VEGF (Vascular Endothelial Growth Factor)

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VEGF (Vascular Endothelial Growth Factor)

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VEGF (Vascular Endothelial Growth Factor)

Pathway Diagram

```mermaid
flowchart TD
BMAL1["BMAL1<br/>Circadian Regulator"]
HIF1A["HIF1A<br/>Hypoxia-Inducible Factor"]
VEGF["VEGF<br/>Vascular Endothelial<br/>Growth Factor"]
Angiogenesis["Angiogenesis<br/>Blood Vessel Formation"]
bevacizumab["Bevacizumab<br/>Anti-VEGF Therapy"]

ALS["ALS<br/>Amyotrophic Lateral<br/>Sclerosis"]
MS["Multiple Sclerosis<br/>Demyelinating Disease"]
Alzheimer["Alzheimer's Disease<br/>Neurodegeneration"]
Dementia["Dementia<br/>Cognitive Decline"]
TBI["Traumatic Brain Injury<br/>Acute Injury"]

Neuropathy["Neuropathy<br/>Nerve Damage"]
Inflammation["Inflammation<br/>Immune Response"]
Cancer["Cancer<br/>Malignancy"]

BMAL1 -->|"regulates"| VEGF
HIF1A -->|"regulates"| VEGF
VEGF -->|"promotes"| Angiogenesis
bevacizumab -->|"inhibits"| VEGF

VEGF -->|"activates"| ALS
VEGF -->|"expressed in"| MS
VEGF -->|"associated with"| Alzheimer
VEGF -->|"associated with"| Dementia
VEGF -->|"protective against"| TBI

VEGF -->|"expressed in"| Neuropathy
VEGF -->|"associated with"| Inflammation
VEGF -->|"activates"| Cancer

Angiogenesis -->|"supports"| TBI
Inflammation -->|"contributes to"| ALS
Inflammation -->|"contributes to"| MS

style VEGF fill:#006494
style BMAL1 fill:#4a1a6b
style HIF1A fill:#4a1a6b
style bevacizumab fill:#1b5e20
style Angiogenesis fill:#1b5e20
style TBI fill:#1b5e20
style ALS fill:#ef5350
style MS fill:#ef5350
style A

...

VEGF (Vascular Endothelial Growth Factor)

Pathway Diagram

Mermaid diagram (expand to render)

<div class="infobox" style="float: right; width: 300px; background: #f5f5f5; border: 1px solid #ddd; padding: 10px; margin: 0 0 10px 10px;">
<h3 style="margin-top: 0; border-bottom: 1px solid #ddd;">VEGF</h3>
<table style="font-size: 0.9em; width: 100%;">
<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>
<tr>
<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>
</tr>
</table>
</div>

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

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)

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Related Entities

VEGF

▸Metadataorigin_type: v1_polymorphic_backfill

slug	genes-vegf
kg_node_id	VEGF
entity_type	gene
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-901db9eb010b
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-vegf'}
_schema_version	1

📊 Evidence Profile Foundational

Evidence Balance

+0%

Certainty

100%

Debates

0

Incoming

40

Outgoing

67

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

VEGF (Vascular Endothelial Growth Factor)

VEGF (Vascular Endothelial Growth Factor)

Pathway Diagram

VEGF (Vascular Endothelial Growth Factor)

Pathway Diagram

Overview

Structure and Expression

Normal Function

Role in Neurodegeneration

Alzheimer's Disease

Parkinson's Disease

Amyotrophic Lateral Sclerosis

Stroke and Vascular Dementia

Therapeutic Targeting

VEGF-Based Therapies

Clinical Considerations

Gene Variants and Risk

Interactions

See Also

External Links

References

Pathway Diagram

💬 Discussion