Cited by 1,296Barrier Structure and Function StudiesAngiogenesis and VEGF in CancerAcute Ischemic Stroke Management

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VEGF enhances angiogenesis and promotes blood–brain barrier leakage in the ischemic brain

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Zhang, Zheng Gang, Zhang, Li, Jiang, Quan, Zhang, Ruilan, Davies, Kenneth, Powers, Cecylia, Bruggen, Nicholas van, Chopp, Michael·2000·Journal of Clinical Investigation

DOI 10.1172/jci9369PMC PMC517814

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Abstract

VEGF is a secreted mitogen associated with angiogenesis and is also a potent vascular permeability factor. The biological role of VEGF in the ischemic brain remains unknown. This study was undertaken to investigate whether VEGF enhances cerebral microvascular perfusion and increases blood-brain barrier (BBB) leakage in the ischemic brain. Using magnetic resonance imaging (MRI), three-dimensional laser-scanning confocal microscope, and functional neurological tests, we measured the effects of administrating recombinant human VEGF(165) (rhVEGF(165)) on angiogenesis, functional neurological outcome, and BBB leakage in a rat model of focal cerebral embolic ischemia. Late (48 hours) administration of rhVEGF(165) to the ischemic rats enhanced angiogenesis in the ischemic penumbra and significantly improved neurological recovery. However, early postischemic (1 hour) administration of rhVEGF(165) to ischemic rats significantly increased BBB leakage, hemorrhagic transformation, and ischemic lesions. Administration of rhVEGF(165) to ischemic rats did not change BBB leakage and cerebral plasma perfusion in the contralateral hemisphere. Our results indicate that VEGF can markedly enhance angiogenesis in the ischemic brain and reduce neurological deficits during stroke recovery and that inhibition of VEGF at the acute stage of stroke may reduce the BBB permeability and the risk of hemorrhagic transformation after focal cerebral ischemia.

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Nogo-A targeted therapy promotes vascular repair and functional recovery following stroke
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“Clinically, treatments to enhance poststroke angiogenesis, for example by VEGF (8), are lacking or not feasible, mainly due to side effects, despite preclinical evidence for beneficial effects (7).”
Background
Vascular endothelial growth factor is upregulated by l-dopa in the parkinsonian brain: implications for the development of dyskinesia
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“This response can be viewed as both protective and potentially harmful because, while increasing tissue vascularization, VEGF also induces blood–brain barrier leakage and inﬂammation (Zhang et al ., 2000; Krum et al ., 2002).”
Background
VEGF and VEGF Receptor Expression after Experimental Brain Contusion in Rat
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“VEGF expression of neurons in response to hypoxia has a paracrine/autocrine role for maintenance of neurons (Ogunshola et al., 2002) and the administration of VEGF in vivo after MCAO occlusion can have beneficial effects (Sun et al., 2003).”
Influential
Angiogenic growth factors in the pathophysiology of a murine model of acute lung injury
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BackgroundResult
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“Conversely, administration of VEGF 1 h after ischemia significantly exacerbates the neurological deficits (32, 33).”
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“Topical administration of VEGF to the surface of rat brains reduces infarct size (Hayashi et al., 1998; Sun et al., 2003), whereas intravenous injection of VEGF improves neuronal outcomes (Zhang et al., 2000).”
Background
Arteriovenous malformation in the adult mouse brain resembling the human disease
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“There were a few fluorescent beads in the lung of AAV-VEGF-injected control mice, consistent with vascular dilation present in VEGF-treated tissues.(27) Second, we perfused the animals with latex through the left ventricle of the heart.”
Method
Matrix Metalloproteinase-9 Inhibition Attenuates Vascular Endothelial Growth Factor-Induced Intracerebral Hemorrhage
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Tadalafil, a long-acting type 5 phosphodiesterase isoenzyme inhibitor, improves neurological functional recovery in a rat model of embolic stroke
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Self-citation
Vulnerability of the developing brain to hypoxic-ischemic damage: contribution of the cerebral vasculature to injury and repair?
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BackgroundInfluential
Combination therapy of stroke in rats with a nitric oxide donor and human bone marrow stromal cells enhances angiogenesis and neurogenesis
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Crosstalk Between the Oxidative Stress and Glia Cells After Stroke: From Mechanism to Therapies
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Method
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Neuroprotection of Ischemic Brain by Vascular Endothelial Growth Factor is Critically Dependent on Proper Dosage and May Be Compromised by Angiogenesis
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“…neurogenesis, chemotaxis of inflammatory cells, and inhibition of apoptosis (Bates and Harper, 2002; Carmeliet et al., 1996; Ferrara and Gerber, 2001; Forstreuter et al., 2002; Lafuente et al., 2002; Rosenstein et al., 1998; Sun et al., 2003; van Bruggen et al., 1999; Zhang et al., 2000).”
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Neuroinflammation, Mast Cells, and Glia: Dangerous Liaisons
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Overcoming the Blood–Brain Barrier: Successes and Challenges in Developing Nanoparticle-Mediated Drug Delivery Systems for the Treatment of Brain Tumours
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“However, VEGF may also enhance ischemic injury due to its ability to increase blood–brain barrier leakage, particularly during the early stage of an ischemic insult (van Bruggen et al., 1999; Zhang et al., 2000).”
Background
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“However, both factors also have undesired side effects when given as treatment, such as erythrocytosis and vascular leakage leading to brain edema.(34,45) Understanding the in vivo situation where not only a single factor but the whole hypoxia-induced pathway is activated might help to find alternative therapeutic str…”
BackgroundResultInfluential
Hepatocyte Growth Factor Suppresses Vascular Endothelial Growth Factor-Induced Expression of Endothelial ICAM-1 and VCAM-1 by Inhibiting the Nuclear Factor-κB Pathway
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“For example, enhancement of cerebral angiogenesis at the ischemic boundary is thought to be an essential ingredient of stroke plasticity (Zhang and Chopp, 2009) and drugs that enhance angiogenesis may prove beneficial in stroke therapy (Zhang et al., 2000).”
Background
Vascular Endothelial Growth Factor Promotes Pericyte Coverage of Brain Capillaries, Improves Cerebral Blood Flow During Subsequent Focal Cerebral Ischemia, and Preserves the Metabolic Penumbra
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Authors: Zhang, Z. G., Zhang, L., Jiang, Q., Zhang, R., Davies, K., Powers, C., Bruggen, N. V., & Chopp, M.
Affiliations: Henry Ford Health (US)
Henry Ford Hospital (US)
Genentech (US)
Oakland University (US)
Corresponding author: Chopp, Michael
ORCID: Zhang, Zheng Gang
Zhang, Li
Jiang, Quan
Chopp, Michael
Venue: Journal of Clinical Investigation
Publisher: American Society for Clinical Investigation
Published: 2000-10-01
Volume: 106
Issue: 7
Pages: 829-838
ISSN: 0021-9738 (ISSN-L)
DOI: 10.1172/jci9369
PMC: PMC517814
OpenAlex: W2084498863
Cited by: 1,296
References: 75
Citations by year: 2026: 32 · 2025: 49 · 2024: 53 · 2023: 52 · 2022: 64 · 2021: 73 · 2020: 58 · 2019: 42 · 2018: 59 · 2017: 59 · 2016: 61 · 2015: 49 · 2014: 70 · 2013: 70 · 2012: 64
FWCI: 13.44
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Journal of Clinical Investigation (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health (5r01ns033627-08)
National Institute of Neurological Disorders and Stroke (P01NS23393, R01NS-33627, P01NS023393)
Topics: Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
Health Sciences › Medicine › Clinical Neurology › Acute Ischemic Stroke Management
Keywords: vascular endothelial growth factor, angiogenesis, blood-brain barrier disruption, cerebral ischemia, hemorrhagic transformation, ischemic penumbra, neurological recovery, VEGF inhibition, stroke
MeSH terms: Animals, Blood-Brain Barrier, Brain Ischemia, Image Processing, Computer-Assisted, Lymphokines, Magnetic Resonance Imaging, Male, Microcirculation, Neovascularization, Pathologic, Regional Blood Flow, Endothelial Growth Factors, Treatment Outcome, Rats, Wistar, Stroke, Vascular Endothelial Growth Factors, Vascular Endothelial Growth Factor A, Rats

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VEGF enhances angiogenesis and promotes blood–brain barrier leakage in the ischemic brain

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