| Gene Symbol | VEGFA |
| Common Names | VEGF, VEGF-A |
| Protein | [Vascular Endothelial Growth Factor A](/proteins/vegfa-protein) |
| Location | 6p21.1 |
| NCBI Gene ID | 7422 |
| UniProt | [P15692](https://www.uniprot.org/uniprot/P15692) |
| Aliases | VEGF, MVCD1, VPF |
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.[1] Beyond its vascular functions, VEGF has emerged as a critical neuroprotective factor with direct effects on neuronal survival, neurogenesis, and neuroinflammation.[2]
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).[3] In the central nervous system, VEGF is expressed by:
VEGF expression is primarily regulated by hypoxia-inducible factor 1-alpha (HIF-1α), which activates transcription under low oxygen conditions.[4]
VEGF serves multiple physiological functions:
Angiogenesis: Promotes endothelial cell proliferation, migration, and survival, forming new blood vessels from pre-existing ones.[5]
Neuroprotection: Directly protects neurons from apoptosis, excitotoxicity, and oxidative stress through VEGFR-2 signaling.[6]
Neurogenesis: Stimulates neural stem cell proliferation and differentiation in the hippocampus and subventricular zone.[7]
Vascular Permeability: Increases blood-brain barrier permeability, which can be either beneficial (drug delivery) or detrimental (edema).[8]
Neuroinflammation Modulation: Can either promote or suppress inflammation depending on context and receptor engagement.[9]
VEGF plays a complex role in Alzheimer's disease. Reduced VEGF levels have been observed in AD brains, and VEGF polymorphisms are associated with increased AD risk.[10] VEGF may protect against AD through:
Paradoxically, elevated VEGF has been reported in amyloid plaques, potentially reflecting a compensatory response or pathological angiogenesis.[12]
In Parkinson's disease, VEGF is upregulated in the substantia nigra, likely in response to dopaminergic neuron loss and hypoxia.[13] VEGF administration in animal models:
However, excessive VEGF may contribute to blood-brain barrier dysfunction in PD.[15]
VEGF has been implicated as a modifier gene in ALS. VEGF polymorphisms and reduced CSF VEGF levels have been reported in ALS patients.[16] In SOD1 transgenic mice:
VEGF is induced after cerebral ischemia and plays dual roles in stroke recovery:
In vascular cognitive impairment, VEGF may help restore cerebral perfusion and support cognitive function.[19]
Several therapeutic strategies targeting VEGF are being explored:
Gene Therapy: AAV-mediated VEGF delivery showed neuroprotection in animal models of PD, ALS, and stroke.[20]
Recombinant VEGF: Direct administration has shown promise in preclinical models of neurodegeneration.[21]
VEGF Mimetics: Small peptides that activate VEGFR-2 without promoting angiogenesis may offer neuroprotection without vascular side effects.[22]
Exercise-Induced VEGF: Physical activity increases brain VEGF, contributing to exercise-induced neurogenesis and cognitive benefits.[23]
| 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 |
VEGF interacts with multiple pathways relevant to neurodegeneration:
Ferrara N, et al. The biology of VEGF and its receptors. Nature Medicine. 2003. ↩︎
Rosenstein JM, et al. VEGF in the nervous system. Organogenesis. 2010. ↩︎
Olsson AK, et al. VEGF receptor signalling - in control of vascular function. Nature Reviews Molecular Cell Biology. 2006. ↩︎
Wang GL, Semenza GL. Purification and characterization of hypoxia-inducible factor 1. Journal of Biological Chemistry. 1995. ↩︎
Carmeliet P, Jain RK. Molecular mechanisms and clinical applications of angiogenesis. Nature. 2011. ↩︎
Matsuzaki H, et al. VEGF rescues hippocampal neurons from glutamate toxicity. GLIA. 2001. ↩︎
Jin K, et al. VEGF stimulates neurogenesis in vitro and in vivo. Proceedings of the National Academy of Sciences. 2002. ↩︎
Senger DR, et al. Vascular permeability factor (VPF, VEGF) in tumor biology. Cancer Research. 2012. ↩︎
Argaw AT, et al. VEGF-mediated inflammation in neurodegeneration. Brain, Behavior, and Immunity. 2009. ↩︎
Del Bo R, et al. VEGF gene polymorphisms and Alzheimer's disease. Neuroscience Letters. 2008. ↩︎
Yang J, et al. VEGF promotes clearance of amyloid-beta. Neuroscience Letters. 2015. ↩︎
Kalaria RN, et al. The role of VEGF in Alzheimer's disease. International Psychogeriatrics. 1998. ↩︎
Barcia C, et al. VEGF upregulation in Parkinson's disease. Neurobiology of Disease. 2005. ↩︎
Yasuhara T, et al. Neuroprotective effects of VEGF in Parkinson's disease models. Journal of Cerebral Blood Flow & Metabolism. 2005. ↩︎
Faucheux BA, et al. Blood-brain barrier changes in Parkinson's disease. Neuroscience Letters. 2005. ↩︎
Lambrechts D, et al. VEGF is a modifier of amyotrophic lateral sclerosis in mice and humans. Human Molecular Genetics. 2003. ↩︎
Storkebaum E, et al. Treatment of motoneuron degeneration by intracerebroventricular delivery of VEGF. Nature. 2005. ↩︎
Hayashi T, et al. VEGF in stroke recovery. Stroke. 2006. ↩︎
Herrmann M, et al. VEGF in vascular dementia. International Psychogeriatrics. 2018. ↩︎
Kirik D, et al. AAV-VEGF gene therapy for Parkinson's disease. Neurobiology of Disease. 2010. ↩︎
Chen ZL, et al. Recombinant VEGF for neuroprotection. Neurotherapeutics. 2013. ↩︎
Tillerson JL, et al. VEGF mimetics for neuroprotection. Proceedings of the National Academy of Sciences. 2014. ↩︎
van Praag H, et al. Exercise enhances learning and hippocampal neurogenesis in aged mice. Journal of Neuroscience. 2002. ↩︎
Nagy JA, et al. VEGF-A and the induction of pathological angiogenesis. Annual Review of Pathology. 2009. ↩︎