Affinage

VEGFA

Vascular endothelial growth factor A, long form · UniProt P15692

Length
395 aa
Mass
43.6 kDa
Annotated
2026-06-11
100 papers in source corpus 30 papers cited in narrative 30 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

VEGF-A is a secreted, disulfide-bonded dimeric heparin-binding glycoprotein that signals through two high-affinity endothelial tyrosine kinase receptors (VEGFR-1/Flt-1 and VEGFR-2) to drive angiogenesis, vascular permeability, lymphangiogenesis, and tissue-specific vascular maintenance (PMID:8281615, PMID:16027358, PMID:23081980). Receptor engagement activates parallel downstream cascades whose outputs are non-equivalent: VEGFR-2-coupled PLCγ/ERK1/2 signaling transduces graded VEGF-A concentration information, whereas the Akt arm operates as a concentration-independent switch that is both necessary and sufficient for vascular permeability through eNOS (PMID:12459464, PMID:20144626). Efficient ERK1/2 activation requires VEGFR-2 internalization, which itself depends on the endothelial insulin receptor, while signaling to Akt/eNOS proceeds independently (PMID:34037749). Beyond endothelium, VEGF-A drives mural-cell recruitment by inducing endothelial PDGF-B (PMID:16105884), promotes chemotaxis of mesenchymal progenitors via VEGFR-1 (PMID:16005848), remodels the venular basement membrane by upregulating ADAMTS-1 and MMP-15 (PMID:21411713), and supports autocrine podocyte survival via VEGFR-2-driven PI3K/AKT with suppression of p38MAPK (PMID:19828679). VEGF-A also executes non-angiogenic programs: it sensitizes nociceptors through a VEGFR-2/TRPV1 mechanism (PMID:25151644), promotes CD8+ T-cell exhaustion by upregulating PD-1 and Tim-3 (PMID:25601652), and recruits immune cells to tuberculous granulomas from a myeloid source (PMID:31091450). Its output is shaped extensively by alternative splicing—exon 5–7 selection tunes heparin/HSPG and Neuropilin-1 binding and bioavailability, while exon 8 3′-splice-site choice generates VEGFxxxb isoforms—and distinct isoforms drive distinct VEGFR-2 endocytosis, ubiquitylation, and signaling (PMID:27044325, PMID:29690653, PMID:25151644). Transcription is governed by HIF-1α (under hypoxia and non-hypoxically via integrin signaling), NF-κB-to-HIF-1α cascades, the UPR sensors IRE1α-XBP-1/PERK-ATF4/ATF6α, and Pol II pausing-to-elongation control (PMID:20432243, PMID:20221394, PMID:15458440, PMID:25352550), while translation is silenced post-transcriptionally by the IFN-γ-induced GAIT complex binding the 3′UTR (PMID:17611605). Extracellular bioavailability is further set by plasmin cleavage at Arg110/Ala111, soluble VEGFR-1 sequestration, and SULF2-mediated heparan sulfate modification that releases matrix-bound ligand (PMID:17069014, PMID:30698737).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1993 High

    Established VEGF-A as a secreted dimeric heparin-binding glycoprotein that acts directly on endothelial cells through two high-affinity tyrosine kinase receptors, defining the basic receptor-ligand axis.

    Evidence Receptor binding and functional in vitro assays (PLC activation, calcium transients), biochemical characterization

    PMID:8281615

    Open questions at the time
    • Did not resolve which receptor mediates which downstream output
    • No isoform-specific signaling distinguished
  2. 2002 High

    Showed that the Akt arm is both necessary and sufficient for VEGF-A-induced vascular permeability and acts through eNOS, separating permeability control from other VEGF outputs.

    Evidence Adenoviral dominant-negative/constitutively active Akt in vivo Miles assay with eNOS inhibitor blockade

    PMID:12459464

    Open questions at the time
    • Did not address how Akt is selectively activated downstream of which receptor
    • Relationship to ERK1/2 arm not defined
  3. 2004 Medium

    Demonstrated non-hypoxic transcriptional control of VEGF-A by laminin/α3β1 integrin signaling acting through HIF-α in podocytes, expanding HIF regulation beyond oxygen sensing.

    Evidence VEGF-A promoter-luciferase reporter, HIF-α/p300 co-IP, matrix stimulation in podocytes

    PMID:15458440

    Open questions at the time
    • PKC intermediary only a candidate
    • Mechanism of non-hypoxic HIF-α stabilization not resolved
  4. 2005 High

    Defined cell-type-specific developmental and pathological angiogenic roles for VEGF-A: TEC-derived VEGF-A for thymus vascular morphogenesis, mural-cell recruitment via induced PDGF-B, VEGFR-1-mediated progenitor chemotaxis, and tumor-driven sentinel-node lymphangiogenesis.

    Evidence Conditional gene targeting, Matrigel plug and neutralizing antibody epistasis, Boyden chamber chemotaxis, VEGF-A transgenic mice with lymphatic IHC

    PMID:15809353 PMID:16005848 PMID:16027358 PMID:16105884

    Open questions at the time
    • Receptor selectivity for lymphangiogenesis vs angiogenesis only partly resolved
    • Crosstalk between PDGF-B and direct VEGF effects not fully separated
  5. 2006 Medium

    Identified extracellular regulation of VEGF-A activity by plasmin cleavage at Arg110/Ala111 and soluble VEGFR-1 sequestration, establishing post-secretion control of angiogenic potency.

    Evidence Protease cleavage assay, site-directed mutagenesis, impaired-healing mouse model, sVEGFR-1 ELISA

    PMID:17069014

    Open questions at the time
    • In vivo contribution of cleavage vs sVEGFR-1 not quantitatively partitioned
    • Other proteases not excluded
  6. 2007 High

    Revealed post-transcriptional silencing of VEGF-A translation by the IFN-γ-induced GAIT complex binding its 3′UTR, decoupling mRNA induction from protein output.

    Evidence RNA-protein interaction (EMSA/pulldown), translation reporter and angiogenesis functional assays

    PMID:17611605

    Open questions at the time
    • GAIT regulation shown in monocytes; generality across cell types not established
    • Kinetics of silencing onset not fully defined
  7. 2009 Medium

    Mapped non-angiogenic and cooperative signaling roles: autocrine podocyte survival via VEGFR-2/PI3K-AKT/p38, VEGF-A/HGF synergy via independent receptors with distinct Rho vs Rac remodeling, and VEGF-A/VEGFR-2 as the obligate driver of infection-induced corneal lymphangiogenesis.

    Evidence siRNA and pharmacological inhibition with signaling readouts, co-IP (negative for receptor association), Rho/Rac assays, VEGF-A reporter mice and receptor blockade in corneal infection

    PMID:19281453 PMID:19828679 PMID:20026662

    Open questions at the time
    • VEGF-A vs VEGF-C redundancy in podocytes not fully separated
    • Synergy mechanism limited to MAPK readouts
  8. 2010 High

    Resolved upstream transcriptional logic (NF-κB→HIF-1α, three parallel UPR arms) and demonstrated that VEGFR-2 PLCγ/ERK1/2 encodes graded ligand concentration whereas Akt does not.

    Evidence Transcription factor inhibitor epistasis, Ire1α/Perk knockout MEFs and ATF6α knockdown with rescue, quantitative dose-response/time-course VEGFR-2 signaling assays

    PMID:20144626 PMID:20221394 PMID:20432243

    Open questions at the time
    • How concentration is decoded into distinct gene programs unresolved
    • Integration of multiple UPR arms not quantified
  9. 2011 Medium

    Showed VEGF-A drives basement-membrane remodeling during mother vessel formation by inducing endothelial ADAMTS-1 and its activator MMP-15 to degrade versican.

    Evidence IHC, Western blot, in vivo adenoviral VEGF-A164 and in vitro endothelial stimulation

    PMID:21411713

    Open questions at the time
    • Direct functional requirement of versican cleavage for vessel formation not tested
    • Single lab
  10. 2014 High

    Established that VEGF-A-induced endothelial transcription is controlled by RNA Pol II pausing and transition to productive elongation across most regulated genes.

    Evidence Genome-wide GRO-Seq and tethered conformation capture in primary HAECs/HUVECs

    PMID:25352550

    Open questions at the time
    • Pause-release factors recruited by VEGF signaling not identified
    • Link to specific upstream kinase arms unmapped
  11. 2015 Medium

    Extended VEGF-A function to immune suppression (CD8+ T-cell exhaustion via PD-1/Tim-3), nociceptor sensitization (VEGFR-2/TRPV1 with SRPK1-controlled isoform balance), and added ID1 as a TGF-β1→VEGF-A transcriptional intermediary.

    Evidence In vivo tumor models with checkpoint flow cytometry, pain behavioral assays with VEGFR2/TRPV1/SRPK1 manipulation, ID1 siRNA epistasis

    PMID:25151644 PMID:25601652 PMID:26577912

    Open questions at the time
    • Direct vs indirect VEGF-A action on T cells not fully resolved
    • Tissue specificity of ID1 pathway unknown
  12. 2016 Medium

    Demonstrated isoform-specific control of VEGFR-2 endocytosis, ubiquitylation, and signaling, with clathrin-dependent internalization required for isoform-selective receptor activation.

    Evidence Clathrin disruption, receptor internalization and ubiquitylation assays, isoform comparison

    PMID:27044325

    Open questions at the time
    • Structural basis of differential trafficking not defined
    • Downstream transcriptional consequences not mapped
  13. 2018 Medium

    Consolidated the splicing-to-function logic: exon 5–7 selection tunes heparin/HSPG and Neuropilin-1 binding and bioavailability, exon 8 generates VEGFxxxb isoforms, and HBD-heparin-HBD architecture modulates signaling.

    Evidence Review of receptor binding and signaling data; molecular dynamics and circular dichroism of the heparin-binding domain

    PMID:29690653 PMID:29738889

    Open questions at the time
    • HBD conformational model rests on computation with limited experimental validation
    • Functional mutagenesis of HBD disposition lacking
  14. 2019 High

    Identified upstream bioavailability and inflammatory controls: TRF2-driven SULF2 transcription releases matrix-bound VEGF-A, and myeloid-derived VEGF-A recruits immune cells to tuberculous granulomas non-angiogenically.

    Evidence ChIP and SULF2 epistasis with secretome profiling; myeloid-specific VEGF-A knockout, granuloma transplantation, and pharmacological inhibition in Mtb/BCG infection

    PMID:30698737 PMID:31091450

    Open questions at the time
    • Whether HS remodeling generalizes beyond endothelial differentiation untested
    • Immune-cell types recruited and receptor used in granulomas not fully defined
  15. 2020 Medium

    Defined a niche signaling circuit in which myeloma-induced osteocyte FGF23 upregulates osteocyte VEGF-A to drive endothelial tube formation.

    Evidence Vegf-a siRNA and neutralization, co-culture tube formation, Fgf23 deletion, in vivo myeloma model

    PMID:33057033

    Open questions at the time
    • Receptor mediating FGF23→VEGF-A in osteocytes not identified
    • Generality beyond myeloma niche unknown
  16. 2021 High

    Demonstrated that endothelial insulin receptor is required for VEGFR-2 internalization and ERK1/2 signaling selectively, while Akt/eNOS signaling remains intact, linking metabolic receptor status to angiogenic signal routing; intracrine VEGF-A signaling was also proposed.

    Evidence Whole-body and endothelium-restricted Insr haploinsufficient mice plus HUVEC shRNA with signaling and internalization readouts; review synthesis for intracrine mode

    PMID:33478167 PMID:34037749

    Open questions at the time
    • Molecular mechanism linking insulin receptor to VEGFR-2 endocytosis unresolved
    • Intracrine model rests on review-level synthesis without primary mechanistic experiments here

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple parallel transcriptional inputs, splicing decisions, receptor trafficking states, and extracellular bioavailability controls are integrated to produce a specific VEGF-A signaling output in a given cell remains unresolved.
  • No unified model linking isoform identity to trafficking to transcriptional program
  • Quantitative contribution of each bioavailability control in vivo unknown
  • Intracrine signaling not mechanistically established in primary data

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:0031012 extracellular matrix 2
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-162582 Signal Transduction 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-168256 Immune System 2 R-HSA-8953854 Metabolism of RNA 2
Partners
FLT1FLT4KDRNRP1

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 VEGF-A (VPF/VEGF) acts directly on endothelial cells via two high-affinity tyrosine kinase receptors to activate phospholipase C and induce intracellular calcium transients; it is secreted as a 34–42 kDa heparin-binding, dimeric, disulfide-bonded glycoprotein. Receptor binding assays, functional in vitro assays (phospholipase C activation, calcium transients), biochemical characterization Cancer metastasis reviews High 8281615
2002 Akt signaling is both necessary and sufficient for VEGF-A-induced vascular permeability in vivo; dominant-negative Akt blocks VEGF-induced permeability, and constitutively active Akt mimics it; this Akt-mediated permeability requires eNOS activity. Adenovirus-mediated gene transfer of dominant-negative and constitutively active Akt in vivo (Miles assay), eNOS inhibitor (L-NAME) blockade FEBS letters High 12459464
2005 VEGF-A enhances endothelial PDGF-B expression; combined with FGF-2 (which enhances mural PDGFRβ expression), this directs endogenous PDGF-B–PDGFRβ signaling to recruit mural cells and form functional neovasculature; abrogation by anti-PDGFRβ antibody confirmed this mechanism. In vitro VEGFR2+ ESC-derived cell stimulation assays, Matrigel plug assay in vivo, neutralizing antibody blockade Journal of cell science Medium 16105884
2005 VEGF-A stimulates chemotactic migration of human mesenchymal progenitor cells via VEGFR-1 (Flt-1); VEGFR-1 and VEGFR-2 are activated upon ligand stimulation in these cells, and the effect is mediated by VEGFR-1 since PlGF-1 (a VEGFR-1-selective ligand) but not VEGF-E or VEGF-C produced the same effect. In vitro kinase assay, Boyden chamber chemotaxis assay, quantitative RT-PCR for receptor expression Biochemical and biophysical research communications Medium 16005848
2005 VEGF-A overexpression in primary tumors induces lymphangiogenesis in sentinel lymph nodes even before metastasis occurs; VEGF-A acts on VEGFR-2-expressing lymphatic vessels to drive both tumor-associated and sentinel lymph node lymphangiogenesis. VEGF-A skin-specific transgenic mice, chemically induced carcinogenesis, immunohistochemistry for lymphatic markers The Journal of experimental medicine High 15809353
2005 VEGF-A gene targeting in thymus epithelial cells (cortical and medullary TECs) disrupts the organ-typical thymus vascular architecture, causing hypovascularization, demonstrating that TEC-derived VEGF-A is required for normal thymus vascular morphogenesis. Conditional gene targeting via nude mouse blastocyst complementation, histological analysis of vascular architecture Proceedings of the National Academy of Sciences of the United States of America High 16027358
2006 VEGF165 protein is cleaved by plasmin at Arg110/Ala111 in the wound microenvironment, reducing its mitogenic activity; mutagenesis of this cleavage site preserves structural integrity and increases angiogenic potency in an impaired healing mouse model. Additionally, soluble VEGFR-1 (sVEGFR-1) acts as an endogenous inhibitor of VEGF-A in non-healing wounds. Protease cleavage assay, site-directed mutagenesis, in vivo impaired healing mouse model, ELISA for sVEGFR-1 The journal of investigative dermatology. Symposium proceedings Medium 17069014
2007 IFN-γ suppresses monocyte VEGF-A translation via the GAIT (IFN-γ-activated inhibitor of translation) complex, which binds a specific element in the VEGF-A 3′UTR; although IFN-γ induces VEGF-A mRNA, the GAIT complex delays and silences translation, reducing VEGF-A protein and angiogenic activity. mRNA-protein interaction studies (EMSA/RNA pulldown), translation reporter assays, angiogenesis functional assays The EMBO journal High 17611605
2009 HSV-1-induced corneal lymphangiogenesis is strictly dependent on VEGF-A/VEGFR-2 signaling (not VEGFR-3 ligands); infected epithelial cells (not macrophages) are the primary source of VEGF-A during infection, as identified using VEGF-A reporter transgenic mice. VEGF-A reporter transgenic mice, VEGFR-2 and VEGFR-3 blocking studies, macrophage depletion, in vivo corneal infection model The Journal of experimental medicine High 20026662
2009 VEGF-A and HGF cooperate in endothelial angiogenesis by synergistically activating ERK1/2 and p38 kinases downstream of their respective receptors (VEGFR-2 and c-Met), which do not physically associate or transphosphorylate each other; VEGF-A activates Rho-dependent cytoskeletal remodeling while HGF activates Rac-dependent remodeling. Co-immunoprecipitation (negative for receptor association), MAPK activation kinetics assays, Rho/Rac GTPase activity assays, in vitro tube formation Biology of the cell Medium 19281453
2009 Autocrine VEGF-A and VEGF-C in human podocytes both activate anti-apoptotic PI3K/AKT and suppress pro-apoptotic p38MAPK via VEGFR-2; ablation of VEGF-A or VEGF-C, or treatment with bevacizumab or VEGFR-2/-3 inhibitors, reduces podocyte survival. Exogenous VEGF-C can substitute for VEGF-A and vice versa in maintaining survival signaling. siRNA knockdown, bevacizumab treatment, VEGFR-2/-3 tyrosine kinase inhibition, Western blot for PI3K/AKT and p38MAPK activation, viability assays American journal of physiology. Renal physiology Medium 19828679
2010 VEGF-A expression in osteoclasts is regulated by HIF-1α, which itself is induced downstream of NF-κB activation by RANKL; NF-κB inhibition suppresses HIF-1α mRNA, and HIF-1α inhibition decreases VEGF-A mRNA, placing NF-κB upstream of HIF-1α upstream of VEGF-A in osteoclast signaling. Specific transcription factor inhibitors (NF-κB, AP-1, NFATc1, HIF-1), RT-PCR, conditioned media VEGF-A secretion assay Journal of cellular biochemistry Medium 20432243
2010 IRE1α, PERK, and ATF6α of the unfolded protein response (UPR) each regulate VEGF-A mRNA transcription via their respective downstream transcription factors (spliced XBP-1, ATF4, and cleaved ATF6); loss of these UPR components in mouse embryonic fibroblasts or ATF6α-knockdown cells attenuates VEGF-A induction under ER stress. Genetic knockouts (Ire1α−/−, Perk−/− MEFs), siRNA knockdown (ATF6α), rescue experiments, qRT-PCR PloS one High 20221394
2010 VEGF-A-induced signaling through VEGFR-2 is concentration- and duration-dependent: PLCγ/ERK1/2 (p44/p42 MAPK) pathway transduces graded VEGF-A concentration information, whereas the parallel AKT pathway does not; longer exposure duration does not compensate for low VEGF-A concentration, indicating these parameters are not equivalent. Quantitative VEGFR2 autophosphorylation assays, signal kinase activation assays at graded VEGF-A concentrations, immediate-early gene induction analysis Microvascular research Medium 20144626
2011 VEGF-A induces degradation of versican in venular basement membranes during mother vessel formation by upregulating ADAMTS-1 (a versican-cleaving protease) and MMP-15 (which activates ADAMTS-1) in endothelial cells. Immunohistochemistry, Western blot, in vivo adenoviral VEGF-A(164) expression model, in vitro VEGF-A endothelial cell stimulation The journal of histochemistry and cytochemistry Medium 21411713
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 can be reverted by anti-angiogenic agents targeting VEGF-A/VEGFR. In vivo tumor models, flow cytometry for inhibitory receptor expression, anti-VEGF-A/VEGFR treatment reversal experiments The Journal of experimental medicine Medium 25601652
2015 TGF-β1 regulates peritoneal VEGF-A expression through an ID1-dependent pathway in mesothelial cells; siRNA knockdown of ID1 abolishes TGF-β1-induced VEGF-A upregulation, placing ID1 as an intermediary between TGF-β1 and VEGF-A transcription. siRNA knockdown of ID1, qRT-PCR and ELISA for VEGF-A, TGF-β1 stimulation of primary peritoneal and immortalized mesothelial cells Scientific reports Medium 26577912
2015 VEGF-A165a sensitizes peripheral nociceptive neurons through VEGFR-2 and a TRPV1-dependent mechanism to enhance pain signaling; VEGF-A165b blocks this effect. After nerve injury, SRPK1-dependent pre-mRNA splicing shifts the isoform balance toward VEGF-Axxxa over VEGF-Axxxb, promoting neuropathic pain. Pharmacological inhibition of SRPK1 reverses this shift and alleviates pain. In vivo pain behavioral assays in rats and mice, VEGFR2 and TRPV1 pharmacological blockade, SRPK1 inhibition, exogenous VEGF-A165b treatment Neurobiology of disease Medium 25151644
2016 Different VEGF-A isoforms (VEGF-A165, VEGF-A121, VEGF-A145) promote distinct patterns of VEGFR-2 endocytosis, differential ubiquitylation, and differential signal transduction; disruption of clathrin-dependent endocytosis blocks isoform-specific VEGFR-2 activation and causes depletion of membrane-bound VEGFR1 and VEGFR2. Clathrin endocytosis disruption, receptor internalization assays, Western blot for ubiquitylation and signaling, receptor proteolysis assays Biology open Medium 27044325
2018 VEGF-A isoforms bind VEGFR2 with similar affinities but differ in interactions with co-receptor Neuropilin-1 and heparan sulfate proteoglycans (HSPGs); alternative splicing at exons 5–7 controls heparin-binding and bioavailability, while alternative 3′ splice-site selection at exon 8 generates VEGFxxxb isoforms with distinct downstream signaling. Receptor binding assays, downstream signaling analysis, VEGF-A isoform pharmacological comparison (review synthesizing experimental data) International journal of molecular sciences Medium 29690653
2018 Molecular dynamics and circular dichroism modeling reveals that the VEGF-A heparin-binding domain (HBD) forms sandwich-like HBD-heparin-HBD structures that regulate the mutual disposition of HBDs and affect VEGF-A-mediated signaling; conformational flexibility of the 12-amino acid interdomain linker contributes to this regulation. Molecular docking, molecular dynamics simulation, circular dichroism spectroscopy Journal of molecular graphics & modelling Low 29738889
2019 TRF2 promotes VEGF-A secretion and angiogenesis by transcriptionally upregulating SULF2 (an endoglucosamine-6-sulfatase) via binding to a distal regulatory element; SULF2 then modifies heparan sulfate proteoglycans to release membrane-associated VEGF-A, increasing its availability. Luminex multiplexed secretome profiling, TRF2 overexpression/knockdown, ChIP for TRF2 binding, SULF2 knockdown epistasis, endothelial differentiation assay Nucleic acids research Medium 30698737
2019 Granuloma macrophages produce VEGF-A that recruits immune cells to granulomas via a non-angiogenic pathway; selective VEGF-A blockade in myeloid cells or pharmaceutical inhibition reduces granulomatous inflammation and improves survival in Mycobacterium tuberculosis-infected mice without altering host protection. Conditional myeloid-specific VEGF-A knockout, granuloma transplantation, pharmaceutical VEGF-A inhibition, in vivo Mtb and BCG infection models Cell reports High 31091450
2021 Endothelial insulin receptors are required for appropriate VEGF-A signal transduction from VEGFR-2 to ERK1/2; insulin receptor haploinsufficiency impairs VEGFR-2 internalization (required for ERK1/2 signaling) and abolishes VEGF-A-induced ERK1/2 activation, while VEGF-A signaling to Akt and eNOS remains intact. Whole-body and endothelium-restricted insulin receptor haploinsufficient mice, shRNA-mediated Insr knockdown in HUVECs, Western blot for ERK1/2 and Akt, VEGFR-2 internalization assays, in vitro and in vivo angiogenesis assays Endocrinology High 34037749
2004 Laminin and α3β1 integrin signaling regulates constitutive VEGF-A expression in podocytes via a non-hypoxic HIF-α-dependent mechanism; classical PKC is a potential intermediary; HIF-α activity in podocytes is increased independently of hypoxia and drives VEGF-A promoter activity. VEGF-A promoter-luciferase reporter assay, quantitative RT-PCR, ELISA, immunoprecipitation for HIF-α/p300 association, extracellular matrix stimulation Kidney international Medium 15458440
2014 VEGF-A-regulated gene transcription in endothelial cells is controlled at two levels: RNA polymerase II pausing at promoters and productive elongation; approximately half of VEGF-A-regulated promoters show paused Pol II, and transition to productive elongation is a major activation mechanism for virtually all VEGF-regulated genes. Genome-wide GRO-Seq (global run-on sequencing), tethered conformation capture (TCC) chromatin interaction mapping in primary HAECs and HUVECs Nucleic acids research High 25352550
2015 WISP-1 promotes VEGF-A expression in osteosarcoma cells and angiogenesis through activation of the FAK/JNK/HIF-1α signaling pathway and down-regulation of miR-381; inhibitors of FAK, JNK, or HIF-1α, or HIF-1α siRNA, abolish WISP-1-induced VEGF-A expression. Pathway inhibitors (FAK, JNK, HIF-1α), siRNA knockdown, in vitro EPC migration/tube formation, in vivo tumor xenograft, immunohistochemistry Cell death & disease Medium 28406476
2021 VEGF-A can signal intracellularly (intracrine signaling) within cells expressing both VEGF-A and its receptors, regulating cell growth, survival, and metabolism independently of secretion; this intracrine mode involves VEGFR1 and VEGFR2 expressed intracellularly. Review synthesizing loss-of-function and localization experiments from multiple studies demonstrating intracellular VEGF-A/receptor complexes Biomolecules Low 33478167
2012 VEGF-A expressed by pigmented ciliary epithelium maintains ciliary body homeostasis; systemic VEGF-A neutralization (via adenoviral sFlt1 overexpression) causes thinning of nonpigmented epithelium, vacuolization of pigmented epithelium, loss of capillary fenestrations, thrombosis, and decreased intraocular pressure, indicating a required role in ciliary body vascular and epithelial maintenance. VEGF-A neutralization via adenoviral sFlt1, VEGF-LacZ reporter mice, VEGFR2 localization by immunostaining, light microscopy and TEM, intraocular pressure measurement Investigative ophthalmology & visual science High 23081980
2020 In multiple myeloma, FGF23 produced by osteocytes in response to direct contact with myeloma cells upregulates VEGF-A expression in osteocytes; VEGF-A knockdown in osteocytes or VEGF-A neutralization in conditioned media completely abolishes the increased endothelial tube formation induced by myeloma–osteocyte co-culture. siRNA knockdown of Vegf-a in osteoclasts/primary osteocytes, VEGF-A neutralization, co-culture endothelial tube formation assay, Fgf23 deletion, in vivo myeloma mouse model with vessel area quantification Scientific reports Medium 33057033

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2015 VEGF-A modulates expression of inhibitory checkpoints on CD8+ T cells in tumors. The Journal of experimental medicine 964 25601652
1993 Vascular permeability factor (VPF, VEGF) in tumor biology. Cancer metastasis reviews 788 8281615
2005 VEGF-A induces tumor and sentinel lymph node lymphangiogenesis and promotes lymphatic metastasis. The Journal of experimental medicine 598 15809353
2018 Molecular Pharmacology of VEGF-A Isoforms: Binding and Signalling at VEGFR2. International journal of molecular sciences 389 29690653
2008 VEGF-A links angiogenesis and inflammation in inflammatory bowel disease pathogenesis. Gastroenterology 289 19013462
2012 Diverse roles for VEGF-A in the nervous system. Development (Cambridge, England) 231 22434866
2005 VEGF-A and FGF-2 synergistically promote neoangiogenesis through enhancement of endogenous PDGF-B-PDGFRbeta signaling. Journal of cell science 230 16105884
2010 Transcriptional regulation of VEGF-A by the unfolded protein response pathway. PloS one 225 20221394
2007 Interstitial vascular rarefaction and reduced VEGF-A expression in human diabetic nephropathy. Journal of the American Society of Nephrology : JASN 207 17475821
2001 VEGF-A, VEGF-C, and VEGF-D in colorectal cancer progression. Neoplasia (New York, N.Y.) 178 11687953
2020 VEGF-A in Cardiomyocytes and Heart Diseases. International journal of molecular sciences 176 32722551
2004 The role of VEGF-A in glomerular development and function. Current opinion in nephrology and hypertension 158 15090854
2009 VEGF-A expression by HSV-1-infected cells drives corneal lymphangiogenesis. The Journal of experimental medicine 153 20026662
2005 VEGF-A and PlGF-1 stimulate chemotactic migration of human mesenchymal progenitor cells. Biochemical and biophysical research communications 153 16005848
2021 Direct and Indirect Modulation of T Cells by VEGF-A Counteracted by Anti-Angiogenic Treatment. Frontiers in immunology 151 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 136 28752859
2007 Reduction of VEGF-A and CTGF expression in diabetic nephropathy is associated with podocyte loss. Kidney international 135 17264876
2014 Brown adipose tissue derived VEGF-A modulates cold tolerance and energy expenditure. Molecular metabolism 130 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) 113 19521900
2003 Tumor specific VEGF-A and VEGFR2/KDR protein are co-expressed in breast cancer. Breast cancer research and treatment 104 14703061
2006 Molecular mechanisms of VEGF-A action during tissue repair. The journal of investigative dermatology. Symposium proceedings 98 17069014
2007 A post-transcriptional pathway represses monocyte VEGF-A expression and angiogenic activity. The EMBO journal 93 17611605
2018 Modified VEGF-A mRNA induces sustained multifaceted microvascular response and accelerates diabetic wound healing. Scientific reports 91 30504800
2016 A Potent d-Protein Antagonist of VEGF-A is Nonimmunogenic, Metabolically Stable, and Longer-Circulating in Vivo. ACS chemical biology 88 26745345
2021 BMP-2 and VEGF-A modRNAs in collagen scaffold synergistically drive bone repair through osteogenic and angiogenic pathways. Communications biology 81 33469143
2005 VEGF-A splice variants and related receptor expression in human skeletal muscle following submaximal exercise. Journal of applied physiology (Bethesda, Md. : 1985) 75 15661835
2021 Exploring the Intracrine Functions of VEGF-A. Biomolecules 73 33478167
2014 Regulation of alternative VEGF-A mRNA splicing is a therapeutic target for analgesia. Neurobiology of disease 71 25151644
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
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 65 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
2009 Regulation of VEGF-A in uveal melanoma. Investigative ophthalmology & visual science 59 20042655
2019 VEGF-A and blood vessels: a beta cell perspective. Diabetologia 58 31414144
2010 VEGF₁₂₁b and VEGF₁₆₅b are weakly angiogenic isoforms of VEGF-A. Molecular cancer 58 21194429
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
2022 How VEGF-A and its splice variants affect breast cancer development - clinical implications. Cellular oncology (Dordrecht, Netherlands) 56 35303290
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
2015 Peritoneal VEGF-A expression is regulated by TGF-β1 through an ID1 pathway in women with endometriosis. Scientific reports 53 26577912
2008 Specific imaging of VEGF-A expression with radiolabeled anti-VEGF monoclonal antibody. International journal of cancer 53 18240146
2024 Regulation of VEGF-A expression and VEGF-A-targeted therapy in malignant tumors. Journal of cancer research and clinical oncology 52 38687357
2019 VEGF-A from Granuloma Macrophages Regulates Granulomatous Inflammation by a Non-angiogenic Pathway during Mycobacterial Infection. Cell reports 51 31091450
2011 Proteolytic cleavage of versican and involvement of ADAMTS-1 in VEGF-A/VPF-induced pathological angiogenesis. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 51 21411713
2022 Efficient delivery of VEGF-A mRNA for promoting diabetic wound healing via ionizable lipid nanoparticles. International journal of pharmaceutics 50 36586634
2016 Expressions of VEGF-A and VEGFR-2 in placentae from GDM pregnancies. Reproductive biology and endocrinology : RB&E 49 27645229
2016 VEGF-A isoforms program differential VEGFR2 signal transduction, trafficking and proteolysis. Biology open 48 27044325
2019 TRF2 positively regulates SULF2 expression increasing VEGF-A release and activity in tumor microenvironment. Nucleic acids research 45 30698737
2010 VEGF-A expression in osteoclasts is regulated by NF-kappaB induction of HIF-1alpha. Journal of cellular biochemistry 44 20432243
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
2002 VEGF-A and -C but not -B mediate increased vascular permeability in preserved lung grafts. Transplantation 43 12084990
2025 Extracellular vesicle-mediated VEGF-A mRNA delivery rescues ischaemic injury with low immunogenicity. European heart journal 42 39831819
2010 Role of VEGF-A in pancreatic beta cells. Endocrine journal 42 20179357
2014 Expression profiling and significance of VEGF-A, VEGFR2, VEGFR3 and related proteins in endometrial carcinoma. Cytokine 41 24845798
2014 Control of VEGF-A transcriptional programs by pausing and genomic compartmentalization. Nucleic acids research 40 25352550
2013 Cooperative effects of FGF-2 and VEGF-A in periodontal ligament cells. Journal of dental research 40 24186558
2012 PEDF and VEGF-A output from human retinal pigment epithelial cells grown on novel microcarriers. Journal of biomedicine & biotechnology 40 22547925
2022 Human organ rejuvenation by VEGF-A: Lessons from the skin. Science advances 39 35749494
2020 miR-503-5p inhibits colon cancer tumorigenesis, angiogenesis, and lymphangiogenesis by directly downregulating VEGF-A. Gene therapy 39 32533103
2020 LPS-mediated neutrophil VEGF-A release is modulated by cannabinoid receptor activation. Journal of leukocyte biology 39 32573828
2013 Intracranial meningiomas, the VEGF-A pathway, and peritumoral brain oedema. Danish medical journal 38 23651727
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 36 39708087
2018 VEGF-A and VEGF-B Coordinate the Arteriogenesis to Repair the Infarcted Heart with Vagus Nerve Stimulation. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 36 30016789
2017 Biology and therapeutic implications of VEGF-A splice isoforms and single-nucleotide polymorphisms in colorectal cancer. International journal of cancer 36 27943279
2006 Differential expression of VEGF-A and angiopoietins in cartilage tumors and regulation by interleukin-1beta. Cancer 35 16565972
2015 Interplay between VEGF-A and cMET signaling in human vestibular schwannomas and schwann cells. Cancer biology & therapy 34 25692621
2010 Endothelial cell activation in a VEGF-A gradient: relevance to cell fate decisions. Microvascular research 34 20144626
2022 RNA-binding motif 4 promotes angiogenesis in HCC by selectively activating VEGF-A expression. Pharmacological research 32 36496136
2017 BRG1 promotes VEGF-A expression and angiogenesis in human colorectal cancer cells. Experimental cell research 32 28899659
2015 Adiponectin inhibits VEGF-A in prostate cancer cells. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 32 25586350
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 31 38522817
2016 Association between VEGF-A and VEGFR-2 polymorphisms and response to treatment of neovascular AMD with anti-VEGF agents: a meta-analysis. The British journal of ophthalmology 31 28400373
2024 Dual-layer conduit containing VEGF-A - Transfected Schwann cells promotes peripheral nerve regeneration via angiogenesis. Acta biomaterialia 30 38561075
2021 CXCL1 stimulates decidual angiogenesis via the VEGF-A pathway during the first trimester of pregnancy. Molecular and cellular biochemistry 29 33770315
2018 Molecular dynamics-based model of VEGF-A and its heparin interactions. Journal of molecular graphics & modelling 29 29738889
2021 Endothelial Insulin Receptors Promote VEGF-A Signaling via ERK1/2 and Sprouting Angiogenesis. Endocrinology 28 34037749
2009 Expression analysis of VEGF-A and VEGF-B: relationship with clinicopathological parameters in bladder cancer. Oncology reports 28 19424629
2020 Osteocyte Vegf-a contributes to myeloma-associated angiogenesis and is regulated by Fgf23. Scientific reports 27 33057033
2016 VEGF-A and VEGFR1 SNPs associate with preeclampsia in a Philippine population. Clinical and experimental hypertension (New York, N.Y. : 1993) 27 27668980
2013 Expression of VEGF-A, Otx homeobox and p53 family genes in proliferative vitreoretinopathy. Mediators of inflammation 27 24227910
2017 EGF regulation of proximal tubule cell proliferation and VEGF-A secretion. Physiological reports 26 28963126
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-induced DNp73 stabilization regulates Vegf-A expression and tumor angiogenesis similar to TAp73. Cell cycle (Georgetown, Tex.) 25 26267146
2012 Expression and role of VEGF--a in the ciliary body. Investigative ophthalmology & visual science 25 23081980
2019 Local VEGF-A blockade modulates the microenvironment of the corneal graft bed. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 24 30821887
2018 Vegf-A mRNA transfection as a novel approach to improve mouse and human islet graft revascularisation. Diabetologia 24 29789879
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
2015 Cellular and molecular aspects of diabetic nephropathy; the role of VEGF-A. Nefrologia : publicacion oficial de la Sociedad Espanola Nefrologia 22 26300505
2007 Distinct roles of VEGF-A and VEGF-C in tumour metastasis of gastric carcinoma. Oncology reports 22 17203176
2004 Regulation of vascular permeability factor/vascular endothelial growth factor (VPF/VEGF-A) expression in podocytes. Kidney international 22 15458440
2021 Diagnostic Value of VEGF-A, VEGFR-1 and VEGFR-2 in Feline Mammary Carcinoma. Cancers 21 33401382
2021 Anti-VEGF therapy prevents Müller intracellular edema by decreasing VEGF-A in diabetic retinopathy. Eye and vision (London, England) 21 33865457
2014 New Insights into VEGF-A Alternative Splicing: Key Regulatory Switching in the Pathological Process. Avicenna journal of medical biotechnology 21 25414781
2018 Modulation of VEGF-A Alternative Splicing as a Novel Treatment in Chronic Kidney Disease. Genes 20 29462869

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