pausing and genomic compartmentalization. Nucleic acids research 40 25352550
2013 Pharmacologically active microcarriers influence VEGF-A effects on mesenchymal stem cell survival. Journal of cellular and molecular medicine 40 23305078
2013 Cooperative effects of FGF-2 and VEGF-A in periodontal ligament cells. Journal of dental research 40 24186558
2020 miR-503-5p inhibits colon cancer tumorigenesis, angiogenesis, and lymphangiogenesis by directly downregulating VEGF-A. Gene therapy 39 32533103
2012 PEDF and VEGF-A output from human retinal pigment epithelial cells grown on novel microcarriers. Journal of biomedicine & biotechnology 39 22547925
2012 Mechanism of selective VEGF-A binding by neuropilin-1 reveals a basis for specific ligand inhibition. PloS one 39 23145112
2022 Human organ rejuvenation by VEGF-A: Lessons from the skin. Science advances 38 35749494
2020 LPS-mediated neutrophil VEGF-A release is modulated by cannabinoid receptor activation. Journal of leukocyte biology 38 32573828
2008 Reduced insulin secretion and content in VEGF-a deficient mouse pancreatic islets. Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association 34 18777454
2025 Extracellular vesicle-mediated VEGF-A mRNA delivery rescues ischaemic injury with low immunogenicity. European heart journal 33 39831819
2013 VEGF-A isoform modulation in an preclinical TNBS model of ulcerative colitis: protective effects of a VEGF164b therapy. Journal of translational medicine 33 24020796
2011 Aldosterone increases VEGF-A production in human neutrophils through PI3K, ERK1/2 and p38 pathways. Biochimica et biophysica acta 33 21803079
2015 Adiponectin inhibits VEGF-A in prostate cancer cells. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 32 25586350
2015 Clinical significance of hypoxia-inducible factor 1 and VEGF-A in osteosarcoma. International journal of clinical oncology 32 26077139
2013 The impact of KRAS mutations on VEGF-A production and tumour vascular network. BMC cancer 31 23506169
2010 CREB activation mediates VEGF-A's protection of neurons and cerebral vascular endothelial cells. Journal of neurochemistry 31 20067582
2002 Spatial expression of VEGF-A in human glioma. Journal of neuro-oncology 31 12222833
2015 Inhibition of ocular neovascularization by co-inhibition of VEGF-A and PLGF. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 30 25832861
2024 Dual-layer conduit containing VEGF-A - Transfected Schwann cells promotes peripheral nerve regeneration via angiogenesis. Acta biomaterialia 29 38561075
2016 Inhibition of fatty acid synthase suppresses neovascularization via regulating the expression of VEGF-A in glioma. Journal of cancer research and clinical oncology 29 27601165
2011 Blockade of VEGF-A suppresses tumor growth via inhibition of autocrine signaling through FAK and AKT. Cancer letters 29 22182449
2021 CXCL1 stimulates decidual angiogenesis via the VEGF-A pathway during the first trimester of pregnancy. Molecular and cellular biochemistry 28 33770315
2021 Endothelial Insulin Receptors Promote VEGF-A Signaling via ERK1/2 and Sprouting Angiogenesis. Endocrinology 28 34037749
2016 MULTIMERIN2 binds VEGF-A primarily via the carbohydrate chains exerting an angiostatic function and impairing tumor growth. Oncotarget 28 26655500
2013 Hedgehog inhibition reduces angiogenesis by downregulation of tumoral VEGF-A expression in hepatocellular carcinoma. United European gastroenterology journal 28 24917971
2024 Extracellular vesicles derived from dendritic cells loaded with VEGF-A siRNA and doxorubicin reduce glioma angiogenesis in vitro. Journal of controlled release : official journal of the Controlled Release Society 27 38522817
2024 Emerging clinical evidence of a dual role for Ang-2 and VEGF-A blockade with faricimab in retinal diseases. Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie 27 39708087
2018 Molecular dynamics-based model of VEGF-A and its heparin interactions. Journal of molecular graphics & modelling 27 29738889
2020 Osteocyte Vegf-a contributes to myeloma-associated angiogenesis and is regulated by Fgf23. Scientific reports 26 33057033
2021 Substrate stiffening promotes VEGF-A functions via the PI3K/Akt/mTOR pathway. Biochemical and biophysical research communications 25 34823219
2020 Cigarette smoking induces human CCR6+Th17 lymphocytes senescence and VEGF-A secretion. Scientific reports 25 32300208
2015 Hypoxia-activated chemotherapeutic TH-302 enhances the effects of VEGF-A inhibition and radiation on sarcomas. British journal of cancer 25 26010414
2012 Unraveling the influence of endothelial cell density on VEGF-A signaling. Blood 25 22510875
2018 Effects of chronically increased VEGF-A on the aging heart. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 24 29146733
2004 Role of Ang1 and its interaction with VEGF-A in astrocytomas. Journal of neuropathology and experimental neurology 24 15453096
2023 A Phase I Trial of VEGF-A Inhibition Combined with PD-L1 Blockade for Recurrent Glioblastoma. Cancer research communications 23 36968223