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VEGF enhances angiogenesis and promotes blood–brain barrier leakage in the ischemic brain
Open accessAbstract
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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“As a pleiotropic growth factor, VEGF is responsible for multiple important physiological functions, particularly BBB permeability [44, 50, 51].”
From Chronic stress-induced depression requires the recruitment of peripheral Th17 cells into the brain (2022) · cites this paper as [50]
Experimental — accuracy not yet measuredIn the citing paper
“Similar findings about the importance of timing for administration of a neurorestorative therapy for stroke have been reported for VEGF94 and modulators of matrix metallo proteinases.95”
From Promoting brain remodelling and plasticity for stroke recovery: therapeutic promise and potential pitfalls of clinical translation (2012) · cites this paper as [94]
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Vascular and neuronal effects of VEGF in the nervous system: implications for neurological disorders
Carmeliet, P., & Storkebaum, E. (2002) · Seminars in Cell and Developmental Biology · doi:10.1006/scdb.2001.0290 · Cited by 252
Rocha, S. F., Schiller, M., Jing, D., Li, H., Butz, S., Vestweber, D., Biljes, D., Drexler, H. C. A., Nieminen-Kelhä, M., Vajkoczy, P., et al. (2014) · Circulation Research · doi:10.1161/circresaha.115.304718 · Cited by 252
Neurological Diseases as Primary Gliopathies: A Reassessment of Neurocentrism
Verkhratsky, A., Sofroniew, M. V., Messing, A., deLanerolle, N. C., Rempe, D. A., Rodriguez, J. J., & Nedergaard, M. (2012) · ASN NEURO · doi:10.1042/an20120010 · Cited by 254
“In the days and weeks after stroke onset, astrocytes release a number of neuroprotectants including EPO (erythropoietin), VEGF (vascular endothelial growth factor) and glialderived neurotrophic factor, all of which may either reduce ischaemic neuronal damage or improve functional recovery following stroke (Kitagawa et…”
BackgroundVEGF: a critical player in neurodegeneration
Storkebaum, E., & Carmeliet, P. (2004) · Journal of Clinical Investigation · doi:10.1172/jci20682 · Cited by 268
“The Journal of Clinical Investigation | January 2004 | Volume 113 | Number 1 17 penumbra and improved neural recovery (44), reduced edema formation and infarct volume (45, 46), and amplified neurogenesis (38), while knockdown of VEGF after ischemic stroke enlarged the infarct volume (47).”
BackgroundResultThe therapeutic potential of the mesenchymal stem cell secretome in ischaemic stroke
Cunningham, C. J., Redondo-Castro, E., & Allan, S. M. (2018) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1177/0271678x18776802 · Cited by 242
“In brief, VEGF increases neuroprotection, angiogenesis and neurogenesis after focal cerebral ischaemia(98) but as a potent inducer of vascular permeability, can also increase blood–brain barrier (BBB) leakage leading to cerebral oedema.(99,100) These dual actions appear to be reflected in the literature on the involve…”
BackgroundMolecular mechanisms of early brain injury after subarachnoid hemorrhage
Ostrowski, R. P., Colohan, A. R. T., & Zhang, J. H. (2006) · Neurological Research · doi:10.1179/016164106x115008 · Cited by 241
Lee, H. J., Kim, K. S., Park, I. H., & Kim, S. U. (2007) · PLoS ONE · doi:10.1371/journal.pone.0000156 · Cited by 239
“In earlier studies, VEGF induces blood-brain barrier (BBB) break down and vascular leakage resulting in brain edema [25,43].”
BackgroundOnda, T., Honmou, O., Harada, K., Houkin, K., Hamada, H., & Kocsis, J. D. (2007) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/sj.jcbfm.9600527 · Cited by 237
“Indeed, early administration of VEGF after MCAO exacerbates blood–brain barrier leakage, causing massive brain edema (Zhang et al, 2000).”
BackgroundBrain Microvascular Pericytes in Vascular Cognitive Impairment and Dementia
Uemura, M. T., Maki, T., Ihara, M., Lee, V. M. ‐., & Trojanowski, J. Q. (2020) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2020.00080 · Cited by 246
Peroxisome proliferator-activated receptor γ (PPARγ): A master gatekeeper in CNS injury and repair
Cai, W., Yang, T., Liu, H., Han, L., Zhang, K., Hu, X., Zhang, X., Yin, K., Gao, Y., Bennett, M. V. L., et al. (2017) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2017.10.002 · Cited by 240
Janelidze, S., Hertze, J., Nägga, K., Nilsson, K., Nilsson, C., Wennström, M., van Westen, D., Blennow, K., Zetterberg, H., & Hansson, O. (2017) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2016.11.017 · Cited by 237
“In rats, administration of VEGF induces leakage of the BBB (Zhang et al., 2000).”
BackgroundBiological hypotheses and biomarkers of bipolar disorder
Sigitova, E., Fišar, Z., Hroudová, J., Cikánková, T., & Raboch, J. (2016) · Psychiatry and Clinical Neurosciences · doi:10.1111/pcn.12476 · Cited by 257
“In contrast, GDNF and VEGF do not cross the BBB(111); VEGF enhances angiogenesis and promotes BBB leakage in the ischemic brain.(112)”
BackgroundSobrino, T., Hurtado, O., Moro, M. Á., Rodríguez‐Yáñez, M., Castellanos, M., Brea, D., Moldes, O., Blanco, M., Arenillas, J. F., Leira, R., et al. (2007) · Stroke · doi:10.1161/strokeaha.107.484386 · Cited by 235
Blood-Brain Barrier Dysfunction in CNS Disorders and Putative Therapeutic Targets: An Overview
Archie, S. R., Shoyaib, A. A., & Cucullo, L. (2021) · Pharmaceutics · doi:10.3390/pharmaceutics13111779 · Cited by 244
“In contrast, astrocytes can perform a protective role during the chronic phase by participating in neurite sprouting, synapse formation, neurotrophic factor secretion, and rebuilding the BBB [137,138].”
BackgroundExosomes in stroke pathogenesis and therapy
Zhang, Z. G., & Chopp, M. (2016) · Journal of Clinical Investigation · doi:10.1172/jci81133 · Cited by 228
“At early stages of recovery, angiogenic vessels are permeable, but new vessels become less leaky and functional when they mature (23, 28).”
BackgroundSelf-citationWang, Y. (2004) · Brain · doi:10.1093/brain/awh325 · Cited by 221
“…of VEGF increased blood–brain barrier (BBB) leakage and tissue damage after stroke, while VEGF antagonization with the high-affinity VEGF-binding protein mFlt(1–3)-IgG improved neurological outcome as well as reduced brain oedema and infarct size (van Bruggen et al., 1999; Zhang et al., 2000).”
InfluentialLi, Y., Fan, L., Liu, S., Liu, W., Zhang, H., Zhou, T., Wu, D., Yang, P., Shen, L., Chen, J., et al. (2013) · Biomaterials · doi:10.1016/j.biomaterials.2013.03.052 · Cited by 220
“Vegf was used as the therapeutic agent to stimulate angiogenesis [37].”
BackgroundMethodKilic, E., Kilic, Ü., Wang, Y., Bassetti, C. L., Marti, H. H., Hermann, D. M., Kilic, E., Kilic, Ü., Wang, Y., Bassetti, C. L., et al. (2006) · The FASEB Journal · doi:10.1096/fj.05-4829fje · Cited by 218
“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).”
BackgroundCathepsin K: The Action in and Beyond Bone
Dai, R., Wu, Z., Chu, H. Y., Lu, J. G., Lü, A., Liu, J., & Zhang, G. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.00433 · Cited by 217
Astrocyte Activation in Neurovascular Damage and Repair Following Ischaemic Stroke
Patabendige, A., Singh, A., Jenkins, S. I., Sen, J., & Chen, R. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22084280 · Cited by 224
“[74] showed that VEGF mediated an increase in CBF that maintained the penumbral blood supply.”
BackgroundIncreased skeletal VEGF enhances β‐catenin activity and results in excessively ossified bones
Maes, C., Goossens, S., Bartunkova, S., Drogat, B., Coenegrachts, L., Stockmans, I., Moermans, K., Nyabi, O., Haigh, K., Naessens, M., et al. (2009) · The EMBO Journal · doi:10.1038/emboj.2009.361 · Cited by 216
“As well, b-catenin has recently been implicated in physiological angiogenesis in the regulation of vascular patterning and development of the blood–brain barrier (Cattelino et al, 2003; Liebner et al, 2008; Stenman et al, 2008), which also requires VEGF (Zhang et al, 2000).”
BackgroundBorlongan, C. V., Glover, L. E., Tajiri, N., Kaneko, Y., & Freeman, T. B. (2011) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2011.08.005 · Cited by 209
“However, VEGF could enhance angiogenesis in the IBZ and significantly improve neurological recovery (Zhang et al., 2000).”
Triggers and Mediators of Hemorrhagic Transformation in Cerebral Ischemia
Wang, X., & Lo, E. H. (2003) · Molecular Neurobiology · doi:10.1385/mn:28:3:229 · Cited by 210
“In particular, the vascular endothelial growth factor (VEGF, also known as vascular permeability factor) has been implicated in endothelial-cell proliferation, permeability and angiogenesis in the reaction to brain injury (83,84).”
BackgroundPhagocytic microglia and macrophages in brain injury and repair
Yu, F., Wang, Y., Stetler, R. A., Leak, R. K., Hu, X., & Chen, J. (2022) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.13899 · Cited by 213
Mechanisms of Hyperbaric Oxygen-Induced Neuroprotection in a Rat Model of Subarachnoid Hemorrhage
Ostrowski, R. P., Colohan, A. R. T., & Zhang, J. H. (2005) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/sj.jcbfm.9600048 · Cited by 207
Loy, D. N., Crawford, C. H., Darnall, J. B., Burke, D. A., Onifer, S. M., & Whittemore, S. R. (2002) · The Journal of Comparative Neurology · doi:10.1002/cne.10168 · Cited by 202
“Furthermore, angiogenic and antiangiogenic therapies have each demonstrated functional efficacy in animal models after CNS insult, raising the question of whether angiogenesis is beneficial or detrimental to neurologic outcomes after SCI (Wamil et al., 1998; Zhang et al., 2000).”
BackgroundNeurogenesis, angiogenesis, and MRI indices of functional recovery from stroke
Chopp, M., Zhang, Z. G., & Jiang, Q. (2007) · Stroke · doi:10.1161/01.str.0000250235.80253.e9 · Cited by 203
Self-citation
Metadata
- 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
- Venue
- Journal of Clinical Investigation
- Published
- 2000-10-01
- Volume
- 106
- Issue
- 7
- Pages
- 829-838
- ISSN
- 0021-9738 (ISSN-L)
- 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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