Intracerebroventricularly delivered VEGF promotes contralesional corticorubral plasticity after focal cerebral ischemia via mechanisms involving anti-inflammatory actions
Open accessAbstract
Vascular endothelial growth factor (VEGF) has potent angiogenic and neuroprotective effects in the ischemic brain. Its effect on axonal plasticity and neurological recovery in the post-acute stroke phase was unknown. Using behavioral tests combined with anterograde tract tracing studies and with immunohistochemical and molecular biological experiments, we examined effects of a delayed i.c.v. delivery of recombinant human VEGF(165), starting 3 days after stroke, on functional neurological recovery, corticorubral plasticity and inflammatory brain responses in mice submitted to 30 min of middle cerebral artery occlusion. We herein show that the slowly progressive functional improvements of motor grip strength and coordination, which are induced by VEGF, are accompanied by enhanced sprouting of contralesional corticorubral fibres that branched off the pyramidal tract in order to cross the midline and innervate the ipsilesional parvocellular red nucleus. Infiltrates of CD45+ leukocytes were noticed in the ischemic striatum of vehicle-treated mice that closely corresponded to areas exhibiting Iba-1+ activated microglia. VEGF attenuated the CD45+ leukocyte infiltrates at 14 but not 30 days post ischemia and diminished the microglial activation. Notably, the VEGF-induced anti-inflammatory effect of VEGF was associated with a downregulation of a broad set of inflammatory cytokines and chemokines in both brain hemispheres. These data suggest a link between VEGF's immunosuppressive and plasticity-promoting actions that may be important for successful brain remodeling. Accordingly, growth factors with anti-inflammatory action may be promising therapeutics in the post-acute stroke phase.
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Contralesional sprouting after growth factor treatment is associated with profound alterations of gene expression, including downregulation of axonal growth inhibitors and inflammatory signals near the contralesional pyramidal tract.
“Contralesional sprouting after treatment with growth factors is associated with profound alterations of gene expression, including the downregulation of axonal growth inhibitors19,24 and inflammatory signals19,31 in the vicinity of the contralesional pyramidal tract.”
From Promoting brain remodelling and plasticity for stroke recovery: therapeutic promise and potential pitfalls of clinical translation (2012) · cites this paper as [31]
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- Authors
- Herz, J., Reitmeir, R., Hagen, S. I., Reinboth, B. S., Guo, Z., Zechariah, A., ElAli, A., Doeppner, T. R., Bacigaluppi, M., Pluchino, S., Kilic, Ü., Kilic, E., & Hermann, D. M.
- Affiliations
- Essen University Hospital (DE)
- IRCCS Ospedale San Raffaele (IT)
- Corresponding author
- Hermann, Dirk M.
- ORCID
- Venue
- Neurobiology of Disease
- Publisher
- Elsevier BV
- Published
- 2012-03
- Volume
- 45
- Issue
- 3
- Pages
- 1077-1085
- ISSN
- 0969-9961 (ISSN-L)
- PMC
- PMC4578250
- OpenAlex
- W2113117126
- Cited by
- 62
- References
- 45
- Citations by year
- 2026: 1 · 2025: 3 · 2022: 5 · 2021: 5 · 2020: 3 · 2019: 5 · 2018: 5 · 2017: 5 · 2016: 5 · 2015: 3 · 2014: 10 · 2013: 5 · 2012: 6
- FWCI
- 3.71
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Neurobiology of Disease (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- BORIS (University Library Bern) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- German Research Foundation (HE3173/2-1, HE3173/3-1)
- Dr. Werner Jackstädt Foundation
- Heinz Nixdorf Foundation
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Rehabilitation › Stroke Rehabilitation and Recovery
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- vascular endothelial growth factor, VEGF165, intracerebroventricular administration, middle cerebral artery occlusion, focal cerebral ischemia, stroke recovery, anti-inflammatory activity, microglial activation, leukocyte infiltration, inflammatory cytokines, chemokines, red nucleus, corticospinal tract, brain remodeling
- MeSH terms
- Animals, Anti-Inflammatory Agents, Biotin, Brain Edema, Cerebral Cortex, Cerebral Infarction, Dextrans, Disease Models, Animal, Gene Expression Regulation, Injections, Intraventricular, Functional Laterality, Male, Mice, Inbred C57BL, Motor Activity, Nerve Degeneration, Neural Pathways, Neuronal Plasticity, Organometallic Compounds, Organophosphorus Compounds, Red Nucleus, Cytokines, Hand Strength, Infarction, Middle Cerebral Artery, Vascular Endothelial Growth Factor A, Mice
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