Cited by 218Barrier Structure and Function StudiesAngiogenesis and VEGF in CancerNeuroprotection in Cerebral Ischemia

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The phosphatidylinositol-3 kinase/Akt pathway mediates VEGF's neuroprotective activity and induces blood brain barrier permeability after focal cerebral ischemia

Kilic, Ertugrul, Kilic, Ülkan, Wang, Yaoming, Bassetti, Claudio L., Marti, Hugo H., Hermann, Dirk M., Kilic, Ertugrul, Kilic, Ülkan, Wang, Yaoming, Bassetti, Claudio L., Marti, Hugo H., Hermann, Dirk M.·2006·The FASEB Journal

DOI 10.1096/fj.05-4829fje

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Abstract

Based on its trophic influence on neurons and vascular cells, vascular endothelial growth factor (VEGF) is a promising candidate for stroke treatment. VEGF's survival-promoting effects are purchased at the expense of an increased blood brain barrier permeability, which potentially compromises tissue survival. The mechanisms via which VEGF protects the brain against ischemia remained unknown. We examined signaling pathways underlying VEGF's neuroprotective activity in our transgenic mouse line, which expresses human VEGF165 under a neuron-specific enolase (NSE) promoter. We show that VEGF receptor-2 (Flk-1) is expressed on ischemic neurons and astrocytes and is activated by VEGF. Following 90-min episodes of middle cerebral artery occlusion, VEGF increased phosphorylated (but not total) Akt and ERK-1/-2 and reduced phosphorylated mitogen activated protein kinase/p38 and c-Jun NH2-terminal kinase (JNK)-1/-2 levels, at the same time decreasing inducible NO synthase expression in ischemic neurons. Inhibition of Akt with Wortmannin reversed VEGF's neuroprotective properties, diminished brain swelling, and restored the vascular permeability induced by VEGF to below levels in WT animals. The aggravation of brain injury by Wortmannin was associated with the restitution of p38, but not of JNK-1/-2, ERK-1/-2, or inducible NOS (iNOS). Our data demonstrate that VEGF mediates both neuroprotection and blood brain barrier permeability via the phosphatidylinositol-3 kinase (PI3K)/Akt pathway. Based on our observation that VEGF neuroprotection and vascular leakage depend on PI3K/Akt, which is putatively regulated by VEGF receptor-2, we predict that it may not easily be possible to make use of VEGF's neuroprotective function without accepting its unfavorable consequence, the increased vascular permeability.

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Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1
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“Indeed, rodent studies have shown that systemic delivery of VEGF in the early postischemic phase may exacerbate vasogenic edema thus increasing brain damage, while VEGF antagonisation with the high-affinity VEGF-binding protein mFlt(1–3)-IgG reduced brain swelling and infarct size (11, 12).”
Background
VEGF-induced neuroprotection, neurogenesis, and angiogenesis after focal cerebral ischemia
Sun, Y., Jin, K., Xie, L., Childs, J., Mao, X. O., Logvinova, A. V., & Greenberg, D. A. (2003) · Journal of Clinical Investigation · doi:10.1172/jci17977 · Cited by 1,201
VEGF-induced neuroprotection, neurogenesis, and angiogenesis after focal cerebral ischemia
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Authors: Kilic, E., Kilic, Ü., Wang, Y., Bassetti, C. L., Marti, H. H., Hermann, D. M., Kilic, E., Kilic, Ü., Wang, Y., Bassetti, C. L., Marti, H. H., & Hermann, D. M.
Venue: The FASEB Journal
Publisher: Wiley
Published: 2006-04-26
Volume: 20
Issue: 8
Pages: 1185-1187
ISSN: 0892-6638 (ISSN-L)
1530-6860
DOI: 10.1096/fj.05-4829fje
OpenAlex: W2153508530
Cited by: 218
References: 26
Citations by year: 2026: 2 · 2025: 3 · 2024: 4 · 2023: 4 · 2022: 14 · 2021: 7 · 2020: 3 · 2019: 8 · 2018: 4 · 2017: 12 · 2016: 12 · 2015: 13 · 2014: 16 · 2013: 11 · 2012: 17
FWCI: 12.50
Type: journal article
Language: en
Open access: closed
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor)
doi.wiley.com/10.1002/tdm_license_1.1 (tdm)
Locations: The FASEB Journal (publishedVersion)
PubMed (publishedVersion)
Funders: Stiftung für die Erforschung der Muskelkrankheiten (3200B0-100790)
nccr – on the move
Hartmann Müller-Stiftung für Medizinische Forschung
Ministerium für Wissenschaft, Forschung und Kunst Baden-Württemberg
Baden-Württemberg Stiftung (23-7532.22-2012/1)
Topics: Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
Life Sciences › Neuroscience › Neurology › Neuroprotection in Cerebral Ischemia
Keywords: vascular endothelial growth factor, VEGF receptor 2, Flk-1, PI3K/Akt signaling, neuroprotection, blood-brain barrier permeability, focal cerebral ischemia, stroke, p38 MAPK, JNK, ERK, inducible nitric oxide synthase, wortmannin, middle cerebral artery occlusion, cerebral edema
MeSH terms: Wortmannin, Phosphoinositide-3 Kinase Inhibitors, Androstadienes, Animals, Astrocytes, Blood-Brain Barrier, Capillary Permeability, Brain Ischemia, Enzyme Inhibitors, Humans, Mice, Transgenic, Neurons, Signal Transduction, Neuroprotective Agents, Phosphatidylinositol 3-Kinases, Mitogen-Activated Protein Kinases, Vascular Endothelial Growth Factor Receptor-2, Vascular Endothelial Growth Factor A, Proto-Oncogene Proteins c-akt, Mice, Nitric Oxide Synthase Type II

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The phosphatidylinositol-3 kinase/Akt pathway mediates VEGF's neuroprotective activity and induces blood brain barrier permeability after focal cerebral ischemia

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