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Vascular Endothelial Growth Factor Has Neurotrophic Activity and Stimulates Axonal Outgrowth, Enhancing Cell Survival and Schwann Cell Proliferation in the Peripheral Nervous System
Open accessAbstract
Vascular endothelial growth factor (VEGF) is a mitogen for endothelial cells, and it promotes angiogenesis in vivo. Here we report that VEGF 165 has neurotrophic actions on cultured adult mouse superior cervical ganglia (SCG) and dorsal root ganglia (DRG), measured as axonal outgrowth. Maximal effect was observed at 10–50 ng/ml for SCG and 100 ng/ml for DRG. VEGF-induced axonal outgrowth was inhibited by the mitogen-activated protein kinase kinase inhibitor PD 98059 but not by the protein kinase inhibitor K252a. VEGF also increased survival of both neurons and satellite cells and the number of proliferating Schwann cells. Immunocytochemistry and immunoblotting revealed that VEGF was expressed in virtually all nerve cells in the SCG but only in a population of small-diameter (<35 μm) neurons representing ∼30% of the neurons in DRG. Immunostaining showed that the VEGF receptor fetal liver kinase receptor (flk-1) was found on nerve cell bodies in DRG and to a lesser extent on neurons in SCG. Growth cones of regenerating axons from both types of ganglia exhibited flk-1 immunoreactivity, as did Schwann cells. We conclude that VEGF has both neurotrophic and mitogenic activity on cells in the peripheral nervous system.
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“Vascular endothelial growth factor (VEGF) is known to promote revascularization, axonal outgrowth, and Schwann cell proliferation.58”
From Regenerative Electrode Interfaces for Neural Prostheses. (2016) · cites this paper as [58]
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Citations
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Items 501–600 of 750
Neurogenic Potential of Engineered Mesenchymal Stem Cells Overexpressing VEGF
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“It has been revealed that VEGF enhances neural survival and decreases cellular toxicity and apoptosis (Sondell et al. 1999).”
BackgroundEffect of intravitreal ranibizumab and aflibercept injections on retinal nerve fiber layer thickness
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BackgroundConnexin 30 deletion exacerbates cochlear senescence and age-related hearing loss
Paciello, F., Zorzi, V., Raspa, M., Scavizzi, F., Grassi, C., Mammano, F., & Fetoni, A. R. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.950837 · Cited by 15
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BackgroundInfluentialControl of neurite growth and guidance by an inhibitory cell-body signal
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“VEGFmediated stimulation of axonal outgrowth was observed in adult superior cervical ganglia and dorsal root ganglia in vitro via the specific receptor tyrosine kinases VEGFR2 (Flk-1) (Sondell et al. 1999).”
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“Vascular endothelial growth factor (VEGF) is another growth factor produced by VSM that has been reported to support the survival of postganglionic sympathetic neurons (21).”
BackgroundIn vitro modulation of Schwann cell behavior by VEGF and PDGF in an inflammatory environment
Basu, S., Choudhury, I. N., Nazareth, L., Chacko, A., Shelper, T., Vial, M., Ekberg, J. A. K., & John, J. A. S. (2022) · Scientific Reports · doi:10.1038/s41598-021-04222-7 · Cited by 14
Reciprocal signaling between adipose tissue depots and the central nervous system
Puente-Ruiz, S. C., & Jaïs, A. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.979251 · Cited by 17
“Interestingly, VEGFA exerts potent neurotrophic and synaptotrophic effects as well (Sondell et al., 1999; Pelletier et al., 2015; Calvo et al., 2018).”
BackgroundEssential Role of Multi-Omics Approaches in the Study of Retinal Vascular Diseases
Lei, Y., Guo, J., He, S., & Yan, H. (2022) · Cells · doi:10.3390/cells12010103 · Cited by 14
Rat Cavernous Nerve Reconstruction with CD133+Cells Derived from Human Bone Marrow
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“vascular endothelial growth factor has also been shown to protect cortical neurons against hypoxic injury, stimulate axon growth and improve survival of ganglion cell in rat neck and dorsal root ganglion [50] .”
BackgroundPromoting melanoma growth and metastasis by enhancing VEGF expression
Ni, C., Sun, B., Dong, X.-Y., Sun, T., Zhao, N., Liu, Y.-R., & Gu, Q. (2012) · Współczesna Onkologia · doi:10.5114/wo.2012.32486 · Cited by 14
“Although endothelial cells are the primary targets of VEGF, several studies have also reported its mitogenic effects on certain nonendothelial cells such as retinal pigment epithelial cells [16], pancreatic duct cells [17], and Schwann cells [18], as well as on cancer cells, including breast cancer [19], prostate canc…”
BackgroundBlocking elevated VEGF‐A attenuates non‐vasculature Fragile X syndrome abnormalities
Belagodu, A. P., Zendeli, L., Slater, B. J., & Galvez, R. (2016) · Developmental Neurobiology · doi:10.1002/dneu.22404 · Cited by 14
“Although VEGF-A has been shown to directly alter neuronal properties independent of vascular changes (Sondell et al., 1999), it is possible that the observed attenuation of FXS abnormalities are not due to direct neuronal modulation, but rather due to indirect Bevacizumab induced VEGF-A modulation…”
BackgroundResultInfluentialEvaluation of direct and cell-mediated triple-gene therapy in spinal cord injury in rats
Islamov, R. R., Izmailov, A., Sokolov, M. E., Fadeev, F., Bashirov, F. V., Eremeev, A. A., Shaymardanova, G. F., Шмаров, М. М., Naroditskiy, B. S., Chelyshev, Y. A., et al. (2017) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2017.05.005 · Cited by 14
The Role of Therapeutic Angiogenesis in Tissue Repair and Regeneration
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Distraction histogenesis of the maxillofacial region
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“axon growth, thereby sparking interest in the possible neurotrophic effects exerted by VEGF [43, 61, 62].”
BackgroundInfluentialIslamov, R. R., Bashirov, F. V., Sokolov, M. E., Izmailov, A., Fadeev, F., Аршалуйсович, М. В., Davleeva, M., Zubkova, O. V., Smarov, M. M., Logunov, D. Y., et al. (2020) · Neural Regeneration Research · doi:10.4103/1673-5374.290902 · Cited by 13
“Recombinant GDNF produced by WBCs will act as a neuroprotective factor (Sondell et al., 1999; Cheng et al., 2002).”
BackgroundChu, T., Baral, K., Labit, E., Rosin, N. L., Sinha, S., Umansky, D., Alzahrani, S., Arora, R., Cao, L., Rancourt, D. E., et al. (2022) · Glia · doi:10.1002/glia.24242 · Cited by 13
“Each DRG was then cut into half to promote adherence to the PDL/ laminin coated— 12 mm coverslips.”
BackgroundInfluentialCD133+ cells from human peripheral blood promote corticospinal axon regeneration
Yamamoto, R., Ishikawa, M., Tanaka, N., Kamei, N., Nakanishi, K., Sasaki, H., Nakamae, T., Mochizuki, Y., Asahara, T., & Ochi, M. (2008) · Neuroreport · doi:10.1097/wnr.0b013e3282ff6396 · Cited by 13
Placental growth factor: a tissue modelling factor with therapeutic potentials in neurology?
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“Likewise, VEGF promotes survival of retinal neurons as well as neurotrophic and angiogenic activities [20, 21].”
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“VEGF165 and HGF both have been shown to have a neurotrophic modality via corresponding signaling axes [37,38] and this has become the basis for their application in peripheral nerve injury, central nerve system diseases and neuropathic conditions [39,40].”
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Vascular pattern of the dentate gyrus is regulated by neural progenitors
Pombero, A., García‐López, R., Estirado, A., & Martı́nez, S. (2018) · Brain Structure and Function · doi:10.1007/s00429-017-1603-z · Cited by 11
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Expression of Inducible Nitric Oxide Synthase in Trigeminal Ganglion Cells during Culture
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“The method used was adapted from the work of Sondell et al. (1999). After being cut into smaller pieces, the ganglia were transferred to Mg2π/Ca2π free phosphate buffered saline (PBS) containing papain (1IU/ml, Sigma-Aldrich, USA), collagenase A (0.”
MethodPigment Epithelium-Derived Factor: Chemistry, Structure, Biology, and Applications
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“VEGF exerts neurotrophic effects which manifest as increased axonal outgrowth and improved cell survival in neuronal cultures (42,43).”
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“Alzheimer’s disease, Huntington’s disease, and Parkinson’s disease.(35) VEGF may achieve neuroprotection via enhancing axonal regeneration, inhibition of caspase-3, improving neurogenesis, and activating Akt.”
BackgroundEvaristo-Mendonça, F., Sardella-Silva, G., Kasai-Brunswick, T. H., Campos, R. M. P., Domizi, P., Santiago, M. F., Reis, R. A. D. M., Méndez‐Otero, R., Ribeiro‐Resende, V. T., & Pimentel‐Coelho, P. M. (2019) · Stem Cells International · doi:10.1155/2019/7692973 · Cited by 11
“Considering that rBM-MSCs constitutively secreted high levels of VEGF, as shown above, and that VEGF has been shown to promote neurite outgrowth in DRG sensory neurons [45, 46], we hypothesized that this neurotrophic activity of rBM-MSCs could be at least partially mediated by VEGF.”
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“VEGF is well known as an angiogenic and permeability regulator [12,13,45], and possesses neurotrophic and neuroprotective activities [46–49].”
Heß, A., Bloch, W., Wittekindt, C., Siodladczek, J., Addicks, K., & Michel, O. (2000) · Neuroscience Letters · doi:10.1016/s0304-3940(00)00774-6 · Cited by 11
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“51,52 VEGF would probably play a key role: for example, it was demonstrated that VEGF and its receptor flk-1 are overexpressed in the DRG following peripheral mechanical nerve injury 53,54 and in spinal cord after compression.”
Roslavtceva, V., Salmina, A. B., Prokopenko, S. V., Пожиленкова, Е. А., Кобаненко, И. В., & Rezvitskaya, G. G. (2016) · Biomeditsinskaya Khimiya · doi:10.18097/pbmc20166202124 · Cited by 10
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Neuroprotective Effects of Ganoderma lucidum on Spinal Cord Injury
Ekinci, A., Özevren, H., Bilgiç, B. E., Ekinci, C., Deveci, S., & Devecí, E. (2018) · International Journal of Morphology · doi:10.4067/s0717-95022018000100175 · Cited by 10
“…play important roles in the development of vascular network, it independently works on neuron to guide neurogenesis (Jin et al. (2002), axon growth (Sondell et al., 1999; Alitalo et al., 2011; Erskine t al., 2011; Ruiz de Almodovar et al. 2011) Nuclear Antigen (PCNA) is a significant cell-cycle…”
BackgroundIntra-arterial administration of cell-based biological agents for ischemic stroke therapy
Spiliοpoulos, S., Festas, G., Reppas, L., & Brountzos, Ε. (2019) · Expert Opinion on Biological Therapy · doi:10.1080/14712598.2019.1566454 · Cited by 10
“Particularly, VEGF in addition to its angiogenic action, also demonstrates the characteristics of a regular neurotrophic factor supporting the survival of sensory [29] and motor neurons [30], stimulating proliferation of neural stem cells [31], astrocytes [32], as well as Schwann cells [29].”
BackgroundShen, Y., Zhu, J., Liu, Q., Ding, S., Dun, X., & He, J. (2021) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2021.743532 · Cited by 10
“It is actively involved in many physiological processes such as organ development, cell migration, angiogenesis, immune response and tissue repair (St Croix, 2015; Tu et al., 2015).”
BackgroundYang, Z., Yu, H., Pengdian, C., Luo, W., Pi, M., Yong-gang, W., & Wang, L. (2014) · Neural Regeneration Research · doi:10.4103/1673-5374.125334 · Cited by 10
“to stimulate axonal outgrowth and enhance cell viability([24]), promote the proliferation and differentiation of endothelial cells, and inhibit cellular apoptosis via inducing Bcl-2 and Survivin expression and down-regulating caspase-3 expression([25-26]).”
BackgroundGalieva, L. R., Mukhamedshina, Y. O., Akhmetzyanova, E. R., Gilazieva, Z., Arkhipova, S. S., Garanina, E. E., & Rizvanov, A. A. (2018) · Stem Cells International · doi:10.1155/2018/4695275 · Cited by 10
“With a plasmid gene delivery, an increased VEGF level in the injured nerve maintains and enhances the growth of regenerating nerve fibers, by combined angiogenic, neurotrophic, and neuroprotective effects, and increases the SC proliferation [36].”
BackgroundBlood vessels and nerves: together or not?
Hogg, P. J., & McLachlan, E. M. (2002) · The Lancet · doi:10.1016/s0140-6736(02)11726-0 · Cited by 10
The therapeutic potential of gene transfer for the treatment of peripheral neuropathies
Goss, J. R. (2007) · Expert Reviews in Molecular Medicine · doi:10.1017/s1462399407000270 · Cited by 10
The Role of Vascularization in Nerve Regeneration: Mechanistic and Therapeutic Perspectives
Malekzadeh, H., Otto-Moudry, R., & Moore, A. M. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26178395 · Cited by 9
“VEGF influences peripheral nerve repair beyond its angiogenic role by promoting and enhancing neurotrophic factor expression (NGF, BDNF) [28] It also modulates the immune response by increasing vascular permeability, facilitating macrophage infiltration, and promoting a regenerative, M2-polarized…”
Zhang, Y., Huang, S., Wang, B., Sun, B., Li, W., Lu, X., & Ding, X. (2012) · Neuroscience Letters · doi:10.1016/j.neulet.2012.07.056 · Cited by 9
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“VEGF promotes neurite growth in cultured rat retinal ganglions explants (Böcker-Meffert et al., 2002), cultured rat fetus cerebral cortical neurons (Rosenstein et al., 2003), cultured mice superior cervical ganglion neurons and dorsal root ganglion neurons (Sondell et al., 1999).”
BackgroundHunt, S., & Navalta, J. W. (2012) · International journal of exercise science · doi:10.70252/azqj3213 · Cited by 9
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“Previous research demonstrated that Lipopolysaccharide stimulated peripheral blood mononuclear cell VEGF protein production was highest among individuals who were VEGF +405GG [11] and high expression of VEGF was protective for ischemic neuronal damage [30, 31].”
MethodKamei, W., Matsumine, H., Osaki, H., Ueta, Y., Tsunoda, S., Shimizu, M., Hashimoto, K., Niimi, Y., Miyata, M., & Sakurai, H. (2018) · Microsurgery · doi:10.1002/micr.30389 · Cited by 9
Saffari, T. M., Mathot, F., Bishop, A. T., & Shin, A. Y. (2019) · Microsurgery · doi:10.1002/micr.30537 · Cited by 9
VEGF Axonal Transport Dependent on Kinesin-1B and Microtubules Dynamics
Yang, P., Sun, X., Kou, Z., Wu, K., Huang, Y.-L., & Sun, F. (2017) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2017.00424 · Cited by 9
“In the developing vertebrate brain, VEGF modulates axonal outgrowth (Sondell et al., 1999) and chemoattraction Abbreviations: BSS, balanced salt solution; CMV, constitutive cytomegalovirus promoter; GABA, g-aminobutyrate; GAPDH, glyceradehyde-3-phosphate dehydrogenase; GFP, green fluorescent…”
BackgroundInfluentialAdvanced nanotherapies to promote neuroregeneration in the injured newborn brain
Arteaga, O., Mikrogeorgiou, A., Kannan, S., & Ferriero, D. M. (2019) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2019.10.005 · Cited by 10
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“It also was reported that VEGF stimulates axonal outgrowth and increases neuronal survival in mouse superior cervical and dorsal root ganglia.(36) Many significant pathways related to cell survival have been involved in the VEGF-induced enhancement of cell viability.”
BackgroundNawaz, S., Kulyar, M. F., Mo, Q., Yao, W., Iqbal, M., & Li, J. (2023) · Animals · doi:10.3390/ani13243750 · Cited by 8
“These chemokines may also play a role in TD’s large-scale apoptosis and vascular necrosis [139].”
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VEGF modulates synaptic activity in the developing spinal cord
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“, 2010), axonal outgrowth, and guidance (Sondell et al., 1999; Ruiz de Almodovar et al., 2011; for review see Mackenzie and Ruhrberg, 2012).”
BackgroundYu, H., Lin, B., He, Y., ZHANG, W., & Xu, Y. (2015) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2015.2368 · Cited by 8
“VEGF signals are considered to act as neurotrophic factors (10,13,32).”
Colafrancesco, V., Cirulli, F., Rossi, S., Berry, A., & Aloe, L. (2009) · Neuroscience Letters · doi:10.1016/j.neulet.2009.07.082 · Cited by 8
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“There is also growing evidence that VEGFR2 (primarily through VEGF-A stimulation) is heavily involved with modulating neuronal properties such as increased axonal and neurite outgrowth (Silverman et al., 1999; Sondell et al., 1999, 2000; Jin et al., 2002).”
BackgroundExpression of the Flk1 receptor and its ligand VEGF in the developing chick central nervous system
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“Especially IGF, VEGF, TGF-b, PDGF, and FGF- II play important roles in nerve regeneration by stimulation of axonal outgrowth and Schwann cell proliferation and protein and lipid synthesis, which are necessary for nerve regeneration [8, 20, 21].”
BackgroundVascular Endothelial Growth Factor Signaling
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“It is highly expressed on the surface of the different endothelial cell populations (quiescent and cycling) such as endothelial cells of liver sinusoids and hepatic arterioles [81, 134, 168], but also on hepatocytes during liver regeneration [107, 134] and on a few other cells such as hepatic stellate cells [2, 99], m…”
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Carpal Tunnel Syndrome and Diabetes Surgical outcome and nerve pathology
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Hypoxia-induced expression of VEGF in the organotypic spinal cord slice culture
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Therapeutic Angiogenesis for Vascular Diseases
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Growth factors and molecular-driven plasticity in neurological systems
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Metadata
- Authors
- Sondell, M., Lundborg, G., & Kanje, M.
- Affiliations
- Lund University (SE)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 1999-07-15
- Volume
- 19
- Issue
- 14
- Pages
- 5731-5740
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6783109
- OpenAlex
- W1962154683
- Cited by
- 750
- References
- 44
- Citations by year
- 2026: 8 · 2025: 14 · 2024: 8 · 2023: 11 · 2022: 16 · 2021: 19 · 2020: 26 · 2019: 25 · 2018: 26 · 2017: 28 · 2016: 33 · 2015: 22 · 2014: 44 · 2013: 42 · 2012: 37
- FWCI
- 8.92
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, public-domain)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Axon Guidance and Neuronal Signaling
- Keywords
- vascular endothelial growth factor, VEGF165, neurotrophic activity, axon growth, Schwann cell proliferation, satellite cells, superior cervical ganglion, dorsal root ganglia, MEK, PD98059, K252a, axon regeneration, peripheral nervous system, small-diameter neurons, cell survival
- MeSH terms
- Animals, Axons, Carbazoles, Cell Survival, Cells, Cultured, Enzyme Inhibitors, Flavonoids, Ganglia, Spinal, Humans, Lymphokines, Male, Mice, Inbred Strains, Nerve Growth Factors, Recombinant Proteins, Schwann Cells, Time Factors, Endothelial Growth Factors, Superior Cervical Ganglion, Indole Alkaloids, Vascular Endothelial Growth Factors, Vascular Endothelial Growth Factor A, Protein Kinase Inhibitors, Mice
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