Attenuation of brain response to vascular endothelial growth factor-mediated angiogenesis and neurogenesis in aged mice
Open accessAbstract
Background and Purpose— Alterations of neuroangiogenic response play important roles in the development of aging-related neurodisorders and affect gene-based therapies. We tested brain response to vascular endothelial growth factor (VEGF) in aged mice. Methods— Adeno-associated viral vector (AAV)-VEGF, an adeno-associated viral vector expressing VEGF, was injected into the brain of 3-, 12-, and 24-month-old mice. AAV-LacZ-injected mice were used as controls (n=6). Before euthanasia at 6 weeks after vector injection, the mice were intraperitoneally injected with 5-bromodeoxyuridine for 3 consecutive days. The vascular density and the number of neuroprogenitors were analyzed. Results— Injection of AAV-VEGF increased the vascular density in the brain of 3-, 12-, and 24-month-old mice by 22%±7% (AAV-VEGF: 320±15 per 10× field versus AAV-LacZ: 263±8, P <0.05), 20%±8 (AAV-VEGF: 300±9 versus AAV-LacZ: 250±11, P <0.05), and 7%±16% (AAV-VEGF: 257±27 versus AAV-LacZ: 236±13, P =0.283), respectively. There were more VEGF receptor-positive neuroprogenitors in the subventricular zone of AAV-VEGF-injected 3- (22±2) and 12-month-old mice (21±5) than that of 24-month-old mice (7±1). More 5-bromodeoxyuridine-positive endothelial cells and neuroprogenitors were detected around the injection site and subventricular zone of 3- (13±4) and 12-month-old mice (14±5) than that of 24-month-old mice (1±1). VEGF receptor 2 was upregulated in AAV-VEGF-injected brains of 3- and 12-month-old mice, but not in 24-month-old mice. Conclusion— The angiogenic and neurogenic response to VEGF stimulation is attenuated in the aged mouse brain, which may be due to reduced VEGF receptor activity.
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Reduced neurogenesis in old animals may relate to lower VEGFR2 expression on neural precursor cells, as reported in 2-year-old mice compared with 3-month-old or 12-month-old mice.
“Reduced neurogenesis in old animals could be related to lower expression of VEGFR2 on the surface of neural precursor cells, as reported in 2-year-old mice compared with 3-month-old or 12-month-old mice.79”
From Promoting brain remodelling and plasticity for stroke recovery: therapeutic promise and potential pitfalls of clinical translation (2012) · cites this paper as [79]
After AAV VEGF vector delivery, proliferation of neural precursor cells and brain capillary formation were compromised in old mice (24 months).
“After delivery of an adeno-associated viral VEGF vector, both proliferation of neural precursor cells and formation of brain capillaries were compromised in old mice (24 months).79”
From Promoting brain remodelling and plasticity for stroke recovery: therapeutic promise and potential pitfalls of clinical translation (2012) · cites this paper as [79]
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References 27 · Cited by 66
- Authors
- Gao, P., Shen, F., Gabriel, R. A., Law, D., Yang, E. Y., Yang, G.-Y., Young, W. L., & Su, H.
- Affiliations
- University of California, San Francisco (US)
- Venue
- Stroke
- Published
- 2009-11
- Volume
- 40
- Issue
- 11
- Pages
- 3596-3600
- ISSN
- 0039-2499 (ISSN-L)
- 1524-4628
- PMC
- PMC2783321
- OpenAlex
- W2160857742
- Cited by
- 66
- References
- 27
- Citations by year
- 2026: 7 · 2025: 1 · 2024: 3 · 2023: 5 · 2022: 3 · 2021: 2 · 2020: 3 · 2019: 2 · 2018: 5 · 2017: 1 · 2015: 8 · 2014: 5 · 2013: 6 · 2012: 8
- FWCI
- 2.00
- Type
- journal article
- Language
- en
- Update notices
- correction (2015-06-01)
- Open access
- bronze
- doi.org
- Locations
- Stroke (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- American Heart Association
- National Institutes of Health
- National Institute of Neurological Disorders and Stroke (P01NS044155, R01NS027713)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Keywords
- vascular endothelial growth factor, angiogenesis, neurogenesis, brain aging, adeno-associated virus vectors, VEGF receptor 2, subventricular zone, vessel density, endothelial cells, aged mice, gene therapy, BrdU labeling, neurodegenerative diseases
- MeSH terms
- Dependovirus, Aging, Animals, Brain Chemistry, Gene Expression Regulation, Genetic Vectors, Mice, Inbred C57BL, Genetic Therapy, Neovascularization, Physiologic, Vascular Endothelial Growth Factor A, Mice, Neurogenesis
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