Cited by 221Angiogenesis and VEGF in CancerBarrier Structure and Function StudiesNeurological Disease Mechanisms and Treatments

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VEGF overexpression induces post-ischaemic neuroprotection, but facilitates haemodynamic steal phenomena

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Wang, Y.·2004·Brain

DOI 10.1093/brain/awh325

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Abstract

Therapeutic angiogenesis with vascular endothelial growth factor (VEGF) is a clinically promising strategy in ischaemic disease. The pathophysiological consequences of enhanced vessel formation, however, are poorly understood. We established mice overexpressing human VEGF165 under a neuron-specific promoter, which exhibited an increased density of brain vessels under physiological conditions and enhanced angiogenesis after brain ischaemia. Following transient intraluminal middle cerebral artery (MCA) occlusions, VEGF overexpression significantly alleviated neurological deficits and infarct volume, and reduced disseminated neuronal injury and caspase-3 activity, confirming earlier observations that VEGF has neuroprotective properties. Brain swelling was not influenced in VEGF-overexpressing animals, while sodium fluorescein extravasation was moderately increased, suggesting that VEGF induces a mild blood-brain barrier leakage. To elucidate whether enhanced angiogenesis improves regional cerebral blood flow in the ischaemic brain, [14C]iodoantipyrine autoradiography was performed. Autoradiographies revealed that VEGF induces haemodynamic steal phenomena with reduced blood flow in ischaemic areas and increased flow values only outside the MCA territory. Our data demonstrate that VEGF protects neurons from ischaemic cell death by a direct action rather than by promoting angiogenesis, and suggest that strategies aiming at increasing vascular density in the whole brain, e.g. by VEGF overexpression, may worsen rather than improve cerebral haemodynamics after stroke.

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Influential
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Authors: Wang, Y.
Affiliations: University of Zurich (CH)
Corresponding author: Wang, Y.
ORCID: Wang, Y.
Venue: Brain
Publisher: Oxford University Press (OUP)
Published: 2004-11-17
Volume: 128
Issue: 1
Pages: 52-63
ISSN: 0006-8950 (ISSN-L)
1460-2156
DOI: 10.1093/brain/awh325
OpenAlex: W2166050160
Cited by: 221
References: 55
Citations by year: 2026: 2 · 2025: 5 · 2024: 4 · 2023: 5 · 2022: 5 · 2021: 10 · 2020: 10 · 2019: 8 · 2018: 9 · 2017: 7 · 2016: 14 · 2015: 5 · 2014: 16 · 2013: 20 · 2012: 12
FWCI: 5.21
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Brain (publishedVersion)
PubMed (publishedVersion)
Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, other-oa)
reroDoc Digital Library (submittedVersion)
MPG.PuRe (Max Planck Society) (submittedVersion)
Zurich Open Repository and Archive (University of Zurich) (submittedVersion, other-oa)
Zurich Open Repository and Archive (University of Zurich)
Funders: National Science Foundation
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (67256, 100790, 3200B0)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
Keywords: VEGF overexpression, therapeutic angiogenesis, cerebral ischemia, neuroprotection, regional cerebral blood flow, middle cerebral artery occlusion, blood-brain barrier disruption, neuronal injury, caspase-3, stroke, VEGF165, cerebral angiogenesis
MeSH terms: Animals, Blood-Brain Barrier, Brain, Capillaries, Capillary Permeability, Brain Ischemia, Cerebrovascular Circulation, Hemodynamics, Humans, Mice, Transgenic, Necrosis, Neovascularization, Pathologic, Neurons, Stroke, Middle Cerebral Artery, Vascular Endothelial Growth Factor A, Mice

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VEGF overexpression induces post-ischaemic neuroprotection, but facilitates haemodynamic steal phenomena

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