Endothelial nitric oxide synthase regulates brain-derived neurotrophic factor expression and neurogenesis after stroke in mice
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Here, we investigate the effects of endothelial nitric oxide synthase (eNOS) on angiogenesis, neurogenesis, neurotrophic factor expression, and neurological functional outcome after stroke. Wild-type and eNOS knock-out ( eNOS -/- ) mice were subjected to permanent occlusion of the right middle cerebral artery. eNOS -/- mice exhibited more severe neurological functional deficit after stroke than wild-type mice. Decreased subventricular zone (SVZ) progenitor cell proliferation and migration, measured using bromodeoxyuridine, Ki-67, nestin, and doublecortin immunostaining in the ischemic brain, and decreased angiogenesis, as demonstrated by reduced endothelial cell proliferation, vessel perimeter, and vascular density in the ischemic border, were evident in eNOS -/- mice compared with wild-type mice. eNOS-deficient mice also exhibited a reduced response to vascular endothelial growth factor (VEGF)-induced angiogenesis in a corneal assay. ELISAs showed that eNOS -/- mice have decreased brain-derived neurotrophic factor (BDNF) expression but not VEGF and basic fibroblast growth factor in the ischemic brain compared with wild-type mice. In addition, cultured SVZ neurosphere formation, proliferation, telomerase activity, and neurite outgrowth but not cell viability from eNOS -/- mice were significantly reduced compared with wild-type mice. BDNF treatment of SVZ cells derived from eNOS -/- mice restored the decreased neurosphere formation, proliferation, neurite outgrowth, and telomerase activity in cultured eNOS -/- SVZ neurospheres. SVZ explant cell migration also was significantly decreased in eNOS -/- mice compared with wild-type mice. These data indicate that eNOS is not only a downstream mediator for VEGF and angiogenesis but also regulates BDNF expression in the ischemic brain and influences progenitor cell proliferation, neuronal migration, and neurite outgrowth and affects functional recovery after stroke.
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Interactions between endothelial cells and neuroblasts are especially strong during the first month after stroke.
“The interactions between endothelial cells and neuroblasts are especially strong during the first month after stroke.57,58”
From Promoting brain remodelling and plasticity for stroke recovery: therapeutic promise and potential pitfalls of clinical translation (2012) · cites this paper as [57]
Newly formed microvessels exert trophic influences on brain parenchyma via release of growth factors such as BDNF.
“Newly formed microvessels exert trophic influences on the brain parenchyma via release of growth factors, such as BDNF.57”
From Promoting brain remodelling and plasticity for stroke recovery: therapeutic promise and potential pitfalls of clinical translation (2012) · cites this paper as [57]
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- Authors
- Chen, J., Zacharek, A., Zhang, C., Jiang, H., Li, Y., Roberts, C., Lu, M., Kapke, A., & Chopp, M.
- Affiliations
- Henry Ford Health (US)
- Oakland University (US)
- Corresponding author
- Chopp, Michael
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2005-03-02
- Volume
- 25
- Issue
- 9
- Pages
- 2366-2375
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC2791344
- OpenAlex
- W1987444038
- Cited by
- 287
- References
- 57
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 6 · 2023: 4 · 2022: 6 · 2021: 16 · 2020: 13 · 2019: 8 · 2018: 14 · 2017: 14 · 2016: 12 · 2015: 24 · 2014: 25 · 2013: 18 · 2012: 17
- FWCI
- 4.99
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (R01NS047682, P01NS023393)
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- endothelial nitric oxide synthase, brain-derived neurotrophic factor, stroke, neurogenesis, angiogenesis, neurosphere formation, telomerase activity, neurite outgrowth, vascular endothelial growth factor, neuronal migration, neurological recovery, middle cerebral artery occlusion, ischemic brain
- MeSH terms
- Doublecortin Domain Proteins, Animals, Blood Pressure, Brain, Bromodeoxyuridine, Cell Count, Cell Movement, Disease Models, Animal, Enzyme-Linked Immunosorbent Assay, Immunohistochemistry, Intermediate Filament Proteins, Male, Mice, Inbred C57BL, Microtubule-Associated Proteins, Naphthalenes, Nerve Tissue Proteins, Neurologic Examination, Neuropeptides, Oxepins, Psychomotor Performance, Time Factors, Gene Expression, Neurites, Corneal Neovascularization, Mice, Knockout, Telomerase, Brain-Derived Neurotrophic Factor, Ki-67 Antigen, Recovery of Function, Infarction, Middle Cerebral Artery, Vascular Endothelial Growth Factor A, Endothelial Cells, Cell Proliferation, Mice, Nitric Oxide Synthase Type III, Nestin
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