Affinage

VEGFB

Vascular endothelial growth factor B · UniProt P49765

Length
207 aa
Mass
21.6 kDa
Annotated
2026-06-11
100 papers in source corpus 34 papers cited in narrative 34 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-B is a secreted disulfide-linked homodimer that exists as two alternatively spliced isoforms (VEGF-B167 and VEGF-B186), the latter O-glycosylated post-secretion and capable of forming heterodimers with VEGF-A (PMID:8702615). Unlike VEGF-A, its expression is not induced by hypoxia, Ras, or mutant p53 and its mRNA is unusually stable, marking it as a constitutive rather than stress-inducible angiogenic factor (PMID:9188862). It signals chiefly by binding VEGFR-1/Flt-1 and neuropilin-1 in a paracrine arrangement, where ligand is produced by myocardium while receptor is restricted to endothelium (PMID:9751730, PMID:10340753, PMID:19369214). Two dominant functional themes emerge. First, VEGF-B is a survival and cytoprotective factor: through VEGFR-1 it suppresses pro-apoptotic BH3-only genes and other death-related genes to protect endothelial cells, pericytes, neurons, and cardiomyocytes (PMID:18259607, PMID:19369214), protects motor and sensory neurons via neuronal Flt-1 tyrosine kinase activity and mitochondrial maintenance (PMID:18923022, PMID:21248239), and upregulates antioxidant defenses—particularly Gpx1—to rescue degenerating retina (PMID:30249667). Second, VEGF-B is a central regulator of tissue lipid handling and metabolism: it controls endothelial fatty acid uptake/transport such that its inhibition prevents ectopic lipid deposition and restores insulin sensitivity in diabetic models (PMID:27076080), is transcriptionally driven by PGC-1α/ERR-α in muscle (PMID:26822083), impairs LDLR recycling to lower membrane cholesterol and GLUT1-dependent glucose uptake (PMID:32449307), and modulates adipose lipolysis through hormone-sensitive lipase to influence NAFLD (PMID:36717026). In the heart, VEGF-B activates VEGFR-1 on cardiomyocytes to drive compensatory hypertrophy, arteriogenesis, and endocardium-derived coronary vessel formation (PMID:20019242, PMID:33203221), while VEGF-B186 can also promote cardiac angiogenesis through RGD-binding integrins (ITGAV/ITGA5) and ER-stress/UPR signaling independently of VEGFR-1 kinase activity (PMID:40083161). VEGF-B additionally engages FGFR1, inducing FGFR1/VEGFR1 complexes that suppress FGF2-driven angiogenesis under high FGF2/FGFR1 conditions, positioning it as a context-dependent endogenous angiogenesis inhibitor (PMID:37591843). VEGF-B is dispensable for developmental blood vessel growth but is required for vascular cell survival and integrity (PMID:19369214, PMID:39215561).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1996 High

    Established the molecular identity and biochemistry of VEGF-B, defining isoforms, dimerization, and heterodimer potential with VEGF-A — the structural foundation for all downstream signaling work.

    Evidence cDNA cloning, transfection, SDS-PAGE and glycosylation analysis of VEGF-B186

    PMID:8702615

    Open questions at the time
    • Receptor and downstream signaling not yet defined
    • Functional difference between isoforms unresolved
  2. 1998 High

    Identified VEGFR-1/Flt-1 as the receptor and showed receptor engagement drives a pro-fibrinolytic endothelial program, while a separate study established that VEGF-B regulation is fundamentally distinct from the hypoxia-driven VEGF-A.

    Evidence Receptor binding assay with site-directed mutagenesis plus endothelial functional readout; Northern blot and mRNA stability assays

    PMID:9188862 PMID:9751730

    Open questions at the time
    • In vivo physiological role not established
    • Downstream signaling cascade beyond uPA/PAI-1 unknown
  3. 1999 Medium

    Defined the paracrine architecture: ligand in myocardium, receptor in endothelium, framing VEGF-B as a cardiac-vascular paracrine signal.

    Evidence In situ hybridization and immunohistochemistry across mouse embryonic stages

    PMID:10340753

    Open questions at the time
    • Paracrine function inferred from localization, not functionally tested here
    • Adult expression pattern not addressed
  4. 2000 High

    First loss-of-function evidence linked VEGF-B to coronary vasculature and recovery from cardiac ischemia, moving it from biochemistry to physiology.

    Evidence Vegfb knockout mice with cardiac phenotyping and coronary occlusion model

    PMID:10666423

    Open questions at the time
    • Cellular mechanism (survival vs growth) unresolved
    • Receptor-dependence in vivo not dissected
  5. 2003 Medium

    Extended VEGF-B to pathological vascular remodeling, showing it drives synovial angiogenesis and inflammation in arthritis.

    Evidence Vegfb-/- mice in antigen- and collagen-induced arthritis with histological and vessel-density scoring

    PMID:13130487

    Open questions at the time
    • Mechanism of synovial angiogenesis not defined
    • Receptor and cell-type specificity unknown
  6. 2008 High

    Defined the core cytoprotective mechanism — VEGFR-1-dependent suppression of BH3-only pro-apoptotic genes — and demonstrated neuroprotection in vivo, recasting VEGF-B as a survival factor rather than a growth factor.

    Evidence Gene expression profiling, qPCR, and in vivo retinal/stroke neuroprotection models

    PMID:18259607

    Open questions at the time
    • Signaling intermediates from VEGFR-1 to gene suppression not mapped
    • Cell-type generality not yet tested
  7. 2009 High

    Established that VEGF-B is dispensable for vessel growth but essential for vascular cell survival via NRP-1 and VEGFR-1, and that VEGF-B186 protects motor neurons through neuronal Flt-1 tyrosine kinase activity.

    Evidence Multiple vascular cell assays and animal models; primary motor neuron cultures, Vegfb/SOD1 double mutants, ICV delivery, kinase inhibitors

    PMID:18923022 PMID:19369214

    Open questions at the time
    • Relative contributions of NRP-1 vs VEGFR-1 not quantified
    • Downstream survival effectors in neurons not fully defined
  8. 2009 High

    Showed VEGF-B186 directly acts on cardiomyocytes through VEGFR-1 to elicit antiapoptotic and compensatory hypertrophic transcriptional programs preserving post-infarct cardiac function.

    Evidence AAV gene delivery in rats, cardiomyocyte culture, gene expression profiling, MI model

    PMID:20019242

    Open questions at the time
    • Long-term safety of induced hypertrophy not assessed
    • Endothelial vs cardiomyocyte contributions not separated
  9. 2011 High

    Demonstrated direct neuronal action on sensory neurons via FLT1 with mitochondrial membrane potential maintenance, distinguishing neuronal from vascular protection.

    Evidence DRG cultures from Vegfb/Flt1 KO mice, paclitaxel neuropathy model, neuronal FLT1 transgenics, recombinant protein

    PMID:21248239

    Open questions at the time
    • Mechanism coupling FLT1 to mitochondrial integrity unresolved
    • Translation to human neuropathy untested
  10. 2010 High

    Established VEGF-B as a master regulator of endothelial fatty acid uptake, linking it to ectopic lipid deposition, insulin resistance, and metabolic disease — a major functional pivot.

    Evidence Vegfb knockout in db/db mice and antibody inhibition in HFD rats with metabolic readouts

    PMID:23023133

    Open questions at the time
    • Identity of regulated lipid transporters not fully defined here
    • Tissue-specific versus systemic effects unresolved
  11. 2016 High

    Mapped upstream transcriptional control (PGC-1α/ERR-α) of Vegfb in muscle and showed VEGFB-VEGFR1 signaling activates VEGF/VEGFR2-dependent angiogenesis to improve adipose perfusion and insulin supply, while reporter studies confirmed the cardiomyocyte-to-endothelium paracrine axis.

    Evidence PGC-1α transgenic and Vegfb KO crosses; Vegfb gene transduction with endothelial Flt1 cKO; β-gal knock-in reporter mice and Flt1 heterozygote phenotyping

    PMID:26822083 PMID:26928042 PMID:27076080

    Open questions at the time
    • Reconciliation of VEGFB as both lipid-uptake promoter and perfusion enhancer not fully integrated
    • Crosstalk to VEGFR2 mechanism not molecularly resolved
  12. 2017 Medium

    Extended the metabolic role to diabetic kidney disease, showing VEGF-B inhibition reduces renal lipotoxicity and restores podocyte insulin signaling, with parallel work defining diabetic-heart heparanase-triggered VEGFB release and PEDF-dependent corneal nerve regeneration.

    Evidence DKD mouse models with anti-VEGF-B antibody; diabetic heart heparanase secretion and ERK assays; diabetic corneal nerve model with VEGFR-1/NRP-1 and PEDF blockade

    PMID:28091556 PMID:28190774 PMID:28314760

    Open questions at the time
    • Receptor-specific genetic dissection limited in heparanase study
    • Whether renal and cardiac effects share a common transporter mechanism unknown
  13. 2018 High

    Identified VEGF-B as a potent antioxidant acting mainly through VEGFR-1 and Gpx1, providing a redox-based arm of its cytoprotection in the retina.

    Evidence Vegfb and Gpx1 KO mice with epistasis, retinitis pigmentosa model, expression profiling

    PMID:30249667

    Open questions at the time
    • Signaling linking VEGFR-1 to antioxidant gene induction not mapped
    • Generality beyond retina untested
  14. 2020 High

    Resolved a key metabolic mechanism — VEGF-B impairs LDLR recycling to reduce membrane cholesterol and GLUT1-dependent glucose uptake — and demonstrated VEGF-B drives endocardium-derived coronary vessel formation, while autocrine VEGF-B sustains Müller glia and high-dose cardiac VEGF-B triggers VEGFR-1-independent sympathetic nerve sprouting with arrhythmia risk.

    Evidence Endothelial LDLR trafficking and cholesterol/GLUT1 assays with in vivo inhibition; lineage tracing and scRNA-seq in VEGF-B transgenic/KO hearts; Müller cell neutralization/rescue; αMHC-VEGF-B transgenic and pig gene transfer

    PMID:32243833 PMID:32449307 PMID:32945843 PMID:33203221

    Open questions at the time
    • Receptor identity for nerve-sprouting and gliotrophic effects not fully defined
    • Dose threshold for beneficial vs arrhythmogenic cardiac effects unclear
  15. 2021 Medium

    Defined VEGFB-VEGFR1-PI3K/Akt control of myoblast proliferation/differentiation and cardiomyocyte-specific metabolic and anti-hypertrophic effects, including reduced coronary LPL activity and protection against Ang II hypertrophy via Ca2+/PKG I.

    Evidence C2C12 receptor knockdown and pathway inhibitors; cardiac transgenic rats with multi-omics and LPL activity; H9C2 Ang II model with VEGFR1 knockdown and PKG pathway analysis

    PMID:28771828 PMID:34747201 PMID:34948148

    Open questions at the time
    • Cell-line-based findings need in vivo confirmation
    • Integration of metabolic and anti-hypertrophic effects mechanistically incomplete
  16. 2023 High

    Uncovered context-dependent angiogenesis inhibition via FGFR1 binding and FGFR1/VEGFR1 complex formation suppressing FGF2/Erk signaling, and defined an adipose lipolysis mechanism (HSL) by which VEGF-B influences NAFLD.

    Evidence In vitro binding, Co-IP, Erk assays and in vivo tumor/angiogenesis models; adipocyte-specific VEGF-B transgenic/KO mice with lipolysis and HSL assays

    PMID:36717026 PMID:37591843

    Open questions at the time
    • Structural basis of FGFR1/VEGFR1 complex unresolved
    • How VEGF-B switches between pro- and anti-angiogenic roles in vivo unclear
  17. 2024 High

    Revealed an autocrine immunometabolic role: VEGF-B sustains T cell survival and memory via a GABPα→SENP2→PPARγ deSUMOylation axis driving cardiolipin synthesis, and a retinal vascular-integrity role via the CDC42/ZO1/VE-cadherin pathway.

    Evidence T cell-specific VEGF-B disruption with cardiolipin mass spec and GABPα/SENP2/PPARγ analysis; STZ diabetic mice and HREC knockdown/overexpression with proteomics

    PMID:39145452 PMID:39215561

    Open questions at the time
    • Receptor mediating T cell autocrine signaling not specified
    • Link between barrier integrity pathway and canonical VEGFR-1 signaling unresolved
  18. 2025 High

    Identified RGD-binding integrins ITGAV and ITGA5 as new VEGF-B186 receptors mediating cardiac angiogenesis through ER stress/UPR, independent of VEGFR-1 kinase activity, expanding the receptor repertoire beyond Flt-1.

    Evidence VEGFR1 TK-KO mice, NRP-binding mutant, adenoviral cardiac gene transfer, cardiac endothelial cells, multi-species validation, integrin identification

    PMID:40083161

    Open questions at the time
    • Relative in vivo contribution of integrin vs VEGFR-1 pathways not quantified
    • Structural basis of integrin engagement unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How VEGF-B integrates its multiple receptors (VEGFR-1, NRP-1, FGFR1, RGD-integrins) into context-specific outputs — survival, lipid handling, angiogenesis promotion vs inhibition — remains unresolved at the level of a unified signaling logic.
  • No structural model of VEGF-B with its non-Flt1 receptors
  • Determinants selecting between pro- and anti-angiogenic outcomes unknown
  • Receptor usage in immune and metabolic contexts not fully mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 5 GO:0098772 molecular function regulator activity 3
Localization
GO:0005576 extracellular region 2
Pathway
R-HSA-1430728 Metabolism 5 R-HSA-162582 Signal Transduction 4 R-HSA-1266738 Developmental Biology 3 R-HSA-5357801 Programmed Cell Death 2 R-HSA-8953897 Cellular responses to stimuli 2
Partners
FGFR1FLT1ITGA5ITGAVNRP1VEGFA
Complex memberships
FGFR1/VEGFR1 complex

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 VEGF-B binds selectively to VEGF receptor-1/Flt-1, with binding blockable by excess VEGF indicating at least partially overlapping binding sites. Mutating putative binding determinants Asp63, Asp64, and Glu67 to alanine reduced but did not abolish Flt-1 affinity. Binding of VEGF-B to its receptor on endothelial cells leads to increased expression and activity of urokinase-type plasminogen activator and plasminogen activator inhibitor-1. Receptor binding assay, site-directed mutagenesis, endothelial cell functional assay Proceedings of the National Academy of Sciences of the United States of America High 9751730
1998 VEGF-B is not regulated by hypoxia, Ras oncoprotein, or mutant p53 (stimuli that potently induce VEGF-A), and its mRNA is highly stable (T1/2 > 8 h), distinguishing its regulation from VEGF-A and VEGF-C. Northern blot, mRNA stability assay in cultured cells Oncogene Medium 9188862
1996 The VEGF-B186 isoform arises by alternative splicing introducing a frameshift, is secreted, undergoes O-linked glycosylation post-secretion (25 kDa → 32 kDa), is expressed as a disulfide-linked homodimer, and forms heterodimers with VEGF-A when co-expressed. cDNA cloning, transfection, SDS-PAGE, biochemical characterization The Journal of biological chemistry High 8702615
2000 Vegfb knockout mice have smaller hearts and dysfunctional coronary vasculature with impaired recovery from experimentally induced myocardial ischemia, establishing a role for VEGF-B in coronary vasculature development and/or function. Gene knockout mouse model, cardiac phenotyping, coronary occlusion model Circulation research High 10666423
2008 VEGF-B inhibits apoptosis via VEGFR-1-mediated suppression of proapoptotic BH3-only protein genes and other apoptosis/cell-death-related genes (including p53 and caspase family members); neuronal rescue in retinal and brain models was confirmed in vivo. Gene expression profiling, real-time PCR, in vivo neuroprotection models (retinal degeneration, stroke), VEGFR-1-dependent mechanism The Journal of clinical investigation High 18259607
2009 VEGF-B is dispensable for blood vessel growth but critical for vascular cell survival (endothelial cells, pericytes, smooth muscle cells, vascular stem/progenitor cells); its vascular survival effect is mediated through both NRP-1 and VEGFR-1 by regulating pro-survival gene expression. Multiple animal models, multiple vascular cell type assays, in vivo choroidal/retinal neovascularization targeting Proceedings of the National Academy of Sciences of the United States of America High 19369214
2009 VEGF-B186 isoform protects primary motor neurons against degeneration via the tyrosine kinase activity of Flt1 (VEGFR-1) expressed on motor neurons; intracerebroventricular delivery prolonged survival of mutant SOD1 rats. Vegfb-knockout mice crossed with mutant SOD1 mice developed more severe motor neuron degeneration. Primary motor neuron culture, Vegfb/SOD1 double-mutant mice, intracerebroventricular delivery, kinase inhibitor experiments The Journal of neuroscience High 18923022
2009 VEGF-B186 activates VEGFR-1 on cardiomyocytes (which also express VEGFR-2 and neuropilin-1; VEGFR-1 is up-regulated under hypoxia/oxidative stress), elicits an antiapoptotic effect, and induces a compensatory hypertrophic gene expression profile (activation of αMHC, repression of βMHC/skeletal α-actin, increase of SERCA2a, RYR, PGC1α), preserving cardiac function after myocardial infarction. AAV-mediated gene delivery in rats, cardiomyocyte culture, gene expression profiling, in vivo myocardial infarction model FASEB journal High 20019242
2011 VEGF-B and its receptor FLT1 are expressed in dorsal root ganglion neurons; VEGF-B186 maintains mitochondrial membrane potential, reduces neuronal stress, and protects against retrograde degeneration of sensory neurons via direct FLT1-mediated effects on neurons (not surrounding vasculature). DRG primary cultures from Vegfb/Flt1 KO mice, paclitaxel neuropathy model, neuronal FLT1 transgenic overexpression, gene transfer, recombinant protein FASEB journal High 21248239
2010 VEGF-B controls endothelial uptake and transport of fatty acids in heart and skeletal muscle. Vegfb knockout in diabetic db/db mice prevented ectopic lipid deposition and increased muscle glucose uptake; pharmacological VEGF-B inhibition restored insulin sensitivity in high-fat-diet rats. Vegfb genetic knockout in db/db mice, antibody pharmacological inhibition, glucose tolerance/insulin sensitivity assays, in vivo imaging Nature High 23023133
2016 VEGFB binding to VEGFR1 activates the VEGF/VEGFR2 pathway and increases capillary density, tissue perfusion, and insulin supply/signaling in adipose tissue; endothelial Flt1 deletion enhances VEGFB effect and activates thermogenic program in subcutaneous adipose tissue. Vegfb gene transduction in mice, endothelial Flt1 conditional knockout, metabolic and vascular phenotyping Cell metabolism High 27076080
2016 PGC-1α together with estrogen-related receptor α (ERR-α) transcriptionally regulates Vegfb expression in skeletal muscle; PGC-1α overexpression increases Vegfb, leading to increased muscular lipid accumulation that is normalized by Vegfb ablation. Muscle-specific PGC-1α transgenic mice, Vegfb knockout crosses, chromatin/transcription factor analysis, metabolic phenotyping Diabetes High 26822083
2017 Renal VEGF-B expression correlates with severity of diabetic kidney disease; inhibiting VEGF-B signaling in DKD mouse models reduces renal lipotoxicity, re-sensitizes podocytes to insulin signaling, and prevents renal dysfunction. DKD mouse models, anti-VEGF-B antibody treatment, renal lipid/insulin signaling assays Cell metabolism High 28190774
2018 VEGF-B is a potent antioxidant; it upregulates numerous antioxidative genes, particularly Gpx1. Loss of Gpx1 activity largely diminished the antioxidative effect of VEGF-B. The antioxidant function is mediated mainly by VEGFR1; Vegfb deletion causes retinal degeneration, and VEGF-B treatment rescues retinal cells in a retinitis pigmentosa model. Vegfb gene deletion in mice, retinitis pigmentosa model, gene expression profiling, Gpx1 loss-of-function, VEGFR1-dependency assay Proceedings of the National Academy of Sciences of the United States of America High 30249667
2020 VEGF-B signaling impairs recycling of low-density lipoprotein receptor (LDLR) to the plasma membrane, reducing cholesterol uptake and membrane cholesterol loading, which decreases GLUT1-dependent endothelial glucose uptake; inhibiting VEGF-B in vivo reconstitutes membrane cholesterol levels and restores glucose uptake. VEGF-B signaling in endothelial cells, LDLR trafficking assay, membrane cholesterol measurement, GLUT1 functional assay, in vivo inhibition EMBO reports High 32449307
2023 VEGF-B inhibits NAFLD development by blocking lipolysis in white adipose tissue (WAT); adipocyte-specific VEGF-B overexpression worsens NAFLD while adipocyte-specific knockout reduces it, acting through regulation of hormone-sensitive lipase activity and WAT insulin resistance. AdipoqCre conditional VEGF-B transgenic and floxed knockout mice, NAFLD model, neutralizing antibody, lipolysis assay, hormone-sensitive lipase activity Journal of hepatology High 36717026
2025 VEGF-B186 promotes cardiac angiogenesis via RGD-binding integrins (ITGAV and ITGA5) as newly identified receptors, independent of VEGFR1 tyrosine kinase activity or neuropilin binding; this involves induction of ER stress via upregulation of BiP and ER stress sensors (ATF6, PERK, IRE1α), activating the unfolded protein response through XBP1. VEGFR1 TK-/- mice, VEGF-B186R127S NRP-binding mutant, adenoviral gene transfer in mouse hearts, in vitro cardiac endothelial cells, pig and wild-type mouse validation, integrin identification Molecular therapy High 40083161
2023 VEGF-B binds to FGFR1, induces FGFR1/VEGFR1 complex formation, and suppresses FGF2-induced Erk activation, thereby inhibiting FGF2-driven angiogenesis and tumor growth when FGF2/FGFR1 levels are high; VEGF-B thus acts as an endogenous inhibitor of angiogenesis under these conditions. In vitro binding assay (VEGF-B to FGFR1), co-immunoprecipitation (FGFR1/VEGFR1 complex), Erk activation assay, in vivo angiogenesis and tumor models Signal transduction and targeted therapy High 37591843
2003 Vegfb knockout mice show reduced synovial angiogenesis and reduced pathology (swelling, inflammation) in both antigen-induced and collagen-induced arthritis models, implicating VEGF-B in pathological vascular remodeling during inflammatory arthritis. Vegfb-/- mice in two arthritis models, histological scoring, synovial vessel density quantification Arthritis and rheumatism Medium 13130487
2005 VEGF-B stimulates neurogenesis in the adult brain; intracerebroventricular VEGF-B administration increased BrdU incorporation into cells of neuronal lineage in the hippocampal dentate gyrus and forebrain subventricular zone both in vitro and in vivo, and Vegfb-KO mice showed impaired neurogenesis. Vegfb-KO mice, intracerebroventricular injection, BrdU incorporation assay, neuronal marker immunostaining Developmental biology Medium 16337622
2010 RTEF-1 in endothelial cells directly increases VEGF-B promoter activity through a direct interaction (confirmed by ChIP and luciferase assay); endothelium-derived VEGF-B then stimulates hypertrophic gene expression in adjacent cardiomyocytes via ERK1/2, which was abrogated by VEGF-B siRNA. Chromatin immunoprecipitation, luciferase promoter assay, siRNA knockdown, cardiomyocyte conditioned medium experiments, VE-Cad/RTEF-1 transgenic mice Cardiovascular research Medium 21169295
2016 VEGFB expression is found in cardiomyocytes with a postnatal ventricular shift, while VEGFR1 expression is restricted to endothelial cells in heart, lung, and kidney, supporting a tightly controlled paracrine signaling mechanism; reduced VEGFR1 expression resulted in decreased cardiac fatty acid accumulation and increased peripheral insulin sensitivity. β-galactosidase knock-in reporter mice, immunofluorescence microscopy, Flt1 heterozygous metabolic phenotyping Cell and tissue research Medium 26928042
2017 In the diabetic heart, surface-bound VEGFB on cardiomyocytes is released by endothelial heparanase secretion; high glucose and heparanase trigger VEGFB release, which then acts on endothelial cells (autocrine) and cardiomyocytes (paracrine) to promote survival via ERK signaling. Under hyperglycemia, VEGFB production is impaired and VEGFR1 expression is compensatorily increased. Diabetic heart models, heparanase secretion experiments, ERK signaling assays, gene expression analysis American journal of physiology. Heart and circulatory physiology Medium 28314760
2017 Exogenous VEGF-B promotes diabetic corneal nerve fiber regeneration through reactivation of PI3K/Akt-GSK3β-mTOR signaling and attenuation of neuronal mitochondrial dysfunction via VEGF receptor-1 and neuropilin-1; VEGF-B also elevated corneal pigment epithelial-derived factor (PEDF), and PEDF blockade partially abolished VEGF-B trophic effects. Type 1 diabetic mouse model, trigeminal ganglion cultures, VEGFR-1/NRP-1 pathway analysis, PEDF blocking antibody Scientific reports Medium 28091556
2020 VEGF-B promotes the formation of endocardium-derived coronary vessels during cardiac development; in adult mice, VEGF-B gene transfer induces endothelial proliferation predominantly in subendocardial coronary vessels and promotes endocardium-derived vessel development into myocardium after infarction. VEGF-B transgenic mice and rats, Vegfb-gene-deleted mice/rats, lineage tracing (apelin-CreERT, NPR3-CreERT), AAV gene transfer, histology, single-cell RNA-seq, microCT Circulation High 33203221
2021 VEGFB promotes C2C12 myoblast proliferation and differentiation through VEGFR1-PI3K/Akt (and PI3K/Akt/mTOR for differentiation); VEGFR1 knockdown abolished VEGFB-stimulated proliferation and differentiation, and NRP1 knockdown did not affect differentiation. C2C12 myoblast cell line, VEGFR1/NRP1 siRNA knockdown, PI3K/Akt inhibitors, proliferation and differentiation assays International journal of molecular sciences Medium 34948148
2020 VEGF-B is expressed in Müller cells and acts as an autocrine gliotrophic factor under pathologic conditions (hypoxia, oxidative stress); VEGF-B neutralization under pathologic conditions enhanced Müller cell death and decreased Kir4.1 and aquaporin-4 expression, while recombinant VEGF-B restored glutamine synthetase and normalized TRPV4 channel expression and activity. Human and mouse Müller cell lines and primary cells, RT-PCR, ELISA, Western blot, VEGF-B neutralization, calcium imaging (Fura-2) Investigative ophthalmology & visual science Medium 32945843
2016 VEGF-B gene therapy prevented doxorubicin-induced cardiac atrophy, capillary rarefaction, and endothelial apoptosis; VEGF-B promoted coronary arteriogenesis and physiological cardiac hypertrophy, and protected cultured endothelial cells from apoptosis restoring tube formation. AAV gene therapy in tumor-bearing mice, endothelial cell culture, apoptosis assay, tube formation assay, cardiac function by echocardiography Proceedings of the National Academy of Sciences of the United States of America Medium 27799559
2017 VEGFB-VEGFR1 signaling prevents Ang II-induced cardiomyocyte hypertrophy via Ca2+-mediated PKG I pathway; VEGFB reduced Ang II-induced Ca2+ elevation, prevented increases in β-MHC/BNP/ANP, and maintained PKG I/p-VASP/RGS2; VEGFR1 knockdown partially reversed these effects. H9C2 cardiomyocyte cell line, Ang II stimulation, VEGFR1 siRNA knockdown, Ca2+ measurement, PKG I/p-VASP/RGS2 Western blot Journal of cellular biochemistry Medium 28771828
2020 High-dose VEGF-B overexpression in the heart induces sympathetic nerve sprouting (increased nerve density ~2-fold) via a VEGFR-1 signaling-independent mechanism, upregulating Nr4a2, ATF6, and MANF, and leading to increased risk of ventricular arrhythmias and sudden cardiac death. αMHC-VEGF-B transgenic mice, adenoviral VEGF-B186 pig cardiac gene transfer, immunostaining for nerve density, dobutamine stress testing, gene expression analysis, survival analysis Molecular therapy Medium 32243833
2024 Autocrine VEGF-B signaling in activated T cells controls lipid synthesis and mitochondrial inner membrane integrity (cardiolipin maintenance) for T cell survival; disruption of VEGF-B signaling reduced cardiolipin mass, increased apoptosis, and reduced memory T cell development. Mechanistically, VEGF-B signaling through GABPα induces SENP2 expression, which de-SUMOylates PPARγ to enhance phospholipid synthesis. T cell-specific VEGF-B disruption, cardiolipin mass spectrometry, apoptosis assays, memory T cell flow cytometry, GABPα/SENP2/PPARγ molecular pathway analysis The Journal of clinical investigation High 39145452
2024 VEGF-B prevents hyperglycemia-induced retinal vascular leakage by upregulating CDC42/ZO1/VE-cadherin expression; VEGF-B knockdown increased hyperglycemia-induced vascular leakage in human retinal endothelial cells, while VEGF-B overexpression or intravitreal injection restored CDC42/ZO1/VE-cadherin and reduced leakage. STZ-induced diabetic mouse model, VEGF-B knockdown/overexpression in HRECs, label-free proteomics, Western blot, whole-mount staining, intravitreal injection FASEB journal Medium 39215561
2021 Cardiac-specific VEGFB overexpression reduces lipoprotein lipase (LPL) activity at the coronary lumen through multiple regulatory mechanisms, lowers accumulation of lipid intermediates (diacylglycerols, lysophosphatidylcholine), and improves cardiac insulin sensitivity. Cardiomyocyte-specific VEGFB transgenic rats, RNA sequencing, Langendorff heart LPL activity assay, untargeted metabolomics, insulin sensitivity assay, high-resolution respirometry American journal of physiology. Endocrinology and metabolism Medium 34747201
1999 VEGF-B is expressed predominantly in the developing myocardium (not endothelial cells), while its receptor VEGFR-1 is almost exclusively present in endothelial cells, supporting a paracrine mode of action in vascular development. In situ hybridization and immunohistochemistry in mouse embryos (E8.5–E17.5) Developmental dynamics Medium 10340753

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 Vascular endothelial growth factor B (VEGF-B) binds to VEGF receptor-1 and regulates plasminogen activator activity in endothelial cells. Proceedings of the National Academy of Sciences of the United States of America 441 9751730
1997 Comparison of VEGF, VEGF-B, VEGF-C and Ang-1 mRNA regulation by serum, growth factors, oncoproteins and hypoxia. Oncogene 389 9188862
1998 Vascular endothelial growth factors VEGF-B and VEGF-C are expressed in human tumors. The American journal of pathology 285 9665470
2012 Targeting VEGF-B as a novel treatment for insulin resistance and type 2 diabetes. Nature 244 23023133
2009 VEGF-B is dispensable for blood vessel growth but critical for their survival, and VEGF-B targeting inhibits pathological angiogenesis. Proceedings of the National Academy of Sciences of the United States of America 243 19369214
2000 Mice lacking the vascular endothelial growth factor-B gene (Vegfb) have smaller hearts, dysfunctional coronary vasculature, and impaired recovery from cardiac ischemia. Circulation research 232 10666423
2016 VEGFB/VEGFR1-Induced Expansion of Adipose Vasculature Counteracts Obesity and Related Metabolic Complications. Cell metabolism 192 27076080
2003 The angiogenic switch for vascular endothelial growth factor (VEGF)-A, VEGF-B, VEGF-C, and VEGF-D in the adenoma-carcinoma sequence during colorectal cancer progression. The Journal of pathology 186 12754739
1996 Genomic organization of the mouse and human genes for vascular endothelial growth factor B (VEGF-B) and characterization of a second splice isoform. The Journal of biological chemistry 169 8702615
2008 VEGF-B inhibits apoptosis via VEGFR-1-mediated suppression of the expression of BH3-only protein genes in mice and rats. The Journal of clinical investigation 168 18259607
1998 Comparison of expression patterns for placenta growth factor, vascular endothelial growth factor (VEGF), VEGF-B and VEGF-C in the human placenta throughout gestation. The Journal of endocrinology 162 9834463
2017 Reducing VEGF-B Signaling Ameliorates Renal Lipotoxicity and Protects against Diabetic Kidney Disease. Cell metabolism 158 28190774
2009 Cardiomyocyte VEGFR-1 activation by VEGF-B induces compensatory hypertrophy and preserves cardiac function after myocardial infarction. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 152 20019242
2005 Vascular endothelial growth factor-B (VEGFB) stimulates neurogenesis: evidence from knockout mice and growth factor administration. Developmental biology 147 16337622
1999 Current biology of VEGF-B and VEGF-C. Current opinion in biotechnology 133 10600689
2000 Vegf, Vegf-B, Vegf-C and their receptors KDR, FLT-1 and FLT-4 during the neoplastic progression of human colonic mucosa. International journal of cancer 124 10738243
2008 Novel role for vascular endothelial growth factor (VEGF) receptor-1 and its ligand VEGF-B in motor neuron degeneration. The Journal of neuroscience : the official journal of the Society for Neuroscience 118 18923022
2016 VEGF-B gene therapy inhibits doxorubicin-induced cardiotoxicity by endothelial protection. Proceedings of the National Academy of Sciences of the United States of America 113 27799559
2022 Resveratrol Treats UVB-Induced Photoaging by Anti-MMP Expression, through Anti-Inflammatory, Antioxidant, and Antiapoptotic Properties, and Treats Photoaging by Upregulating VEGF-B Expression. Oxidative medicine and cellular longevity 109 35028009
1997 Differential hormonal regulation of vascular endothelial growth factors VEGF, VEGF-B, and VEGF-C messenger ribonucleic acid levels in cultured human granulosa-luteal cells. Endocrinology 108 9348202
2003 Vegfb gene knockout mice display reduced pathology and synovial angiogenesis in both antigen-induced and collagen-induced models of arthritis. Arthritis and rheumatism 106 13130487
2001 Novel VEGF family members: VEGF-B, VEGF-C and VEGF-D. The international journal of biochemistry & cell biology 102 11312110
2009 VEGF-B: a survival, or an angiogenic factor? Cell adhesion & migration 88 19684473
2020 VEGF-B Promotes Endocardium-Derived Coronary Vessel Development and Cardiac Regeneration. Circulation 86 33203221
1996 Novel human vascular endothelial growth factor genes VEGF-B and VEGF-C localize to chromosomes 11q13 and 4q34, respectively. Circulation 82 8653826
1999 Localization of VEGF-B in the mouse embryo suggests a paracrine role of the growth factor in the developing vasculature. Developmental dynamics : an official publication of the American Association of Anatomists 77 10340753
2005 The biology of vascular endothelial growth factor-B (VEGF-B). Pulmonary pharmacology & therapeutics 75 16286239
2002 Differential expression of vascular endothelial growth factor-A (VEGF-A) and VEGF-B after brain injury. Journal of neuropathology and experimental neurology 70 12230324
2001 Isoform-specific expression of VEGF-B in normal tissues and tumors. Growth factors (Chur, Switzerland) 69 11678209
1998 A comparative study of the expression patterns for vegf, vegf-b/vrf and vegf-c in the developing and adult mouse. Biochimica et biophysica acta 68 9689915
2012 AAV9-mediated VEGF-B gene transfer improves systolic function in progressive left ventricular hypertrophy. Molecular therapy : the journal of the American Society of Gene Therapy 67 23089731
2010 Heme oxygenase-1 and carbon monoxide promote neovascularization after myocardial infarction by modulating the expression of HIF-1alpha, SDF-1alpha and VEGF-B. European journal of pharmacology 64 20303947
2009 Vascular endothelial growth factor B (VEGF-B) is up-regulated and exogenous VEGF-B is neuroprotective in a culture model of Parkinson's disease. Molecular neurodegeneration 58 20003314
2018 A peptide mimicking the binding sites of VEGF-A and VEGF-B inhibits VEGFR-1/-2 driven angiogenesis, tumor growth and metastasis. Scientific reports 56 30560942
2023 VEGF-B prevents excessive angiogenesis by inhibiting FGF2/FGFR1 pathway. Signal transduction and targeted therapy 55 37591843
2020 VEGF-B antibody and interleukin-22 fusion protein ameliorates diabetic nephropathy through inhibiting lipid accumulation and inflammatory responses. Acta pharmaceutica Sinica. B 54 33532185
2008 Cellular distribution of vascular endothelial growth factor A (VEGFA) and B (VEGFB) and VEGF receptors 1 and 2 in focal cortical dysplasia type IIB. Acta neuropathologica 53 18317782
2018 VEGF-B is a potent antioxidant. Proceedings of the National Academy of Sciences of the United States of America 52 30249667
2016 PGC-1α Coordinates Mitochondrial Respiratory Capacity and Muscular Fatty Acid Uptake via Regulation of VEGF-B. Diabetes 52 26822083
2013 Comparative study of the neurotrophic effects elicited by VEGF-B and GDNF in preclinical in vivo models of Parkinson's disease. Neuroscience 51 24291725
2004 Comparative expression of vascular endothelial growth factor family members, VEGF-B, -C and -D, by normal human keratinocytes and fibroblasts. Experimental dermatology 51 15009103
2001 VEGF-B expression in human primary breast cancers is associated with lymph node metastasis but not angiogenesis. The Journal of pathology 49 11241411
2011 Neuronal FLT1 receptor and its selective ligand VEGF-B protect against retrograde degeneration of sensory neurons. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 48 21248239
2003 Role of VEGF-B in the lung during development of chronic hypoxic pulmonary hypertension. American journal of physiology. Lung cellular and molecular physiology 48 12547729
2017 VEGF-B promotes recovery of corneal innervations and trophic functions in diabetic mice. Scientific reports 46 28091556
2023 Inhibition of VEGF-B signaling prevents non-alcoholic fatty liver disease development by targeting lipolysis in the white adipose tissue. Journal of hepatology 45 36717026
2021 VEGFB Promotes Myoblasts Proliferation and Differentiation through VEGFR1-PI3K/Akt Signaling Pathway. International journal of molecular sciences 44 34948148
2016 Expression of vascular endothelial growth factor (VEGF)-B and its receptor (VEGFR1) in murine heart, lung and kidney. Cell and tissue research 37 26928042
2020 VEGF-B signaling impairs endothelial glucose transcytosis by decreasing membrane cholesterol content. EMBO reports 36 32449307
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
2014 Lack of cardiac and high-fat diet induced metabolic phenotypes in two independent strains of Vegf-b knockout mice. Scientific reports 36 25168313
2019 Novel function of VEGF-B as an antioxidant and therapeutic implications. Pharmacological research 35 30851357
2017 Insights into the Mechanisms Involved in Protective Effects of VEGF-B in Dopaminergic Neurons. Parkinson's disease 35 28473940
2005 Redundant roles of VEGF-B and PlGF during selective VEGF-A blockade in mice. Blood 33 16189273
2016 Metformin potentiates anti-tumor effect of resveratrol on pancreatic cancer by down-regulation of VEGF-B signaling pathway. Oncotarget 31 27705937
2016 Dual effects of VEGF-B on activating cardiomyocytes and cardiac stem cells to protect the heart against short- and long-term ischemia-reperfusion injury. Journal of translational medicine 30 27146579
2022 Reducing VEGFB accelerates NAFLD and insulin resistance in mice via inhibiting AMPK signaling pathway. Journal of translational medicine 29 35907871
2020 Susceptibility to Cardiac Arrhythmias and Sympathetic Nerve Growth in VEGF-B Overexpressing Myocardium. Molecular therapy : the journal of the American Society of Gene Therapy 29 32243833
2019 A cyclic peptide reproducing the α1 helix of VEGF-B binds to VEGFR-1 and VEGFR-2 and inhibits angiogenesis and tumor growth. The Biochemical journal 29 30700502
2017 Loss of VEGFB and its signaling in the diabetic heart is associated with increased cell death signaling. American journal of physiology. Heart and circulatory physiology 28 28314760
2009 Expression analysis of VEGF-A and VEGF-B: relationship with clinicopathological parameters in bladder cancer. Oncology reports 28 19424629
2020 VEGF-B ablation in pancreatic β-cells upregulates insulin expression without affecting glucose homeostasis or islet lipid uptake. Scientific reports 25 31969592
2023 Simultaneous blockade of VEGF-B and IL-17A ameliorated diabetic kidney disease by reducing ectopic lipid deposition and alleviating inflammation response. Cell death discovery 24 36646672
2023 A VEGFB-Based Peptidomimetic Inhibits VEGFR2-Mediated PI3K/Akt/mTOR and PLCγ/ERK Signaling and Elicits Apoptotic, Antiangiogenic, and Antitumor Activities. Pharmaceuticals (Basel, Switzerland) 24 37375853
2014 Clinical association of circulating VEGF-B levels with hyperlipidemia and target organ damage in type 2 diabetic patients. Journal of biological regulators and homeostatic agents 24 25001655
2016 VEGF-B inhibits hyperglycemia- and Macugen-induced retinal apoptosis. Scientific reports 22 27189805
2024 VEGFB ameliorates insulin resistance in NAFLD via the PI3K/AKT signal pathway. Journal of translational medicine 21 39468621
2002 Effects of vascular endothelial growth factor (VEGF)A and VEGFB gene transfer on vascular reserve in a conscious rabbit hindlimb ischaemia model. Clinical and experimental pharmacology & physiology 18 12366398
2022 Therapeutic Potential of VEGF-B in Coronary Heart Disease and Heart Failure: Dream or Vision? Cells 17 36552897
2020 Oxidative Stress in Canine Histiocytic Sarcoma Cells Induced by an Infection with Canine Distemper Virus Led to a Dysregulation of HIF-1α Downstream Pathway Resulting in a Reduced Expression of VEGF-B in vitro. Viruses 17 32054075
2024 Autocrine VEGF-B signaling maintains lipid synthesis and mitochondrial fitness to support T cell immune responses. The Journal of clinical investigation 16 39145452
2022 Reducing VEGFB expression regulates the balance of glucose and lipid metabolism in mice via VEGFR1. Molecular medicine reports 16 35894135
2022 Knockdown of VEGFB/VEGFR1 Signaling Promotes White Adipose Tissue Browning and Skeletal Muscle Development. International journal of molecular sciences 15 35886871
2021 Cardiac-specific VEGFB overexpression reduces lipoprotein lipase activity and improves insulin action in rat heart. American journal of physiology. Endocrinology and metabolism 15 34747201
2017 VEGF-B Levels in the Vitreous of Diabetic and Non-Diabetic Patients with Ocular Diseases and Its Correlation with Structural Parameters. Medical sciences (Basel, Switzerland) 15 29099033
2010 The endothelium-dependent effect of RTEF-1 in pressure overload cardiac hypertrophy: role of VEGF-B. Cardiovascular research 15 21169295
2022 Optimized riboswitch-regulated AAV vector for VEGF-B gene therapy. Frontiers in medicine 13 36582287
2021 Elastin-Like Polypeptide: VEGF-B Fusion Protein for Treatment of Preeclampsia. Hypertension (Dallas, Tex. : 1979) 12 34719237
2020 miR-345-5p regulates adipogenesis via targeting VEGF-B. Aging 12 32927430
2020 VEGF-B Is an Autocrine Gliotrophic Factor for Müller Cells under Pathologic Conditions. Investigative ophthalmology & visual science 12 32945843
2019 Effect of ghrelin on VEGF-B and connexin-43 in a rat model of doxorubicin-induced cardiomyopathy. Journal of basic and clinical physiology and pharmacology 11 31730522
2017 VEGFB-VEGFR1 ameliorates Ang II-induced cardiomyocyte hypertrophy through Ca2+ -mediated PKG I pathway. Journal of cellular biochemistry 11 28771828
2020 Gemcitabine potentiates anti-tumor effect of resveratrol on pancreatic cancer via down-regulation of VEGF-B. Journal of cancer research and clinical oncology 10 32897433
2025 VEGF-B is a novel mediator of ER stress which induces cardiac angiogenesis via RGD-binding integrins independent of VEGFR1/NRP activities. Molecular therapy : the journal of the American Society of Gene Therapy 9 40083161
2013 VEGF-B expression in colorectal carcinomas and its relevance for tumor progression. Histology and histopathology 9 23417498
2012 VEGF-A and VEGF-B mRNA expression in gastro-oesophageal cancers. Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico 9 22872519
2025 Vitamin D and exercise improve VEGF-B production and IGF-1 levels in diabetic rats: insights the role of miR-1 suppression. Scientific reports 8 39779732
2022 Long non-coding RNA XIST promotes the malignant features of oral squamous cell carcinoma (OSCC) cells through regulating miR-133a-5p/VEGFB. Histology and histopathology 8 35912960
2018 Silencing VEGF-B Diminishes the Neuroprotective Effect of Candesartan Treatment After Experimental Focal Cerebral Ischemia. Neurochemical research 8 30088238
2024 VEGF-B prevents chronic hyperglycemia-induced retinal vascular leakage by regulating the CDC42-ZO1/VE-cadherin pathway. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 7 39215561
2023 Clinical efficacy and changes of serum VEGF-A, VEGF-B, and PLGF after conbercept treating neovascular age-related macular degeneration. International journal of ophthalmology 6 37724264
2024 Knockdown of the VEGFB/VEGFR1 signaling suppresses pubertal mammary gland development of mice via the inhibition of PI3K/Akt pathway. International journal of biological macromolecules 5 38471613
2021 A Cyclic Peptide Epitope of an Under-Explored VEGF-B Loop 1 Demonstrated In Vivo Anti-Angiogenic and Anti-Tumor Activities. Frontiers in pharmacology 5 34658874
2021 VEGF-B, VEGF-A, FLT-1, KDR, ERBB2, EGFR, GRB2, RAC1, CDH1 and HYAL-1 Genes Expression Analysis in Canine Mammary Gland Tumors and the Association with Tumor ClinicoPathological Parameters and Dog Breed Assessment. Veterinary sciences 5 34679042
2021 LncRNA TINCR improves cardiac hypertrophy by regulating the miR-211-3p-VEGFB-SDF-1α-CXCR4 pathway. Laboratory investigation; a journal of technical methods and pathology 5 34732848
2025 Neuroprotective Effects of VEGF-B in a Murine Model of Aggressive Neuronal Loss with Childhood Onset. International journal of molecular sciences 4 39859255
2024 Knockdown of VEGF-B improves HFD-induced insulin resistance by enhancing glucose uptake in vascular endothelial cells via the PI3K/Akt pathway. International journal of biological macromolecules 4 39631591
2023 Reduction in Insulin Uncovers a Novel Effect of VEGFB on Cardiac Substrate Utilization. Arteriosclerosis, thrombosis, and vascular biology 4 38150518
2022 Role of VEGFB in electrical pulse stimulation inhibits apoptosis in C2C12 myotubes. Peptides 4 35660637
2015 Binding of VEGF-A is sufficient to abrogate the disturbing effects of VEGF-B together with VEGF-A on retinal endothelial cells. Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie 4 25663437

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