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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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Cerebral Hypoperfusion and the Energy Deficit in A lzheimer's Disease
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BackgroundThe Medical Management of Cerebral Edema: Past, Present, and Future Therapies
Halstead, M., & Geocadin, R. G. (2019) · Neurotherapeutics · doi:10.1007/s13311-019-00779-4 · Cited by 87
Adult Neural Stem Cells: Response to Stroke Injury and Potential for Therapeutic Applications
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Self-citationNanotechnology for treatment of glioblastoma multiforme
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BackgroundVEGF165 Therapy Exacerbates Secondary Damage Following Spinal Cord Injury
Benton, R. L., & Whittemore, S. R. (2003) · Neurochemical Research · doi:10.1023/a:1026013106016 · Cited by 82
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“…a study reporting that overexpression of BDNF in mouse hearts resulted in increased capillary density and reduced endothelial cell apoptosis (Donovan et al. 2000), whereas after upregulation of VEGF, enhanced neovascularization and angiogenesis were observed in ischemic brain (Zhang et al. 2000).”
BackgroundPro‐ and antiangiogenic therapies: current status and clinical implications
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BackgroundRecombinant ADAMTS13 reduces tissue plasminogen activator‐induced hemorrhage after stroke in mice
Wang, L., Fan, W., Cai, P., Fan, M., Zhu, X., Dai, Y., Sun, C., Cheng, Y., Zheng, P., & Zhao, B. (2012) · Annals of Neurology · doi:10.1002/ana.23762 · Cited by 79
“VEGF, the major proangiogenic factor, increased microvascular permeability, leading to exacerbated edema and hemorrhage after cerebral ischemia.(34,35) We therefore examined whether tPA treatment could substantially affect VEGF expression.”
BackgroundHydrogen sulfide treatment induces angiogenesis after cerebral ischemia
Jang, H., Oh, M., Kim, Y., Choi, I., Yang, H. S., Ryu, W., Lee, S., & Yoon, B. (2014) · Journal of Neuroscience Research · doi:10.1002/jnr.23427 · Cited by 78
“In a previous study, the administration of recombinant VEGF to ischemic rats enhanced angiogenesis in the ischemic penumbra and improved neurological recovery (Zhang et al., 2000; Sun et al., 2003; Chen et al., 2007).”
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Risk factors for hemorrhage of brain arteriovenous malformation
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“Despite the role of VEGF in neuronal survival and angiogenesis (49) and neurovascular remodeling post-stroke (50), VEGF also induces endothelial proliferation and increases endothelial permeability, leading to BBB breakdown (51, 52).”
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“In trying to define the molecular mechanisms that regulate cerebral angiogenesis, studies have revealed a role for specific transcription factors, including hypoxia inducible factor-1α (HIF-1α) (Chavez et al. 2000) and the Hox family (Chen et al. 2004), growth factors, including vascular endothelial growth factor (VEG…”
InfluentialShimamura, N., Matchett, G. A., Yatsushige, H., Calvert, J. W., Ohkuma, H., & Zhang, J. H. (2006) · Stroke · doi:10.1161/01.str.0000226991.27540.f2 · Cited by 78
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“Examples include FGF-2 (Berry et al., 2005; Kawamata et al., 1997), BDNF (Schabitz et al., 2004), VEGF (Z. G. Zhang et al., 2000), EPO (Tsai et al., 2006; L. Wang, Zhang, Wang, Zhang, & Chopp, 2004), G-CSF (Schneider et al., 2007), and GDF10 (Li et al., 2015).”
Recent Advances in Cell-Based Therapies for Ischemic Stroke
Suda, S., Nito, C., Yokobori, S., Sakamoto, Y., Nakajima, M., Sowa, K., Obinata, H., Sasaki, K., Savitz, S. I., & Kimura, K. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21186718 · Cited by 77
“Similarly, VEGF expressed in macrophages, neurons, glia, and vascular ECs promotes angiogenesis in the ischemic brain during tissue repair [75].”
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“However, timing is important since treatment with VEGF in the earlyphaseof stroke, 1hafter lesion induction, increasedblood– brain barrier leakage and thereby worsened lesion formation (Zhang et al., 2000).”
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“Recent insights into the role of VEGF-A in a variety of neurological disorders suggest that VEGF-A and its downstream effectors may be promising therapeutic targets in these diseases (Zhang et al., 2000; Yang et al., 2002; Rosenstein et al., 2003; Cao et al., 2004; Greenberg and Jin, 2005).”
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“VEGF, one of the key factors induced by hypoxia, exerts a major role in critical disruption of the BBB leading to subsequent edema in the brain during ischemic injury [49,50].”
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“Late intracerebroventricular administration (48 h after focal ischemia) of VEGF165 dramatically improved microvascular perfusion and angiogenesis in the penumbra and improved neurological recovery (Zhang et al., 2000).”
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MethodNeuroprotection in the Newborn Infant
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“increases blood-brain barrier leakage and lesion size, but late administration 48 hours after ischemia enhances angiogenesis and functional performance.(73) Both topical and intracerebroventricular injection reduced infarct volume,(74,75) and benefit has been”
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“The latter is associated with edema formation and an increased haemorrhagic risk, which may have fatal consequences for the patient.(11) Administration of VEGF in the hyperacute phase following stroke has been shown to enhance edema formation and its pharmacological blockage led to improved blood–brain barrier integri…”
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“Exogenous delivery of VEGF into the brain protects neurons against ischemic injury (Hayashi et al., 1998; Sun et al., 2003; van Bruggen et al., 1999; Zhang et al., 2000) and decreases hypoxic neuronal apoptosis by modulating ion channel function(Ma et al., 2009; Wu et al., 2015) and inhibiting the…”
Wagenaar, N., de Theije, C. G. M., de Vries, L. S., Groenendaal, F., Benders, M. J. N. L., & Nijboer, C. H. A. (2017) · Pediatric Research · doi:10.1038/pr.2017.243 · Cited by 79
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Rate of serious adverse effects in a series of bevacizumab and ranibizumab injections
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“Thus, timing of exogenous VEGF administration is crucial for therapeutic use as studies have shown early administration of VEGF increases brain edema and infarct volume, while late application leads to decreased injury volume, increased vessel volume in the injury site, decreased glial response, and increased MBP prod…”
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Self-citationPositive effects of intermittent fasting in ischemic stroke
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“…SVZ mediated possibly via the PI3-AkT pathway in themouse ischemic penumbra, however, more experimental studies are needed to confirm the precise mechanism(s) (Chiba et al., 2008; Harms et al., 2010; Kaya et al., 2005; Marti et al., 2000; Stowe et al., 2008; Sun et al., 2003; Zhang et al., 2000).”
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“However, some caveats may exist in terms VEGF-induced alterations in BBB permeability (Valable et al, 2005; Zhang et al, 2000).”
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“VEGF is in part responsible for the BBB disruption during the early stage of focal cerebral ischemia [37].”
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“The effect of VEGF on nerves has been studied in neurodegenerative disease (such as amyotrophic lateral sclerosis) (15), and in acute neurological disease (such as cerebral ischemia) (29, 30).”
BackgroundMiyashita, K., Itoh, H., Arai, H., Suganami, T., Sawada, N., Fukunaga, Y., Sone, M., Yamahara, K., Yurugi-Kobayashi, T., Park, K., et al. (2005) · Endocrinology · doi:10.1210/en.2005-1038 · Cited by 72
Regulation of Neurogenesis and Angiogenesis in Depression
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“the peri-infarct region that include the promotion of neuronal survival [23, 29], angiogenesis [29, 34], and neural progenitor cell proliferation, migration and differentiation [23, 30].”
BackgroundLong Non-Coding RNA Malat1 Regulates Angiogenesis in Hindlimb Ischemia
Zhang, X., Tang, X., Hamblin, M. H., & Yin, K. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19061723 · Cited by 72
“Angiogenic response can be triggered under ischemic conditions such as ischemic stroke and myocardial infarction [6,50].”
BackgroundEndothelial activation and dysregulation in malaria: a potential target for novel therapeutics
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“Administration of VEGF in the brain resulted in a decrease of infarct formation, an increase of brain edema, and promotion of neovascularization after focal cerebral ischemia (21, 27).”
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“, IA, IV, or IP) of VEGF exhibited harmful effects to the brain, like an increase in hemorrhagic transformation, microvascular injury, and inflammation (52).”
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TRPC-mediated actin-myosin contraction is critical for BBB disruption following hypoxic stress
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“In addition, it was reported that late administration of VEGF provided neuroprotective effect to cerebral ischemia [5,32,33], and our preliminary experiment on ICH also obtained similar results.”
ResultGene therapy for neurological disorders
Choong, C., Baba, K., & Mochizuki, H. (2015) · Expert Opinion on Biological Therapy · doi:10.1517/14712598.2016.1114096 · Cited by 71
Endogenous regeneration: Engineering growth factors for stroke
Chan, S. J., Love, C. J., Spector, M., Cool, S. M., Nurcombe, V., & Lo, E. H. (2017) · Neurochemistry International · doi:10.1016/j.neuint.2017.03.024 · Cited by 66
“48 h after MCAO) was shown to enhance angiogenesis and improve neurological outcome in a rat model of focal cerebral embolic ischemia (Zhang et al., 2000).”
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Netrin-4 Enhances Angiogenesis and Neurologic Outcome after Cerebral Ischemia
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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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