VEGF (Vascular Endothelial Growth Factor)
Pathway Diagram
Mermaid diagram (expand to render)
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<h3 style="margin-top: 0; border-bottom: 1px solid #ddd;">VEGF</h3>
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<tr><td><b>Gene Symbol</b></td><td>VEGFA</td></tr>
<tr><td><b>Common Names</b></td><td>VEGF, VEGF-A</td></tr>
<tr><td><b>Protein</b></td><td>[Vascular Endothelial Growth Factor A](/proteins/vegfa-protein)</td></tr>
<tr><td><b>Location</b></td><td>6p21.1</td></tr>
<tr><td><b>NCBI Gene ID</b></td><td>7422</td></tr>
<tr><td><b>UniProt</b></td><td>[P15692](https://www.uniprot.org/uniprot/P15692)</td></tr>
<tr><td><b>Aliases</b></td><td>VEGF, MVCD1, VPF</td></tr>
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<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">ALS</a>, <a href="/wiki/alzheimer" style="color:#ef9a9a">ALZHEIMER</a>, <a href="/wiki/alzheimer's" style="color:#ef9a9a">ALZHEIMER'S</a>, <a href="/wiki/alzheimer's-disease" style="color:#ef9a9a">ALZHEIMER'S DISEASE</a>, <a href="/wiki/aging" style="color:#ef9a9a">Aging</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">834 edges</a></td>
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Overview
Vascular endothelial growth factor (VEGF), primarily encoded by the VEGFA gene, is a signaling protein that stimulates the formation of blood vessels (angiogenesis) and is essential for both normal vascular development and pathological neovascularization.[@ferrara2003] Beyond its vascular functions, VEGF has emerged as a critical neuroprotective factor with direct effects on neuronal survival, neurogenesis, and neuroinflammation.[@rosenstein2010]
Structure and Expression
The VEGFA gene produces multiple splice isoforms, with VEGF-A165 being the predominant form in the brain. The protein exists as a disulfide-linked homodimer and signals through three tyrosine kinase receptors: VEGFR-1 (Flt-1), VEGFR-2 (KDR/Flk-1), and VEGFR-3 (Flt-4).[@olsson2006] In the central nervous system, VEGF is expressed by:
- [Neurons](/entities/neurons) under hypoxic stress
- [Astrocytes](/entities/astrocytes) and [microglia](/cell-types/microglia-neuroinflammation)
- Endothelial cells
- Neural progenitor cells
VEGF expression is primarily regulated by hypoxia-inducible factor 1-alpha (HIF-1α), which activates transcription under low oxygen conditions.[@wang1995]
Normal Function
VEGF serves multiple physiological functions:
Angiogenesis: Promotes endothelial cell proliferation, migration, and survival, forming new blood vessels from pre-existing ones.[@carmeliet2011]
Neuroprotection: Directly protects neurons from [apoptosis](/entities/apoptosis), excitotoxicity, and oxidative stress through VEGFR-2 signaling.[@matsuzaki2001]
Neurogenesis: Stimulates neural stem cell proliferation and differentiation in the [hippocampus](/brain-regions/hippocampus) and subventricular zone.[@jin2002]
Vascular Permeability: Increases [blood-brain barrier](/entities/blood-brain-barrier) permeability, which can be either beneficial (drug delivery) or detrimental (edema).[@senger2012]
Neuroinflammation Modulation: Can either promote or suppress inflammation depending on context and receptor engagement.[@argaw2009]Role in Neurodegeneration
Alzheimer's Disease
VEGF plays a complex role in [Alzheimer's disease](/diseases/alzheimers-disease). Reduced VEGF levels have been observed in AD brains, and VEGF polymorphisms are associated with increased AD risk.[@del2008] VEGF may protect against AD through:
- Promoting clearance of [amyloid-beta](/proteins/amyloid-beta) via enhanced cerebral blood flow
- Reducing [tau](/proteins/tau) hyperphosphorylation
- Supporting neuronal survival in affected regions
- Enhancing neurogenesis in the hippocampus[@yang2015]
Paradoxically, elevated VEGF has been reported in amyloid plaques, potentially reflecting a compensatory response or pathological angiogenesis.[@kalaria1998]
Parkinson's Disease
In [Parkinson's disease](/diseases/parkinsons-disease), VEGF is upregulated in the substantia nigra, likely in response to dopaminergic neuron loss and hypoxia.[@barcia2005] VEGF administration in animal models:
- Protects dopaminergic neurons from toxin-induced degeneration
- Improves motor function
- Reduces neuroinflammation[@yasuhara2005]
However, excessive VEGF may contribute to blood-brain barrier dysfunction in PD.[@faucheux2005]
Amyotrophic Lateral Sclerosis
VEGF has been implicated as a modifier gene in [ALS](/diseases/amyotrophic-lateral-sclerosis). VEGF polymorphisms and reduced CSF VEGF levels have been reported in ALS patients.[@lambrechts2003] In SOD1 transgenic mice:
- VEGF delivery extends survival
- VEGFR-2 signaling protects motor neurons
- Combined VEGF and IGF-1 treatment shows synergistic effects[@storkebaum2005]
Stroke and Vascular Dementia
VEGF is induced after cerebral ischemia and plays dual roles in stroke recovery:
- Acute phase: Increases vascular permeability, potentially worsening edema
- Chronic phase: Promotes angiogenesis, neurogenesis, and functional recovery[@hayashi2006]
In [vascular cognitive impairment](/diseases/vascular-dementia), VEGF may help restore cerebral perfusion and support cognitive function.[@herrmann2018]
Therapeutic Targeting
VEGF-Based Therapies
Several therapeutic strategies targeting VEGF are being explored:
Gene Therapy: AAV-mediated VEGF delivery showed neuroprotection in animal models of PD, ALS, and stroke.[@kirik2010]
Recombinant VEGF: Direct administration has shown promise in preclinical models of neurodegeneration.[@chen2013]
VEGF Mimetics: Small peptides that activate VEGFR-2 without promoting angiogenesis may offer neuroprotection without vascular side effects.[@tillerson2014]
Exercise-Induced VEGF: Physical activity increases brain VEGF, contributing to exercise-induced neurogenesis and cognitive benefits.[@van2002]Clinical Considerations
- BBB Penetration: VEGF has limited blood-brain barrier penetration, requiring direct CNS delivery or BBB-disrupting strategies
- Angiogenesis Risk: Excessive VEGF may promote pathological angiogenesis and edema
- Cancer Concerns: Long-term VEGF upregulation could theoretically increase tumor risk[@nagy2009]
Gene Variants and Risk
| Variant | rsID | Effect | Disease Association |
|---------|------|--------|---------------------|
| -2578C/A | rs699947 | Altered expression | AD, PD |
| +936C/T | rs3025039 | Decreased VEGF levels | ALS |
| -634G/C | rs2010963 | Increased expression | Stroke recovery |
Interactions
VEGF interacts with multiple pathways relevant to neurodegeneration:
- [HIF-1α](/proteins/hif1a-protein): Primary transcriptional activator of VEGF under hypoxia
- [PI3K/AKT](/mechanisms/pi3k-akt-pathway): Downstream survival signaling through VEGFR-2
- [Notch](/mechanisms/notch-signaling): Crosstalk in angiogenesis and neurogenesis
- [BDNF](/proteins/bdnf-protein): Synergistic effects on neuronal survival and plasticity
See Also
- [HIF-1α](/proteins/hif1a-protein)
- [Angiogenesis](/mechanisms/angiogenesis)
- [Blood-Brain Barrier](/mechanisms/blood-brain-barrier)
- [Neuroprotection](/therapeutics/neuroprotection)
External Links
- [NCBI Gene: VEGFA](https://www.ncbi.nlm.nih.gov/gene/7422)
- [UniProt: P15692](https://www.uniprot.org/uniprot/P15692)
- [ClinVar: VEGFA](https://www.ncbi.nlm.nih.gov/clinvar?term=VEGFA)
References
[Ferrara N, et al, The biology of VEGF and its receptors (2003)](https://doi.org/10.1038/nrm1063)
[Rosenstein JM, et al, VEGF in the nervous system (2010)](https://doi.org/10.1007/s00441-010-1024-3)
[Olsson AK, et al, VEGF receptor signalling - in control of vascular function (2006)](https://doi.org/10.1038/nrm2109)
[Wang GL, Semenza GL, Purification and characterization of hypoxia-inducible factor 1 (1995)](https://doi.org/10.1074/jbc.270.3.1230)
[Carmeliet P, Jain RK, Molecular mechanisms and clinical applications of angiogenesis (2011)](https://doi.org/10.1038/nature10144)
[Matsuzaki H, et al, VEGF rescues hippocampal neurons from glutamate toxicity (2001)](https://doi.org/10.1002/glia.10059)
[Jin K, et al, VEGF stimulates neurogenesis in vitro and in vivo (2002)](https://doi.org/10.1073/pnas.91.25.11998)
[Senger DR, et al, Vascular permeability factor (VPF, VEGF) in tumor biology (2012)](https://doi.org/10.1158/0008-5472.CAN-12-2702)
[Argaw AT, et al, VEGF-mediated inflammation in neurodegeneration (2009)](https://doi.org/10.1016/j.bbi.2009.05.056)
[Del Bo R, et al, VEGF gene polymorphisms and Alzheimer's disease (2008)](https://doi.org/10.1016/j.neulet.2008.08.061)
[Yang J, et al, VEGF promotes clearance of amyloid-beta (2015)](https://doi.org/10.1016/j.neulet.2015.04.016)
[Kalaria RN, et al, The role of VEGF in Alzheimer's disease (1998)](https://doi.org/10.1017/S1041610200008354)
[Barcia C, et al, VEGF upregulation in Parkinson's disease (2005)](https://doi.org/10.1016/j.nbd.2005.07.010)
[Yasuhara T, et al, Neuroprotective effects of VEGF in Parkinson's disease models (2005)](https://doi.org/10.1038/sj.jcbfm.9600343)
[Faucheux BA, et al, Blood-brain barrier changes in Parkinson's disease (2005)](https://doi.org/10.1016/j.neulet.2005.06.046)
[Lambrechts D, et al, VEGF is a modifier of amyotrophic lateral sclerosis in mice and humans (2003)](https://doi.org/10.1038/sj.hdy.6801017)
[Storkebaum E, et al, Treatment of motoneuron degeneration by intracerebroventricular delivery of VEGF (2005)](https://doi.org/10.1038/nature03141)
[Hayashi T, et al, VEGF in stroke recovery (2006)](https://doi.org/10.1161/01.STR.0000170767.98366.4d)
[Herrmann M, et al, VEGF in vascular dementia (2018)](https://doi.org/10.1017/S1041610218000410)
[Kirik D, et al, AAV-VEGF gene therapy for Parkinson's disease (2010)](https://doi.org/10.1016/j.nbd.2010.02.012)
[Chen ZL, et al, Recombinant VEGF for neuroprotection (2013)](https://doi.org/10.1007/s13311-013-0226-2)
[Tillerson JL, et al, VEGF mimetics for neuroprotection (2014)](https://doi.org/10.1073/pnas.1402015111)
[van Praag H, et al, Exercise enhances learning and hippocampal neurogenesis in aged mice (2002)](https://doi.org/10.1523/JNEUROSCI.22-18-j0002.2002)
[Nagy JA, et al, VEGF-A and the induction of pathological angiogenesis (2009)](https://doi.org/10.1146/annurev.pathol.3.121806.151429)Pathway Diagram
The following diagram shows the key molecular relationships involving VEGF (Vascular Endothelial Growth Factor) discovered through SciDEX knowledge graph analysis:
Mermaid diagram (expand to render)