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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VEGF is responsible for multiple important physiological functions, particularly BBB permeability.
“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]
The Discussion (page not provided) describes VEGF’s roles in angiogenesis and possible neuronal effects, and reports increased BBB leakage after early VEGF administration in ischemic rats. The claim is broader than the evidence: the study found no increased leakage in nonischemic areas or rats and does not establish BBB permeability as a general physiological function of VEGF. (LLM, conf=0.86)
Experimental — accuracy not yet measuredSimilar findings about the importance of timing for administration of a neurorestorative therapy for stroke have been reported for VEGF and modulators of matrix metalloproteinases.
“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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BackgroundMatrix metalloproteinases and their multiple roles in neurodegenerative diseases
Rosenberg, G. A. (2009) · The Lancet Neurology · doi:10.1016/s1474-4422(09)70016-x · Cited by 594 · see citing works
Hemorrhagic Transformation after Ischemic Stroke in Animals and Humans
Jickling, G. C., Liu, D., Stamova, B. S., Ander, B. P., Zhan, X., Lu, A., & Sharp, F. R. (2013) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2013.203 · Cited by 550 · see citing works
Dual Functions of Microglia in Ischemic Stroke
Qin, C., Zhou, L., Ma, X.-T., Hu, Z.-W., Yang, S., Chen, M., Bosco, D. B., Wu, L., & Tian, D. (2019) · Neuroscience Bulletin · doi:10.1007/s12264-019-00388-3 · Cited by 546 · see citing works
From angiogenesis to neuropathology
Greenberg, D. A., & Jin, K. (2005) · Nature · doi:10.1038/nature04481 · Cited by 532 · see citing works
“An increase in angiogenesis by VEGF in rats is associated with reduced neurological deficit”
BackgroundBrain Endothelial Cell-Cell Junctions: How to “Open” the Blood Brain Barrier
Stamatovic, S. M., Keep, R. F., & Andjelkovic, A. V. (2008) · Current Neuropharmacology · doi:10.2174/157015908785777210 · Cited by 516 · see citing works
“These include a group of vasogenic agents including histamine, substance P, endothelin-1 and bradikinin; growth factors such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor bFGF and transforming growth factor– (TGF ); a heterogenic group of inflammatory mediators including cytokines [inter…”
BackgroundVEGF: once regarded as a specific angiogenic factor, now implicated in neuroprotection
Storkebaum, E., Lambrechts, D., & Carmeliet, P. (2004) · BioEssays · doi:10.1002/bies.20092 · Cited by 505 · see citing works
“cerebral ischemia enhances angiogenesis in the penumbra and improves neural recovery.((86)) Therefore, VEGF may have”
BackgroundZhang, Z. G., Zhang, L., Jiang, Q., & Chopp, M. (2002) · Circulation Research · doi:10.1161/hh0302.104460 · Cited by 453 · see citing works
Self-citationRole and Therapeutic Potential of VEGF in the Nervous System
de Almodóvar, C. R., Lambrechts, D., Mazzone, M., & Carmeliet, P. (2009) · Physiological Reviews · doi:10.1152/physrev.00031.2008 · Cited by 443 · see citing works
Hypoxia-induced vascular endothelial growth factor expression causes vascular leakage in the brain
Schoch, H. (2002) · Brain · doi:10.1093/brain/awf257 · Cited by 433 · see citing works
“, 1997) as well as in cerebral ischaemia (Zhang et al., 2000).”
The seed and soil hypothesis: vascularisation and brain metastases
Fidler, I. J., Yano, S., Zhang, R.-D., Fujimaki, T., & Bucana, C. D. (2002) · The Lancet Oncology · doi:10.1016/s1470-2045(01)00622-2 · Cited by 432 · see citing works
Self-citationSadick, J. S., O’Dea, M. R., Hasel, P., Dykstra, T., Faustin, A., & Liddelow, S. A. (2022) · Neuron · doi:10.1016/j.neuron.2022.03.008 · Cited by 415 · see citing works
Multiple roles for MMPs and TIMPs in cerebral ischemia
Cunningham, L. A., Wetzel, M. K., & Rosenberg, G. A. (2005) · Glia · doi:10.1002/glia.20169 · Cited by 410 · see citing works
“Support for this possibility is the observation that VEGF application at early times after cerebral ischemia, when MMP activity is high, results in augmentation of tissue damage, increased vascular permeability, and increased incidence of hemorrhage (Zhang et al., 2000).”
BackgroundZhang, Z. G., Li, Z., Tsang, W., Hamid Soltanian-zadeh, A., Morris, D. C., Zhang, R., Goussev, A. V., Powers, C., Yeich, T., & Chopp, M. (2002) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1097/00004647-200204000-00002 · Cited by 399 · see citing works
“, 48 hours after stroke) when endogenous VEGF/VEGF receptors and Ang/Tie2 were upregulated enhanced neovascularization in ischemic brain (Zhang et al., 2000).”
BackgroundSelf-citationTemporal Profile of Angiogenesis and Expression of Related Genes in the Brain after Ischemia
Hayashi, T., Noshita, N., Sugawara, T., & Chan, P. H. (2003) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1097/01.wcb.0000041283.53351.cb · Cited by 391 · see citing works
“Previous reports have demonstrated that VEGF is effective for ischemic stroke (Hayashi et al., 1998; Harrigan et al., 2002), but others have shown its detrimental effects (Zhang et al., 2000).”
BackgroundResultAngiogenesis after cerebral ischemia
Beck, H., & Plate, K. H. (2009) · Acta Neuropathologica · doi:10.1007/s00401-009-0483-6 · Cited by 377 · see citing works
“[189] intravenously applied recombinant human (rh)VEGF following embolic stroke in a rat model”
MethodVascular endothelial growth factor: a neurovascular target in neurological diseases
Lange, C. M., Storkebaum, E., de Almodóvar, C. R., Dewerchin, M. A., & Carmeliet, P. (2016) · Nature Reviews Neurology · doi:10.1038/nrneurol.2016.88 · Cited by 374 · see citing works
Ischemic rat brain extracts induce human marrow stromal cell growth factor production
Chen, X., Li, Y., Wang, L., Katakowski, M., Zhang, L., Chen, J., Xu, Y., Gautam, S. C., & Chopp, M. (2002) · Neuropathology · doi:10.1046/j.1440-1789.2002.00450.x · Cited by 382 · see citing works
Self-citationNeuroglobin protects the brain from experimental stroke <i>in</i> <i>vivo</i>
Sun, Y., Jin, K., Peel, A., Mao, X. O., Xie, L., & Greenberg, D. A. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0637726100 · Cited by 354 · see citing works
Src deficiency or blockade of Src activity in mice provides cerebral protection following stroke
Paul, R. H., Zhang, Z. G., Eliceiri, B. P., Jiang, Q., Boccia, A., Zhang, R. L., Chopp, M., & Cheresh, D. A. (2001) · Nature Medicine · doi:10.1038/84675 · Cited by 342 · see citing works
“It was also shown that application of recombinant VEGF, one hour after stroke, increased BBB leakage and ischemic lesions indicating that VEGF exacerbates tissue damage by promoting edem”
BackgroundSelf-citationHermann, D. M., & Chopp, M. (2012) · The Lancet Neurology · doi:10.1016/s1474-4422(12)70039-x · Cited by 333 · see citing works
Self-citationDual-function injectable angiogenic biomaterial for the repair of brain tissue following stroke
Nih, L. R., Gojgini, S., Carmichael, S. T., & Segura, T. (2018) · Nature Materials · doi:10.1038/s41563-018-0083-8 · Cited by 325 · see citing works
Microglia–blood vessel interactions: a double-edged sword in brain pathologies
Dudvarski Stankovic, N., Teodorczyk, M., Ploen, R., Zipp, F., & Schmidt, M. H. H. (2016) · Acta Neuropathologica · doi:10.1007/s00401-015-1524-y · Cited by 301 · see citing works
Signaling Pathways for Early Brain Injury after Subarachnoid Hemorrhage
Kusaka, G., Ishikawa, M., Nanda, A., Granger, D. N., & Zhang, J. H. (2004) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1097/01.wcb.0000125886.48838.7e · Cited by 319 · see citing works
“The levels of VEGF in the bloody cerebral spinal fluid and the expression of VEGF in the brain tissues are increased after SAH (Borel et al., 2003; Josko et al., 2001; McGirt et al., 2002), which might enhance BBB permeability (Mayhan, 1999; Zhang et al., 2000).”
BackgroundWang, L., Zhang, Z. G., Zhang, R. L., Gregg, S. R., Hozeska-Solgot, A., LeTourneau, Y., Wang, Y., & Chopp, M. (2006) · The Journal of Neuroscience · doi:10.1523/jneurosci.5380-05.2006 · Cited by 316 · see citing works
“Single immunostaining and double immunofluorescent staining for brain tissue was performed, as previously described (Zhang et al., 2000; Wang et al., 2004; R. Zhang et al., 2004).”
Self-citationZhang, J., Takahashi, H. K., Liu, K., Wake, H., Liu, R., Maruo, T., Date, I., Yoshino, T., Ohtsuka, A., Mori, S., et al. (2011) · Stroke · doi:10.1161/strokeaha.110.598334 · Cited by 315 · see citing works
“In the case of neurons, the time-dependent translocation of HMGB1 can be summarized into 3 steps: (1) its redistribution inside the nucleus; (2) the translocation of HMGB1 from the nucleus into the cytosolic compartment; and (3) the release of HMGB1 into the extracellular space.”
BackgroundRosenstein, J. M., Krum, J. M., & Ruhrberg, C. (2010) · Organogenesis · doi:10.4161/org.6.2.11687 · Cited by 315 · see citing works
Hypoxia-ischemia and retinal ganglion cell damage
Kaur, C. (2008) · Clinical ophthalmology · doi:10.2147/opth.s3361 · Cited by 309 · see citing works
“Upregulation of endogenous VEGF in astrocytes in hypoxia-ischemia is believed to interact with receptors for VEGF on the vessels and contribute to the disruption of blood-brain barrier (BBB) resulting in vascular leakage (Zhang et al 2000, 2002).”
BackgroundInfluentialFactors controlling permeability of the blood–brain barrier
Almutairi, M. M., Chen, G., Xu, Y. G., Chang, Y., & Shi, H. (2015) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-015-2050-8 · Cited by 308 · see citing works
“VEGF exerted a major role in BBB disruption leading to subsequent edema during ischemic brain injury [181, 182].”
BackgroundInfluentialFree radicals as triggers of brain edema formation after stroke
Heo, J. H., Han, S., & Lee, S. (2005) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2005.03.035 · Cited by 306 · see citing works
Response of the cerebral vasculature following traumatic brain injury
Salehi, A., Zhang, J. H., & Obenaus, A. (2017) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1177/0271678x17701460 · Cited by 299 · see citing works
“Studies have demonstrated that VEGF treatment can lead to increased cerebral edema, but this is dependent on the timing of the treatment.(134,193) Delayed administration has been shown to be the most efficacious in terms of vascularization.”
BackgroundCoupling of neurogenesis and angiogenesis after ischemic stroke
Ruan, L., Wang, B. Z., Zhuge, Q., & Jin, K. (2015) · Brain Research · doi:10.1016/j.brainres.2015.02.042 · Cited by 300 · see citing works
Zhang, R., Wang, L., Li, Z., Chen, J., Zhu, Z., Zhang, Z., & Chopp, M. (2003) · Circulation Research · doi:10.1161/01.res.0000056757.93432.8c · Cited by 298 · see citing works
Self-citationComparison of mesenchymal stem cells from adipose tissue and bone marrow for ischemic stroke therapy
Ikegame, Y., Yamashita, K., Hayashi, S.-I., Mizuno, H., Tawada, M., You, F., Yamada, K., Tanaka, Y., Egashira, Y., Nakashima, S., et al. (2011) · Cytotherapy · doi:10.3109/14653249.2010.549122 · Cited by 293 · see citing works
“Although a high level of VEGF secretion alone may enhance vascular permeability and induce brain swelling (37,38), combined secretion of VEGF, HGF and angiopoietin-1 from ASC seems to be associated with a better outcome without brain swelling in the acute stage.”
BackgroundChen, X., Katakowski, M., Li, Y., Lu, D., Wang, L., Zhang, L., Chen, J., Xu, Y., Gautam, S. C., Mahmood, A., et al. (2002) · Journal of Neuroscience Research · doi:10.1002/jnr.10334 · Cited by 293 · see citing works
“Treatment of experimental stroke in the rat with VEGF significantly reduces functional deficits (Zhang et al., 2000b).”
BackgroundInfluentialSelf-citationZhu, T., Wang, L., Wang, L.-P., & Wan, Q. (2022) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2022.112719 · Cited by 298 · see citing works
Factors influencing the blood-brain barrier permeability
Zhao, Y., Gan, L., Ren, L., Lin, Y., Ma, C., & Lin, X. (2022) · Brain Research · doi:10.1016/j.brainres.2022.147937 · Cited by 291 · see citing works
Diverse roles for VEGF-A in the nervous system
Mackenzie, F., & Ruhrberg, C. (2012) · Development · doi:10.1242/dev.072348 · Cited by 266 · see citing works
“Most importantly, VEGF-A can increase vascular permeability and thereby disrupt the blood-brain barrier and promote inflammatory cell infiltration (Kalaria et al., 1998; Krum and Khaibullina, 2003; Krum et al., 2002; Proescholdt et al., 1999; Zhang et al., 2000).”
BackgroundArai, K., Jin, G., Navaratna, D., & Lo, E. H. (2009) · FEBS Journal · doi:10.1111/j.1742-4658.2009.07176.x · Cited by 286 · see citing works
New roles for VEGF in nervous tissue?beyond blood vessels
Rosenstein, J. M. (2004) · Experimental Neurology · doi:10.1016/j.expneurol.2004.01.022 · Cited by 281 · see citing works
Adult Neurogenesis and the Ischemic Forebrain
Lichtenwalner, R. J., & Parent, J. M. (2005) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/sj.jcbfm.9600170 · Cited by 281 · see citing works
Ergul, A., Alhusban, A., & Fagan, S. C. (2012) · Stroke · doi:10.1161/strokeaha.111.642710 · Cited by 275 · see citing works
Ayata, C., & Ropper, A. H. (2002) · Journal of Clinical Neuroscience · doi:10.1054/jocn.2001.1031 · Cited by 276 · see citing works
Vascular endothelial growth factors (VEGFs) and stroke
Greenberg, D. A., & Jin, K. (2013) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-013-1282-8 · Cited by 269 · see citing works
“For example, intravenous VEGF-A increased microvessel density in the cortical ischemia penumbra [31] and intraventricular VEGF increased the number of von Willebrand factor-immunoreactive endothelial cells in the ischemic caudate-putamen after MCA occlusion in rats [50].”
BackgroundMethodInfluentialBone Marrow as a Source of Endothelial Cells and NeuN-Expressing Cells After Stroke
Hess, D. C., Hill, W., Martin-Studdard, A., Carroll, J. E., Brailer, J., & Carothers, J. (2002) · Stroke · doi:10.1161/01.str.0000014925.09415.c3 · Cited by 269 · see citing works
Zachary, I. C. (2005) · Neurosignals · doi:10.1159/000088637 · Cited by 267 · see citing works
Gerstner, E. R., & Fine, R. L. (2007) · Journal of Clinical Oncology · doi:10.1200/jco.2006.10.0677 · Cited by 266 · see citing works
Perivascular microglia promote blood vessel disintegration in the ischemic penumbra
Jolivel, V., Bicker, F., Binamé, F., Ploen, R., Keller, S., Gollan, R., Jurek, B., Birkenstock, J., Poisa-Beiro, L., Bruttger, J., et al. (2014) · Acta Neuropathologica · doi:10.1007/s00401-014-1372-1 · Cited by 267 · see citing works
Engineering Bacteria‐Activated Multifunctionalized Hydrogel for Promoting Diabetic Wound Healing
Lu, Y., Li, H., Wang, J., Yao, M., Peng, Y. Y., Liu, T., Li, Z., Luo, G., & Deng, J. (2021) · Advanced Functional Materials · doi:10.1002/adfm.202105749 · Cited by 264 · see citing works
Astrocytes are necessary for blood–brain barrier maintenance in the adult mouse brain
Heithoff, B. P., George, K. K., Phares, A. N., Zuidhoek, I. A., Muñoz‐Ballester, C., & Robel, S. (2020) · Glia · doi:10.1002/glia.23908 · Cited by 256 · see citing works
Suzuki, S., Brown, C. M., Cruz, C. D. D., Yang, E., Bridwell, D. A., & Wise, P. M. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0610394104 · Cited by 257 · see citing works
Elahi, F. M., Casaletto, K. B., Joie, R. L., Walters, S. M., Harvey, D. J., Wolf, A. A., Edwards, L., Contreras, W. R., Karydas, A., Cobigo, Y., et al. (2019) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2019.09.004 · Cited by 250 · see citing works
Modulation of Neural Plasticity as a Basis for Stroke Rehabilitation
Pekna, M., Pekny, M., & Nilsson, M. (2012) · Stroke · doi:10.1161/strokeaha.112.654228 · Cited by 258 · see citing works
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 249 · see citing works
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 246 · see citing works
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 247 · see citing works
“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 258 · see citing works
“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 · see citing works
“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 · see citing works
Lee, H. J., Kim, K. S., Park, I. H., & Kim, S. U. (2007) · PLoS ONE · doi:10.1371/journal.pone.0000156 · Cited by 238 · see citing works
“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 · see citing works
“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 239 · see citing works
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 238 · see citing works
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 · see citing works
“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 247 · see citing works
“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 232 · see citing works
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 232 · see citing works
“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 226 · see citing works
“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 · see citing works
“…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 · see citing works
“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 · see citing works
“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 · see citing works
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 216 · see citing works
“[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 212 · see citing works
“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 210 · see citing works
“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 · see citing works
“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 209 · see citing works
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 · see citing works
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 · see citing works
“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 · see citing works
Self-citation
- 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 › Epidemiology › 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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