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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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BackgroundUsing Dual-Target rTMS, Single-Target rTMS, or Sham rTMS on Post-Stroke Cognitive Impairment
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“VEGF is a major mediator of angiogenesis as well as being a strong vascular permeability factor and a notable stroke-related pathogenic factor for the formation of brain edema (54-56), which limits its therapeutic applications.”
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“…of recombinant VEGF 24 hours after ischemia (via intracerebroventricular route) demonstrates enhanced cerebral angiogenesis and microvascular perfusion, and significantly improves neurological recovery and reduces damaged brain volume (Guaiquil et al., 2014; Sun et al., 2003; Zhang et al., 2000).”
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“After brain ischemia, VEGF could significantly increase BBB leakage [52].”
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“After a stroke, disruption of the BBB occurs acutely whereas regeneration of cerebral microvessels develops relatively late in ischemic brain (40), the body's own recovery is relatively slow, among which the acceleration of angiogenesis may be expected to enhance the prognosis (39), and STS accelerates neovascularizat…”
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“VEGF can improve cerebral vascular perfusion 48 h after cerebral ischemia and can promote angiogenesis and coordinate neurogenesis at the injury site but does not further increase or disrupt vascular penetration (39).”
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“Subsequently, microglia released the proangiogenic factor VEGF, suggesting that microglia can promote cerebral vascular remodeling after ischemic stroke [126].”
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“…which is upregulated in many brain diseases (Suidan et al., 2010; Ohlin et al., 2011), is known to promote BBB leakage in the ischemic brain (Zhang et al., 2000), in brain tumors (Plate et al., 1992; Takano et al., 1996; Leung et al., 1997; Provias et al., 1997; Norden et al., 2008), and in…”
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Self-citationBlocking endothelial apoptosis revascularizes the retina in a model of ischemic retinopathy
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“While increased angiogenesis correlates with better outcomes in ischemic diseases like stroke (6), ischemia and the upregulation of VEGFA can drive aberrant angiogenesis, exacerbating certain diseases.”
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“Following stroke, VEGF is expressed in neurons for days and for up to 2 weeks in astrocytes [33].”
BackgroundVascular Endothelial Growth Factor
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Pathophysiology of Ischemic Stroke
Li, Y., & Yang, G.-Y. (2017) · Translational medicine research · doi:10.1007/978-981-10-5804-2_4 · Cited by 22
Gabbert, L., Dilling, C., Meybohm, P., & Burek, M. (2020) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.590144 · Cited by 21
Shoyaib, A. A., Alamri, F. F., Biggers, A., Karamyan, S. T., Arumugam, T. V., Ahsan, F., Mikelis, C. M., Al-Hilal, T. A., & Karamyan, V. T. (2021) · Neuroscience · doi:10.1016/j.neuroscience.2021.02.023 · Cited by 19
Almeida, R. S., Ferreira, M. L. B., Sonon, P., Cordeiro, M. T., Sadissou, I. A., Diniz, G. T. N., Albuquerque, M. F. P. M., França, R. F. D. O., Donadi, E. A., & Lucena‐Silva, N. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.582935 · Cited by 20
“If, by one hand, VEGF and HGF increase vascular permeability contributing to inflammation and nerve damage, and permitting disruption of the blood-brain barrier (BBB) (52, 55, 56), on the other hand, EGF has a neuroprotective ro le in neurolog ica l d iseases (57–59) .”
BackgroundInfluentialCentral nervous system injury meets nanoceria: opportunities and challenges
Wang, Y., Zhang, M., He, J., Gong, M., Sun, J. H., & Yang, X. (2022) · Regenerative Biomaterials · doi:10.1093/rb/rbac037 · Cited by 21
“Notably, ischemic stroke can promote BBB leakage and active angiogenesis of microvessels in the penumbra [115], during which vascular endothelial growth factor (VEGF) is known to play an important role [116].”
BackgroundSalidroside promotes angiogenesis after cerebral ischemia in mice through Shh signaling pathway
Li, Y., Xue, W., Li, S., Cui, L., Gao, Y., Li, L., Chen, R., Zhang, X., Xu, R., Jiang, W., et al. (2024) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2024.116625 · Cited by 20
The Janus face of HIF-1α in ischemic stroke and the possible associated pathways
Amin, N., Abbasi, I. N., Wu, F., Shi, Z., Sundus, J., Badry, A., Yuan, X., Zhao, B., Pan, J., Mi, X., et al. (2024) · Neurochemistry International · doi:10.1016/j.neuint.2024.105747 · Cited by 23
Enhancing gliotic cyst wall with microvascular proliferation adjacent to a meningioma
Arai, M., Kashihara, K., & Kaizaki, Y. (2006) · Journal of Clinical Neuroscience · doi:10.1016/j.jocn.2005.02.015 · Cited by 20
Moore, T. L., Pessina, M. A., Finklestein, S. P., Kramer, B. C., Killiany, R., & Rosene, D. L. (2013) · Somatosensory & Motor Research · doi:10.3109/08990220.2013.790806 · Cited by 20
“This scale was adapted from Zhang et al. (2000) and the National Institutes of Health Stroke Scale.”
BackgroundMethodProtective effects of VEGF treatment on focal cerebral ischemia in rats
Zhang, A., Liang, L., Niu, H., XU, P., & Hao, Y. (2012) · Molecular Medicine Reports · doi:10.3892/mmr.2012.1069 · Cited by 20
Wang, L., Zhang, G.-L., Liu, X., Peng, A. F., Ren, H., Huang, S., Liu, T., & Wang, X. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21041267 · Cited by 20
“Cerebral ischemia injury can stimulate the expression of endogenous vascular-related factors, thereby promoting the rapid proliferation of vascular endothelial cells, and migrate to the damaged areas to form new blood vessels, providing nutrients and oxygen for the neurons in the ischemic penumbra [5,10].”
BackgroundSobrino, T., Millán, M., Castellanos, M., BLANCO, M., Brea, D., Dorado, L., Rodríguez‐González, R., Rodríguez‐Yáñez, M., Serena, J. L., Leira, R., et al. (2010) · Journal of Thrombosis and Haemostasis · doi:10.1111/j.1538-7836.2010.03897.x · Cited by 20
Iijima, K., Kurachi, M., Shibasaki, K., Naruse, M., Puentes, S., Imai, H., Yoshimoto, Y., Mikuni, M., & Ishizaki, Y. (2015) · Journal of Neurochemistry · doi:10.1111/jnc.13262 · Cited by 20
Perlecan Domain V Therapy for Stroke: A Beacon of Hope?
Bix, G. J. (2012) · ACS Chemical Neuroscience · doi:10.1021/cn300197y · Cited by 20
New Targets of Neuroprotection in Ischemic Stroke
Bacigaluppi, M., & Hermann, D. M. (2008) · The Scientific World JOURNAL · doi:10.1100/tsw.2008.94 · Cited by 19
Gene delivery with viral vectors for cerebrovascular diseases
Gan, Y. (2012) · Frontiers in Bioscience-Elite · doi:10.2741/e607 · Cited by 20
Navarro-Sobrino, M., Rosell, A., Peñalba, A., Ribó, M., Álvarez‐Sabín, J., Fernández‐Cadenas, I., & Montaner, J. (2009) · Current Neurovascular Research · doi:10.2174/156720209789630366 · Cited by 20
Non-moyamoya vessel network formation along steno-occlusive middle cerebral artery
Xu, Y., Li, M. L., Gao, S., Hou, B., Sun, Z.-Y., Zhou, H.-L., Feng, F., & Xu, W. (2016) · Neurology · doi:10.1212/wnl.0000000000002698 · Cited by 20
Tado, M., Mori, T., Fukushima, M., Oshima, H., Maeda, T., Yoshino, A., Aizawa, S., & Katayama, Y. (2013) · Journal of Neurotrauma · doi:10.1089/neu.2013.2940 · Cited by 20
“Zhang and colleagues 38 reported that administration of VEGF in a rat model of cerebral embolism increased angiogenesis and improved the microcirculation in the peripheral region of the cerebral infarct at 9 days after induction of ischemia.”
Circulating Tissue Kallikrein Levels Correlate With Severity of Carotid Atherosclerosis
Porcu, P., Emanueli, C., Desortes, E., Marongiu, G., Piredda, F., Chao, L., Chao, J., & Madeddu, P. (2004) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/01.atv.0000128126.57688.a9 · Cited by 21
Wallensten, J., Mobarrez, F., Åsberg, M., Borg, K., Beser, A., Wilczek, A., & Nager, A. (2021) · Scientific Reports · doi:10.1038/s41598-021-96313-8 · Cited by 19
The role of VEGF in vascular dementia: impact of aging and cellular senescence
Agrawal, N., Afzal, M., Khan, N. H., Ganesan, S., Kumari, M., Sunitha, S., Dash, A., Goyal, K., Kushwaha, B., Rekha, A., et al. (2025) · Biogerontology · doi:10.1007/s10522-025-10219-w · Cited by 21
“Additionally, these therapies have demonstrated positive outcomes in epilepsy and stroke (Zhang et al. 2000; Nicoletti et al. 2010).”
Systemic Neurotransplantation - A Problem-Oriented Systematic Review
Janowski, M., & Date, I. (2009) · Reviews in the Neurosciences · doi:10.1515/revneuro.2009.20.1.39 · Cited by 19
Wei, S., Chen, T., Kao, F., Hsu, Y.-J., & Chen, Y. (2022) · Journal of Tissue Engineering · doi:10.1177/20417314221084096 · Cited by 19
Sánchez-Garibay, C., Salinas‐Lara, C., Gómez-López, M. A., Soto-Rojas, L. O., Castillón-Benavides, N. K., Castillón-Benavides, O. J., Hernández‐Campos, M. E., Hernández‐Pando, R., Marquina‐Castillo, B., Flores-Barrada, M. A., et al. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23126436 · Cited by 19
“VEGF augments permeability and disrupts several endothelial barriers, including the BBB [24], whereas its role in the loss of BCSFB properties is not clear.”
BackgroundA high-resolution view of the heterogeneous aging endothelium
Dobner, S., Tóth, F., & de Rooij, L. P. M. H. (2024) · Angiogenesis · doi:10.1007/s10456-023-09904-6 · Cited by 23
Wang, K., Zhou, W., Wen, L., Jin, X., Meng, T., Li, S., Hong, Y., Xu, Y., Yuan, H., & Hu, F. (2024) · Experimental Neurology · doi:10.1016/j.expneurol.2024.114870 · Cited by 19
Zheng, X., Tan, J.-L., Zhang, S., Yang, Y., Wang, X., Yu, X., & Zhong, L. (2014) · Neural Regeneration Research · doi:10.4103/1673-5374.141785 · Cited by 19
“Vascular endothelial growth factor (VEGF)-mediated effects on vascular endothelial cells include accelerated proliferation and migration of these cells, the formation of new blood vessels, and an increase in vascular permeability (Zhang et al., 2000).”
BackgroundYang, Z., Liu, L., Zhao, L., Liu, Y., & Xue, Y. (2014) · Journal of Neuroscience Research · doi:10.1002/jnr.23348 · Cited by 19
“Research has revealed that VEGF increased the permeability of the BBB via the synthesis/release of nitric oxide and that subsequent activation of soluble guanylate cyclase (sGC) produced a high concentration cGMP (Mayhan, 1999; Zhang et al., 2000; Davies, 2002; Faehling et al., 2002; Fischer et al., 2002; Lund et al.,…”
BackgroundThe role of vascular endothelial growth factor in angiogenesis and brain circulation after stroke
Cosky, E. E. P., & Ding, Y. (2018) · Brain Circulation · doi:10.4103/bc.bc_8_18 · Cited by 20
“[9,10] Perhaps, these inconsistencies are best reconciled through realizing the dual role of VEGF‐A in AIS; it establishes the endothelial network through enhancing endothelial cell migration and proliferation, but also induces vascular leakiness and permeability.[11,12]”
BackgroundLuo, Y., Yin, X., Shi, S., Ren, X., Zhang, H., Wang, Z., Cao, Y. B., Tang, M., Xiao, B., & Zhang, M. (2019) · Frontiers in Neuroanatomy · doi:10.3389/fnana.2019.00005 · Cited by 19
“A great number of researches indicate that those with a higher density of neovasculature have both a higher survival rate and better outcomes (Zhang et al., 2000).”
BackgroundWang, Q., Deng, Y., Huang, L., Zeng, W., Chen, S., Lv, B., Jiang, W., Han, Y., Ding, H., Wen, M., et al. (2019) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2019.4262 · Cited by 19
“It has been reported that increased VEGF induces BBB leakage (31).”
Background
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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