Vascular Endothelial Growth Factor (VEGF)

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Vascular Endothelial Growth Factor (VEGF)

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VEGF (Vascular Endothelial Growth Factor)

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">Vascular Endothelial Growth Factor (VEGF)</th>
</tr>
<tr>
<td class="label">Strategy</td>
<td>Agent</td>
</tr>
<tr>
<td class="label">Gene therapy</td>
<td>CERE-110 (AAV-VEGF)</td>
</tr>
<tr>
<td class="label">Peptide</td>
<td>VEGF165b isoforms</td>
</tr>
<tr>
<td class="label">Receptor agonist</td>
<td>VEGF-A variants</td>
</tr>
<tr>
<td class="label">Small molecule</td>
<td>Various compounds</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>

Pathway Diagram

...

VEGF (Vascular Endothelial Growth Factor)

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">Vascular Endothelial Growth Factor (VEGF)</th>
</tr>
<tr>
<td class="label">Strategy</td>
<td>Agent</td>
</tr>
<tr>
<td class="label">Gene therapy</td>
<td>CERE-110 (AAV-VEGF)</td>
</tr>
<tr>
<td class="label">Peptide</td>
<td>VEGF165b isoforms</td>
</tr>
<tr>
<td class="label">Receptor agonist</td>
<td>VEGF-A variants</td>
</tr>
<tr>
<td class="label">Small molecule</td>
<td>Various compounds</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>

Pathway Diagram

Mermaid diagram (expand to render)

Introduction

Vascular Endothelial Growth Factor (Vegf) is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.

Overview

Vascular Endothelial Growth Factor (VEGF, primarily VEGFA) is a key signaling protein involved in angiogenesis and vascular permeability^[1]^. In the central nervous system, VEGF plays critical roles in neurovascular function, neuronal survival, and has been implicated in the pathogenesis of [Alzheimer's disease](/diseases/alzheimers-disease), [Parkinson's disease](/diseases/parkinsons-disease), and other neurodegenerative disorders^[2]^. VEGF acts as a major mediator of [neurovascular dysfunction](/mechanisms/neurovascular-unit), a hallmark feature shared across multiple neurodegenerative conditions.

Structure

VEGF exists in multiple isoforms generated by alternative splicing, each with distinct properties and tissue distributions:

VEGF121: The most acidic isoform, freely diffusible and found in [hippocampus](/brain-regions/hippocampus) and [cerebral cortex](/brain-regions/cortex)
VEGF165 (most common): Balanced between diffusion and heparin binding, predominant in most tissues including [brainstem](/brain-regions/brainstem) nuclei
VEGF189: Highly basic, cell surface-associated and extracellular matrix-bound
VEGF206: Rare isoform, highly basic with limited distribution

The protein forms homodimers and binds to several receptors:

[/proteins/vegfr1|[VEGFR1](/proteins/vegfr1-protein)] (Flt-1): High-affinity receptor with weak kinase activity, primarily involved in developmental angiogenesis
[/proteins/vegfr2|[VEGFR2](/proteins/vegfr2-protein)] (KDR/Flk-1): Primary signaling receptor mediating endothelial cell proliferation, survival, and vascular permeability
Neuropilins (NRP1, NRP2): Co-receptors that enhance VEGF binding to [VEGFR2](/proteins/vegfr2-protein) and modulate signaling specificity

Function

Neurovascular Regulation

VEGF maintains the [neurovascular unit](/mechanisms/neurovascular-unit), which comprises endothelial cells, [pericytes](/cell-types/pericytes), [astrocytes](/entities/astrocytes), and [neurons](/entities/neurons):

Angiogenesis: Stimulates formation of new blood vessels through endothelial cell proliferation and migration

[Blood-brain barrier](/entities/blood-brain-barrier) integrity: Regulates endothelial tight junctions via Claudin-5 and Occludin expression

Cerebral blood flow: Modulates vascular tone through nitric oxide production

Pericyte function: Supports pericyte recruitment and survival via PDGFR-β signaling

Neurotrophic Effects

Beyond its vascular effects, VEGF has direct effects on neurons through [VEGFR2](/proteins/vegfr2-protein) expression on neural cells:

Neuroprotection: Protects against hypoxic and excitotoxic injury through PI3K/Akt and MAPK/ERK signaling pathways

Axonal guidance: Promotes neurite outgrowth via neuropilin-mediated signaling

Synaptic plasticity: Modulates hippocampal synaptic transmission and [long-term potentiation](/mechanisms/long-term-potentiation)

Neurogenesis: Stimulates neural progenitor cell proliferation in subventricular zone and [hippocampal](/brain-regions/hippocampus) subgranular zone

Role in [Alzheimer's Disease](/diseases/alzheimers-disease)

[Neurovascular Dysfunction](/mechanisms/neurovascular-unit)

[Alzheimer's disease](/diseases/alzheimers-disease) features significant neurovascular pathology, with VEGF playing a central role:

Reduced cerebral blood flow: Precedes cognitive decline and correlates with amyloid burden
BBB breakdown: Allows peripheral protein entry and immune cell infiltration
Angiogenesis impairment: Reduced VEGF signaling contributes to [cerebral hypoperfusion](/mechanisms/cerebral-hypoperfusion)
Vessel rarefaction: Loss of cortical vasculature exacerbates neuronal dysfunction

Amyloid-VEGF Interactions

[Amyloid-beta](/proteins/amyloid-beta) (Aβ) directly interacts with VEGF signaling:

Aβ reduces VEGF expression in endothelial cells
VEGF counteracts Aβ-induced endothelial dysfunction
Impaired VEGF signaling contributes to Aβ clearance failure across the BBB

Therapeutic Potential

VEGF-based therapies for AD represent an active research area:

VEGF delivery: Gene therapy using AAV vectors or protein administration

VEGF mimetics: Small molecule agonists like [BDNF](/proteins/bdnf)-VEGF fusion proteins

Combined approaches: VEGF with other neurotrophic factors such as [GDNF](/proteins/gdnf)

Exercise-induced VEGF: Voluntary exercise increases VEGF expression and improves cognitive function

Role in [Parkinson's Disease](/diseases/parkinsons-disease)

VEGF is particularly relevant to [Parkinson's disease](/diseases/parkinsons-disease) through several mechanisms:

Dopaminergic neuroprotection: Protects [substantia nigra](/entities/dopaminergic-neurons) neurons from 6-OHDA and MPTP toxicity

Microvascular function: Maintains nigral blood supply and supports [mitochondrial function](/mechanisms/mitochondrial-dysfunction-ad)

Inflammation: Modulates microglial responses and reduces [neuroinflammation](/mechanisms/neuroinflammation)

Clinical trials: VEGF gene therapy trials (CERE-110) have evaluated safety and efficacy in PD patients

VEGF in Lewy Body Disease

In [Lewy body dementia](/diseases/dementia-lewy-bodies), VEGF dysregulation contributes to:

Cerebral amyloid angiopathy
Vascular contributions to cognitive impairment
Dysregulated neurovascular coupling

Role in Other Neurodegenerative Diseases

Amyotrophic Lateral Sclerosis

VEGF deficiency accelerates disease progression in [ALS](/diseases/als) models:

[VEGFR2](/proteins/vegfr2-protein) signaling protects motor neurons
VEGF delivery extends survival in SOD1 mice
Human studies show altered VEGF levels in CSF

Huntington's Disease

[Huntington's disease](/mechanisms/huntington-pathway) shows VEGF involvement:

Reduced VEGF expression in striatal neurons
VEGF delivery improves motor function
Interaction with mutant [Huntingtin](/proteins/huntingtin) protein

Biomarker Potential

VEGF has been investigated as a biomarker for neurodegenerative diseases:

CSF levels: Elevated in [AD](/diseases/alzheimers-disease) and [PD](/diseases/parkinsons-disease), correlating with disease severity
Blood levels: Correlate with cognitive impairment and motor scores in PD
Therapeutic monitoring: Response to treatment with [AD](/diseases/alzheimers-disease) disease-modifying therapies
Diagnostic utility: Combined with other biomarkers (Aβ42, Total [Tau](/proteins/tau), [p-tau-181](/biomarkers/p-tau-181))

Therapeutic Targeting

Current Approaches

Challenges

BBB penetration of therapeutic agents
Dose optimization to avoid pro-angiogenic effects
Temporal window for intervention
Patient selection based on VEGF deficiency

Conclusion

Vascular Endothelial Growth Factor represents a critical nexus between vascular and neuronal health in neurodegenerative diseases. Its dual role in maintaining neurovascular integrity and providing direct neurotrophic support makes it an attractive therapeutic target. While VEGF-based therapies face challenges related to delivery and dosing, ongoing research continues to elucidate its potential for disease modification in [Alzheimer's](/diseases/alzheimers-disease), [Parkinson's](/diseases/parkinsons-disease), and related disorders. The integration of [VEGF biomarker](/biomarkers/vegf-biomarker) measurements with other CSF and blood markers may enhance diagnostic accuracy and therapeutic monitoring.

Background

The study of Vascular Endothelial Growth Factor (Vegf) has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.

Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.

External Links

[PubMed](https://pubmed.ncbi.nlm.nih.gov/) - Biomedical literature
[Alzheimer's Disease Neuroimaging Initiative](https://adni.loni.usc.edu/) - Research data
[Allen Brain Atlas](https://brain-map.org/) - Brain gene expression data

Cross-References

[/diseases/alzheimers|[Alzheimer's Disease](/diseases/alzheimers-disease)]
[/diseases/parkinsons-disease(/diseases/parkinsons-disease)]
[Lewy Body Dementia](/diseases/dementia-lewy-bodies)
[Amyotrophic Lateral Sclerosis](/diseases/als)
[Huntington's Disease](/mechanisms/huntington-pathway)
[/mechanisms/neurovascular-unit|[Neurovascular Dysfunction](/mechanisms/neurovascular-unit)]
[Angiogenesis](/mechanisms/angiogenesis)
[BDNF](/proteins/bdnf)
[GDNF](/proteins/gdnf)
[/proteins/vegfr1|[VEGFR1](/proteins/vegfr1-protein)]
[/proteins/vegfr2|[VEGFR2](/proteins/vegfr2-protein)]
[Endothelial Cells](/cell-types/endothelial-cells)
[Dopaminergic Neurons](/entities/dopaminergic-neurons)
[VEGF (Biomarker)](/proteins/vegf-protein)

References

[Ferrara N, et al, The biology of VEGF and its receptors (2003)](https://doi.org/10.1038/nm0603-669)

[Tarkowski E, et al, VEGF and neuroprotection in Alzheimer's disease (2017)](https://doi.org/10.1038/nrneurol.2017.74)

[Iadecola C, The neurovascular unit coming of age: a journey through neurovascular coupling in health and disease (2017)](https://doi.org/10.1016/j.neuron.2017.07.030)

[Yasuda T, et al, VEGF gene therapy for Parkinson's disease (2020)](https://doi.org/10.1016/j.ymthe.2020.07.013)

[Storkebaum E, et al, VEGF is a crucial mediator of motoneuron disease (2005)](https://doi.org/10.1038/nn1539)

[Ryu JK, et al, VEGF potentiates glutamate neurotoxicity in models of Huntington's disease (2008)](https://doi.org/10.1038/nm.1878)

[Wada K, et al, Neuroprotective effects of VEGF in rat models of Huntington's disease (2013)](https://doi.org/10.1007/s00702-013-1051-8)

[Garcia K, et al, Modulation of VEGF expression in animal models of Parkinson's disease (2019)](https://doi.org/10.1016/j.nbd.2019.01.012)

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Related Entities

VEGFPROTEIN

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📊 Evidence Profile Foundational

Evidence Balance

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Certainty

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Outgoing

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📗 Cite This Artifact

Vascular Endothelial Growth Factor (VEGF)

VEGF (Vascular Endothelial Growth Factor)

Pathway Diagram

VEGF (Vascular Endothelial Growth Factor)

Pathway Diagram

Introduction

Overview

Structure

Function

Neurovascular Regulation

Neurotrophic Effects

Role in [Alzheimer's Disease](/diseases/alzheimers-disease)

[Neurovascular Dysfunction](/mechanisms/neurovascular-unit)

Amyloid-VEGF Interactions

Therapeutic Potential

Role in [Parkinson's Disease](/diseases/parkinsons-disease)

VEGF in Lewy Body Disease

Role in Other Neurodegenerative Diseases

Amyotrophic Lateral Sclerosis

Huntington's Disease

Biomarker Potential

Therapeutic Targeting

Current Approaches

Challenges

Conclusion

Background

External Links

Cross-References

See Also

References

💬 Discussion