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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]
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“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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BackgroundSelf-citationMechanisms and targets for angiogenic therapy after stroke
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BackgroundInfluentialElectrical preconditioning of stem cells with a conductive polymer scaffold enhances stroke recovery
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“This physiological response would be expected to promote angiogenesis and improve blood supply in human brain tissue, as it does in the rat (Zhang et al., 2000; Sun et al., 2003).”
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Self-citationIn Vivo and in Vitro Characterization of the Angiogenic Effect of CTX0E03 Human Neural Stem Cells
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“VEGFA, an angiogenic growth factor, potent mitogen, and survival factor specific to endothelial cells (11,21), also demonstrates neuroprotective effects against ischemic injury (13,14,19,32,35).”
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“However, late (48 h after MCAO) administration of VEGF-A to ischemic rats enhances angiogenesis in the ischemic penumbra, which is conductive to the brain, since it improves neurological recovery [199].”
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Perlecan regulates pericyte dynamics in the maintenance and repair of the blood–brain barrier
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“In addition, perlecan DV enhances endothelial cell – derived VEGF production through integrin α 5 β 1 (Lee et al., 2011); however, VEGF can induce BBB permeability in the acute phase of ischemic stroke (Zhang et al., 2000; Jiang et al., 2014).”
Survivin-Dependent Angiogenesis in Ischemic Brain
Conway, E. M., Zwerts, F., Eygen, V. V., Vriese, A. D., Nagai, N., Luo, W., & Collen, D. (2003) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)63453-0 · Cited by 92
“Administration of VEGF in small animal stroke models has met with variable results, depending on the dose, time, and duration of administration.(16) Shortly after an ischemic event, the capillary leakage induced by VEGF may be deleterious, whereas the angiogenic effect of VEGF may be beneficial for long-term recovery.”
BackgroundResultInfluentialInjury and repair in the neurovascular unit
Xing, C., Hayakawa, K., Lok, J. M., Arai, K., & Lo, E. H. (2012) · Neurological Research · doi:10.1179/1743132812y.0000000019 · Cited by 93
Chu, K., Lee, S., Koo, J.-S., Jung, K., Kim, E., Sinn, D.-I., Kim, J., Ko, S., Kim, S., Song, E.-C., et al. (2006) · Brain Research · doi:10.1016/j.brainres.2006.03.114 · Cited by 87
Zhang, C., Li, Y., Chen, J. R., Gao, Q., Zacharek, A., Kapke, A., & Chopp, M. (2006) · Neuroscience · doi:10.1016/j.neuroscience.2006.04.054 · Cited by 91
Self-citationBouleti, C., Mathivet, T., Coqueran, B., Serfaty, J., Lesage, M., Berland, E., Ardidie‐Robouant, C., Kauffenstein, G., Henrion, D., Lapergue, B., et al. (2013) · European Heart Journal · doi:10.1093/eurheartj/eht153 · Cited by 92
“Whereas HIFs are protective in long-term responses to hypoxic injury, VEGF also increases BBB leakage and oedema at the acute phase and thereby exacerbates tissue damage.(7,8) Given the contribution of vascular leakage and oedema formation to tissue damage during stroke,(6) a relevant therapeutic approach would be to…”
Cerebrovascular Remodeling and Epilepsy
Marchi, N., & Lerner‐Natoli, M. (2012) · The Neuroscientist · doi:10.1177/1073858412462747 · Cited by 92
Hypoxia-inducible factor-1: Regulatory mechanisms and drug development in stroke
Pan, Z., Ma, G., Kong, L., & Du, G. (2021) · Pharmacological Research · doi:10.1016/j.phrs.2021.105742 · Cited by 93
microRNAs Involved in Regulating Spontaneous Recovery in Embolic Stroke Model
Liu, F. J., Lim, K. Y., Kaur, P., Sepramaniam, S., Armugam, A., Wong, P. T.-H., & Jeyaseelan, K. (2013) · PLoS ONE · doi:10.1371/journal.pone.0066393 · Cited by 89
Choi, E., Walker, E. J., Shen, F., Oh, S. P., Arthur, H. M., Young, W. L., & Su, H. (2012) · Cerebrovascular Diseases · doi:10.1159/000337762 · Cited by 89
Harms, K. M., Li, L., & Cunningham, L. A. (2010) · PLoS ONE · doi:10.1371/journal.pone.0009767 · Cited by 91
“Administration of exogenous VEGF following stroke results in reduced neuronal cell death, increased angiogenesis and increased vascular permeability [30,42,43] (reviewed in [42,44,45]).”
Inhibition of VEGF signaling pathway attenuates hemorrhage after tPA treatment
Kanazawa, M., Igarashi, H., Kawamura, K., Takahashi, T., Kakita, A., Takahashi, H., Nakada, T., Nishizawa, M., & Shimohata, T. (2011) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2011.9 · Cited by 88
“Topical application of VEGF on the ischemic cortex or intravenous administration of VEGF to rats 1 hour after ischemic stroke exacerbated BBB disruption (Zhang et al, 2000; Chi et al, 2005).”
BackgroundFrom Neurodevelopmental to Neurodegenerative Disorders: The Vascular Continuum
Ouellette, J., & Lacoste, B. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.749026 · Cited by 91
“Findings of elevated VEGF could also be linked to vascular hyperpermeability, as VEGF not only regulates angiogenesis but increases BBB leakage (Mayhan, 1999; Zhang et al., 2000).”
BackgroundVEGF, a Key Factor for Blood Brain Barrier Injury After Cerebral Ischemic Stroke
Hu, Y., Zheng, Y., Wang, T., Jiao, L., & Luo, Y. (2022) · Aging and Disease · doi:10.14336/ad.2021.1121 · Cited by 100
“However, the deleterious effects of VEGF on vascular integrity are transient, and both VEGF preconditioning [3] and VEGF treatment after the acute phase [4, 5] have neuroprotective effects.”
BackgroundT cell interactions with microglia in immune-inflammatory processes of ischemic stroke
Zheng, Y., Ren, Z., Liu, Y., Yan, J., Chen, C., He, Y., Shi, Y., Cheng, F., Wang, Q., Li, C., et al. (2024) · Neural Regeneration Research · doi:10.4103/nrr.nrr-d-23-01385 · Cited by 93
Cui, X., Chen, J., Zacharek, A., Li, Y., Roberts, C. J., Kapke, A., Savant‐Bhonsale, S., & Chopp, M. (2007) · Stem Cells · doi:10.1634/stemcells.2007-0169 · Cited by 87
“Upregulation of circulating progenitor endothelial cells by exogenous cell and pharmacological monotherapies may also enhance functional recovery from stroke [2,3,13,37–41].”
BackgroundSelf-citationStroke-Evoked Angiogenesis Results in a Transient Population of Microvessels
Yu, S. W., Friedman, B., Cheng, Q., & Lyden, P. D. (2006) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/sj.jcbfm.9600378 · Cited by 85
“…infarction zone (Manoonkitiwongsa et al, 2001a) and is consistent with previous studies that indicate that angiogenesis induced by ischemia is not a widespread reaction of parenchymal microvessels in the entire ischemic zone distal to MCA occlusion (Marti et al, 2000; Zhang et al, 2000, 2002).”
BackgroundResultInfluentialVascular Growth Factors in Cerebral Ischemia
Croll, S. D., & Wiegand, S. J. (2001) · Molecular Neurobiology · doi:10.1385/mn:23:2-3:121 · Cited by 88
“Although administration of additional exogenous VEGF may induce more angiogenesis or EC survival ( 112 ), the quality of the vasculature formed may be highly abnormal (50,51,59,60,112).”
BackgroundInfluentialTherapeutics for neonatal brain injury
Gonzalez, F. F., & Ferriero, D. M. (2008) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2008.07.003 · Cited by 87
Therapeutic Angiogenesis for Brain Ischemia: A Brief Review
Fan, Y., & Yang, G. (2007) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-007-9073-3 · Cited by 86
“It has been noted that intraventricular administration of VEGF after 48 h of ischemia, not early postischemic stage (1 h), can protect ischemia-induced BBB leakage (Zhang et al. 2000).”
BackgroundArdelt, A. A., McCullough, L. D., Korach, K. S., Wang, M. M., Munzenmaier, D. H., & Hurn, P. D. (2005) · Stroke · doi:10.1161/01.str.0000153795.38388.72 · Cited by 87
Goussev, S., Hsu, J.-Y. C., Lin, Y., Tjoa, T., Maida, N., Werb, Z., & Noble‐Haeusslein, L. J. (2003) · Journal of Neurosurgery Spine · doi:10.3171/spi.2003.99.2.0188 · Cited by 91
VEGF Promotes Angiogenesis and Functional Recovery in Stroke Rats
Yang, J., Liu, H., & Liu, X. (2010) · Journal of Investigative Surgery · doi:10.3109/08941930903469482 · Cited by 85
“In the ischemic rat brain, intravenously administered VEGF also triggers angiogenesis, as manifested by an increase in the number and volume of FITC-dextran-perfused cerebral cortical microvessels 7 days later [31].”
BackgroundEnzyme‐Responsive Delivery of Multiple Proteins with Spatiotemporal Control
Zhu, S., Nih, L. R., Carmichael, S. T., Lu, Y., & Segura, T. (2015) · Advanced Materials · doi:10.1002/adma.201500417 · Cited by 86
Microglia and Macrophages in Neuroprotection, Neurogenesis, and Emerging Therapies for Stroke
Var, S. R., Shetty, A. V., Grande, A. W., Low, W. C., & Cheeran, M. C. ‐. (2021) · Cells · doi:10.3390/cells10123555 · Cited by 86
Shibuya, M. (2009) · FEBS Journal · doi:10.1111/j.1742-4658.2009.07175.x · Cited by 85
Sun, Y., Jin, K., Childs, J., Xie, L., Mao, X. O., & Greenberg, D. A. (2004) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1097/01.wcb.0000134477.38980.38 · Cited by 86
“…topical, intravenous, or intraventricular administration of VegfA improves outcome from experimental stroke in rodents (Hayashi et al., 1998; Sun et al., 2003b; Zhang et al., 2000), whereas intraventricular administration of an anti-VEGF antibody increases infarct size (Bao et al., 1999).”
BackgroundChen, H., Qi, S., & Shen, J. (2016) · Current Neuropharmacology · doi:10.2174/1570159x14666160620102055 · Cited by 86
Min, J., Hu, J.-J., He, M., Sanchez, R. M., Huang, W., Liu, Y., Bsoul, N., Han, S. H., Yin, J., Liu, W., et al. (2015) · Neuropharmacology · doi:10.1016/j.neuropharm.2015.07.007 · Cited by 87
Du, J., Yin, G., Hu, Y., Shi, S., Jiang, J., Song, X., Zhang, Z., Wei, Z., Tang, C., & Lyu, H. (2020) · Aging · doi:10.18632/aging.202194 · Cited by 85
“The mice were subjected to MCAO, the method that produces injury most similar to human stroke, as previously described [12, 52].”
BackgroundMethodSelf-citationThe Potential Role of Vascular Endothelial Growth Factor in the Central Nervous System
Yasuhara, T., Shingo, T., & Date, I. (2004) · Reviews in the Neurosciences · doi:10.1515/revneuro.2004.15.4.293 · Cited by 85
Kim, Y., Lee, S., Zhang, H., Lee, S., Kim, H., Kim, Y., Won, M., Kim, Y., & Kwon, Y. (2020) · Journal of Neuroinflammation · doi:10.1186/s12974-020-1727-6 · Cited by 84
Rissanen, T. T., Vajanto, I., & Ylä‐Herttuala, S. (2001) · European Journal of Clinical Investigation · doi:10.1046/j.1365-2362.2001.00864.x · Cited by 84
An engineered transcription factor which activates VEGF-A enhances recovery after spinal cord injury
Liu, Y., Figley, S. A., Spratt, S. K., Lee, G., Ando, D. G., Surosky, R. T., & Fehlings, M. G. (2009) · Neurobiology of Disease · doi:10.1016/j.nbd.2009.10.018 · Cited by 84
Up-Regulation of Neuropilin-1 in Neovasculature after Focal Cerebral Ischemia in the Adult Rat
Zhang, Z. G., Tsang, W., Zhang, L., Powers, C., & Chopp, M. (2001) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1097/00004647-200105000-00008 · Cited by 84
“The authors recently showed that administration of VEGF165 2 days after embolic stroke in rats enhances angiogenesis in ischemic brain and improves functional neurologic recovery (Zhang et al., 2000).”
BackgroundSelf-citationShen, F., Walker, E. J., Jiang, L., Degos, V., Li, J., Sun, B., Heriyanto, F., Young, W. L., & Su, H. (2011) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2011.97 · Cited by 82
“Unfortunately, the innate increase of angiogenic factors is not sufficient to compensate for most clinically significant instances of cerebral ischemic injury (Zhang et al, 2000).”
BackgroundInfluential
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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