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FLASH GENE
Symbol VEGFA contributors: mct/npt/pgu/shn - updated : 19-07-2018
HGNC name vascular endothelial growth factor A
HGNC id 12680
Corresponding disease
HLHS6 hypoplastic left heart syndrome 6
Location 6p21.1      Physical location : 43.737.945 - 43.754.221
Synonym name
  • vascular permeability factor, vasculotropin
  • vascular endothelial growth factor isoform VEGF165
  • vascular endothelial growth factor, VEGF
    • Synonym symbol(s) VPF, VEGF, VEGA, VEGF164, VEGF165, MGC70609, MVCD1
    DNA
    TYPE functioning gene
    STRUCTURE 16.28 kb     8 Exon(s)
    regulatory sequence Binding site   HRE
    text structure
  • hypoxia response element (stimulating angiogenesis through the binding of hypoxia-inducible factors in hypoxia )
  • CTCF binding site from the VEGF promoter behaved like a classic enhancer blocker, interfering strongly with enhancer action in a position-dependent manner
  • GATA5 activation of the VEGFA promoter
    • MAPPING cloned Y linked N status confirmed
    Map pter - D6S271 - D6S1604 - VEGFA - D6S451 - D6S1650 - cen
    RNA
    TRANSCRIPTS type messenger
    text multiple, homodimeric isoforms that are formed as a result of differential splicing of the VEGFA pre-mRNA
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    8 splicing 3614 - 395 widely 2011 21168388
  • also called variant 2 or VEGF189
  • a 8 exons variant
  • containing exon 6b
  • containing exon 7a (longer than 7b)
  • containing exon 8a (longer than 8b)
  • encoding for a 189 amino acids mature peptide (22.03 kDa)
  • cell associated after secretions
  • mostly extracellular cell matrix-associated due to its strong heparin sulfate proteoglycan-binding ability
  • displayed a transient and less marked increase in response to hypoxia as VEGF165
    • 8 splicing 3596 - 389 widely 2001 11352659
  • also called variant 3 or VEGF183
  • a 8 exons variant
  • containing exon 6c (shorter than 6a & 6b)
  • containing exon 7a (longer than 7b)
  • containing exon 8a (longer than 8b)
  • encoding for a 183 amino acids mature peptide (21.28 kDa)
    • 7 splicing 3542 - 371 widely, predominant brain isoform 2011 21168388
  • also called variant 4 or VEGF165
  • a 7 exons variant
  • containing exon 7a (longer than 7b)
  • containing exon 8a (longer than 8b)
  • lacking exon 6
  • a highly basic heparin-binding domain (HBD)
  • secreted protein
  • binding to ADAMTS1 for inhibition of endothelial cell proliferation
  • expression 3-fold higher under hypoxia than normoxia
  • isoform implicated in pro-angiogenic signaling in the endothelium
    • 6 splicing 3410 - 327 widely 2001 11352659
  • also called variant 6 or VEGF121
  • a 6 exons variant
  • containing exon 8a (longer than 8b)
  • lacking exons 6 & 7
  • lacks the highly basic domain and is freely diffusible upon secretion
  • secreted protein
    • 7 splicing 3476 - 371 uncommon 2001 11352659
  • also called variant 7 or VEGF165b
  • a 7 exons variant
  • containing exon 7a (longer than 7b)
  • containing exon 8b (shorter than 8a)
  • lacking exon 6
  • encoding for a 165 amino acids mature peptide (19.11 kDa)
    • 8 splicing 3608 - 209 - - 21168388
    8 splicing 3626 - 215 - - 21168388
  • VEGF189
    • 8 splicing 3665 - 412 widely 2001 11352659
  • also called variant 1 or VEGF206
  • a 8 exons variant
  • containing exon 6a (longer than 6b & 6c)
  • containing exon 7a (longer than 7b)
  • containing exon 8a (longer than 8b)
  • encoding for a 206 amino acids mature peptide (23.90 kDa)
    • 7 splicing 3507 - 354 - 2001 11352659
  • also called variant 5 or VEGF148
  • a 7 exons variant
  • containing exon 7b (shorter than 7a)
  • containing exon 8a (longer than 8b)
  • lacking exon 6
  • encoding for a 148 amino acids mature peptide (17.07 kDa)
    • 7 splicing 3554 - 191 - - 21168388
    VEGF165
    5 splicing 3392 - 317 - - 21168388
    8 splicing 3677 - 232 - - 21168388
    VEGF206
    7 splicing 3519 - 174 - - 21168388
    VEGF148
    6 splicing 3422 - 147 - - 21168388
    VEGF121
    7 splicing 3488 - 191 - 2011 21168388
    VEGF165b
    5 splicing 3392 - 137 - - 21168388
    VEGF111
    7 splicing 3494 - 171 - - 21168388
    VEGF145
    7 splicing 3494 - 351 - - 21168388
    EXPRESSION
    Type widely
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Cardiovascularheart   lowly
    Digestiveliver   highly
    Endocrinepancreas   moderately
     thyroid   highly
    Hearing/Equilibriumearinner    Homo sapiens
    Nervousbrain   moderately
     spinal cord   moderately
    Reproductivefemale systemuterus  moderately
    Respiratoryrespiratory tractlarynx  highly
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Connectiveadipose  moderately
    Epithelialsecretoryglandularendocrine 
    Muscularsmooth   
    Nervouscentral   
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Visualamacrine cell
    VisualMuller cell
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • a 26 AAs signal peptide (3.17 kDa)
  • a platelet-derived growth factor (PDGF) domain
  • two highly basic heparin-binding domain (HBD)encoded by exons 6 and 7, which imparts the ability of these isoforms to be deposited in the heparan sulfate-rich extracellular matrix and to interact with the prototype sulfated glycosaminoglycan, heparin, two basic heparin-binding
  • carboxyl-terminal domain critical for mitogenic potency
    • conjugated GlycoP
    mono polymer homomer , heteromer , dimer
    isoforms Precursor a 206 amino acids mature peptide (23.90 kDa)
    HOMOLOGY
    interspecies ortholog to Vegfa, orthologue
    ortholog to Vegfa, Mus musculus
    ortholog to vegfaa, Danio rerio
    Homologene
    FAMILY
  • PDGF/VEGF growth factor family
    • CATEGORY signaling growth factor
    SUBCELLULAR LOCALIZATION extracellular
    basic FUNCTION
  • vascular endothelial growth factor, key regulator of blood vessel growth, and protecting endothelial cells from apoptosis
  • an essential coordinator of chondrocyte death, chondroclast function, extracellular matrix remodeling, angiogenesis and bone formation in the growth plate
  • angioneurin, involved in vasculogenesis and acting as a neurotrophic factor for motor neurons (protection against ischemic death)
  • a modifier of cardiovascular birth defects in the del22q11 syndrome
  • modulating erythropoiesis through regulation of adult hepatic erythropoietin synthesis and negative regulator of hepatic EPO synthesis and erythropoiesis
  • acting in concert with TGF-beta1 to induce endothelial cell apoptosis
  • having a functional role for recruitment of osteoprogenitor cells in the course of endochondral bone formation or remodeling
  • controls angiogenic sprouting in the early postnatal retina by guiding filopodial extension from specialized endothelial cells situated at the tips of the vascular sprouts
  • role for VEGFA and TNFSF14 in macrophage apoptosis during wound healing, an event critical in the resolution of inflammation
  • playing a role as an inhibitor of neovascularization on the basis of its capacity to disrupt vascular smooth muscle cellsfunction
  • essential role for endocardial cushion formation
  • in primary endothelial cells, hypoxia stimulates VEGFA and FLT1 expression but decreases KDR levels
  • is the most important IL17A-induced angiogenic factor
  • predominant Hh-induced proangiogenic factor driving tumor angiogenesis
  • modulator of NMDAR function in neurons before synapses are formed
  • important for endothelial cell migration and angiogenesis mediated via complex formation between NRP1 and KDR and increased signaling to focal adhesions
  • VEGFA and extracellular collagen matrix (FRK/COL10A1) pathways contribute to the development of advanced age-related macular degeneration
  • plays a key role in controlling neural precursor populations in developing cortex
  • balance between the pro-leakage effects of VEGFA and anti-leakage effects of the angiopoietins (ANGPT1, ANGPT2), in part, modulates vascular integrity and oxygen delivery
  • RUNX2, HIF1A, and VEGFA may regulate vascular angiogenesis spatially and temporally in the hypertrophic zone of the growth plate during endochondral bone formation
  • regulator of vascularization in development and is a key growth factor in tissue repair
  • essential roles in blood vessel growth
  • also promotes a wide range of neuronal functions, including neurogenesis, neuronal migration, neuronal survival and axon guidance
  • mesenchymal stem cells (MSCs)-secreted IL6 and VEGFA may act as paracrine factors to sustain breast cancer cell migration
  • is involved in angiogenesis and osteogenesis coupled during bone formation
  • VEGFA pathway could play a predominant role in the cause of atrioventricular septal defects (AVSD) in Down syndrome
  • myocardially produced VEGFA signals through endocardial KDR to stimulate ventricular endocardial cells to undergo angiogenesis that generates coronary arteries
  • VEGFA and ANGPT1 regulate endothelial cell (EC) junctions by determining the localization of the RHOA-specific guanine nucleotide exchange factor PLEKHG5
  • crucial proangiogenic factor, which regulates blood vessel supply under physiologic and pathologic conditions
  • VEGFA and FGF2 are potent pro-angiogenic factors and play a critical role in cancer development and progression
    • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS angiogenesis
    text
  • a major regulator of blood vessel formation and function
    • PATHWAY
    metabolism
    signaling
  • COL6A1, COL6A2, CRELD1, FBLN2, FRZB, and GATA5 harboring purportedly deleterious case-specific variants in atrioventricular septal defects (AVSD)are associated in some way with VEGFA
  • STAT5A/PRL/VEGFA signaling cascade in human brain endothelial cells (EC)
    • a component
  • homodimer, disulfide-linked
  • also found as heterodimer with PLGF
    • INTERACTION
    DNA
    RNA
    small molecule
    protein
  • secreted protein, acidic and rich in cysteine, SPARC (
  • full-length mTNX (
  • Glypican-1 (
  • connection between EMP2 and VEGFA
  • neuropilin-2, NRP2 (
  • connective tissue growth factor, CTGF
  • SEMA3B
  • neuropilin-1, NRP1 ( and
  • HNRNPD and ELAVL1 (
  • CTCF binds to the proximal promoter of VEGFA
  • HNRNPD regulates VEGFA expression, and it is an RGG peptide that suppresses VEGFA gene expression
  • EDN1 is potent lymphangiogenic factor that relies on the interplay with hypoxic microenvironment and with VEGFA, VEGFC, and FIGF
  • SP7 regulation of VEGFA is independent of HIF1A expression level 6)
  • FLT1 subunits modulate VEGFA activity predominantly by forming heterodimer receptors with KDR subunits and such heterodimers regulate endothelial cell homeostasis
  • HPSE is involved in hypoxia-induced neovascularization through promoting VEGFA expression
  • STAT1 inhibited VEGFA expression, while STAT3 promoted the expression of VEGFA
  • cooperative regulation of VEGFA signaling by FHL1 and SMAD4 was evidenced, which may provide a novel regulation mechanism underlying cancer development and progression
  • caused translocation of PLEKHG5 from cell junctions, promoting junction disassembly
  • hypoxia-induced DDX6 reduction positively affects proangiogenic VEGFA expression
  • VEGFA inhibits EPHB4 and stimulates DLL4 expression in adult endothelial cells
  • PRKD2, mediated BCL6B gene expression by VEGFA stimulation
  • NF1 gene silencing induces upregulation of VEGFA expression in both Schwann and non-Schwann cells
  • VEGFA-induced sFLT1 upregulation can operate as a negative feedback system, which if modulated can become a novel therapeutic target for regulating pathological angiogenesis
  • major role of VEGFA in the regulation of RELN signaling, and DAB1 as a key molecule in the cross talk between reelin and VEGFA signaling pathways
  • LCK upregulates FOXP3 by tyrosine phosphorylation, resulting in decreased MMP9, SKP2, and VEGFA expression, and suppressed cellular invasion
  • MMP9 enhances PRKD2-mediated tumor angiogenesis by releasing extracellular matrix-bound VEGFA, increasing its bioavailability and angiogenesis
  • VEGFA activates EPOR and enhances VEGFR2-mediated pathological angiogenesis
  • FABP4 induction by VEGFA was reduced by blockade of DLL4 binding to NOTCH1 or inhibition of NOTCH1 signal transduction
  • ATF2 is likely functionally required for VEGFA-stimulated endothelial VCAM1 gene expression
  • EHMT2 is an epigenetic regulator of VEGFA alternative splicing
  • overexpression of CASP5 can promote the angiogenesis significantly, possibly by inhibiting the ANGPT1/TEK pathway and promoting VEGFA pathway
  • FGF2 was superior, stimulating cell infiltration and angiogenesis better than TNFSF10 and VEGFA
  • MDK is responsible for increased plasma levels of vascular endothelial growth factor A (VEGFA), necessary and sufficient to promote endothelial cell proliferation in growing collaterals
  • METTL3 regulates osteogenic differentiation and alternative splicing of VEGFA in bone marrow mesenchymal stem cells
    • cell & other
    REGULATION
    activated by HPV oncoprotein E6 in a TP53 independent manner (contributing to tumor angiogenesis)
    induced by hypoxia
    TEAD4, resulting in an increase of angiogenic processes including endothelial cells proliferation and vascular structure formation
    vascular endothelial growth factor A (VEGF-A)
    TGFB1
    repressed by downregulated by VHL
    Other regulated by PI3K, by growth factors, cytokines, gonadotropins, nitric oxide, hypoxia, hypoglycemia and oncogenic mutations
    regulated by hypoxia and cytokines, including insulin-like growth factor-1 (IGF1)
    ASSOCIATED DISORDERS
    corresponding disease(s) HLHS6
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral     --over  
    overexpressed in prostate carcinoma
    constitutional     --over  
    by intensive insulin therapy may cause a transient worsening of retinopathy in patients with diabetes
    tumoral     --over  
    in head and neck squamous cell carcinoma
    tumoral     --over  
    in chondrosarcoma cells
    constitutional     --low  
    decreased expression of FLT1 in decidua and weaker VEGFA and KDR expression in placental villi and decidua may be associated with early pregnancy loss
    Susceptibility
  • to ALS (lateral amyotrophic sclerosis) and other motor neuron degenerations
  • to vascular dementia
  • to neovascular age-related macular degeneration
  • to endocardial cushion defects (ECD)
    • Variant & Polymorphism SNP , other
  • increasing the risk of vascular dementia
  • haplotype increasing the risk of neovascular age-related macular degeneration
  • mutation gain of function provides neuroprotection in models of ALS, parkinson disease, in CNS and PNS injury, and in neuropathy and retinal degeneration
  • mutation loss of function increase risk of ALS
  • 2578 C, -1154 G alleles, and the AAG haplotype are associated with ECD
  • rs4711751 on 6p12 near VEGFA associated with advanced age-related macular degeneration
    • Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    neurologyneurodegenerativeParkinson/dementia Parkinsonism
    VEGFA-expressing human umbilical cord mesenchymal stem cells, an improved therapy strategy for Parkinson's disease
    neuromuscularlaterale amyotrophy sclerosis 
    VEGF treatment increased the life expectancy of ALS mice by 30 per cent without causing toxic side effects
    neurosensorialvisualdegenerative
    therapeutic inhibition of both VEGFA and IL1B or the NLRP3 inflammasome is therefore likely to suppress both forms of AMD
    ANIMAL & CELL MODELS
  • that formation of blood vessels was abnormal, but not abolished, in heterozygous VEGF-deficient (VEGF+/-) mouse embryos and even more impaired in homozygous VEGF-deficient (VEGF-/-) T-ES embryos, resulting in death at mid-gestation
  • loss of a single VEGF allele is lethal in the mouse embryo between days 11 and 12 due to impairment of angiogenesis and blood-island formation
  • Blood vessel invasion is almost completely suppressed, concomitant with impaired trabecular bone formation and expansion of hypertrophic chondrocyte zone in mice inactivated for Vegf
  • deletion of the hypoxia-response element in the Vegf mouse promotor reduced hypoxic Vegf expression in the spinal cord and caused adult-onset progressive motor neuron degeneration, reminiscent of amyotrophic lateral sclerosis
  • absence of the Vegf164 isoform caused birth defects in mice
  • lung-targeted VEGF(165) induced in mice through IL-13-dependent and -independent pathways, an asthma-like phenotype with inflammation, parenchymal and vascular remodeling, edema, mucus metaplasia, myocyte hyperplasia and airway hyper-responsiveness
  • In mouse cerebral cortex, microinjection of VEGF-A disrupted CLN-5 and OCLN and induced loss of barrier function