VEGF-B is a potent antioxidant

Arjunan, Pachiappan; Lin, Xianchai; Tang, Zhongshu; Du, Yi; Kumar, Anil; Liu, Lixian; Yin, Xiaokang; Huang, Lijuan; Chen, Wei; Chen, Qishan; Ye, Zhimin; Wang, Shasha; Kuang, Haiqing; Zhou, Leocadia; Xu, Kai; Chen, Xue; Zeng, Haitao; Lu, Weisi; Cao, Yihai; Liu, Yizhi; Zhao, Chunxia; Li, Xuri

doi:10.1073/pnas.1801379115

Cited by 48 publications

(50 citation statements)

References 35 publications

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“…VEGF-B, the most elusive member of the VEGF family, binds exclusively to VEGFR1, although its functions remain to be fully elucidated. [13][14][15] Recently, the neuroprotective role of different VEGF family members has received increasing attention. [16][17][18][19] The use of VEGF-A as a neuroprotective therapy, however, has been hindered by its proangiogenic effects.…”

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confidence: 99%

“…21 An association between VEGF-B and advanced stages of diabetic retinopathy has also been described, although the cellular source of retinal VEGF-B and exactly how VEGF-B contributes to retinal disease remain elusive. 15,22 The current study investigated the role of VEGF family members in Müller glia pathophysiology. We found that, among the different VEGF family members, Müller cells produce more VEGF-B than other VEGF members, and that VEGF-B protects Müller cells under oxidative and hypoxic conditions.…”

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confidence: 99%

“…VEGF-B, the most elusive member of the VEGF family, binds exclusively to VEGFR1, although its functions remain to be fully elucidated. 13 – 15 …”

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confidence: 99%

“… 16 – 19 The use of VEGF-A as a neuroprotective therapy, however, has been hindered by its proangiogenic effects. 17 , 20 There is some preclinical evidence that VEGF-B is protective in pathologies in which oxidative stress is a key pathologic factor, including amylotrophic lateral sclerosis, Parkinson's disease, 18 retinitis pigmentosa 15 and Alzheimer's disease. 21 An association between VEGF-B and advanced stages of diabetic retinopathy has also been described, although the cellular source of retinal VEGF-B and exactly how VEGF-B contributes to retinal disease remain elusive.…”

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confidence: 99%

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VEGF-B Is an Autocrine Gliotrophic Factor for Müller Cells under Pathologic Conditions

Llorián-Salvador

Barabás

Byrne

et al. 2020

Invest. Ophthalmol. Vis. Sci.

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Müller glia are important in retinal health and disease and are a major source of retinal VEGF-A. Of the different VEGF family members, the role of VEGF-A in retinal health and disease has been studied extensively. The potential contribution of other VEGF family members to retinal pathophysiology, however, remains poorly defined. This study aimed to understand the role of VEGF-B in Müller cell pathophysiology. METHODS. The expression of different VEGFs and their receptors in human MIO-M1 and mouse QMMuC-1 Müller cell lines and primary murine Müller cells was examined by RT-PCR, ELISA, and Western blot. The effect of recombinant VEGF-B or VEGF-B neutralization on Müller cell viability and survival under normal, hypoxic, and oxidative (4-hydroxynonenal [4-HNE]) conditions was evaluated by Alamar Blue, Yo-Pro uptake, and immunocytochemistry. The expression of glial fibrillary acidic protein, aquaporin-4, inward rectifying K + channel subtype 4.1, glutamine synthetase, and transient receptor potential vanilloid 4 under different treatment conditions was examined by RT-PCR, immunocytochemistry, and Western blot. Transient receptor potential vanilloid 4 channel activity was assessed using a Fura-2-based calcium assay. RESULTS. VEGF-B was expressed in Müller cells at the highest levels compared with other members of the VEGF family. VEGF-B neutralization did not affect Müller cell viability or functionality under normal conditions, but enhanced hypoxia-or 4-HNE-induced Müller cell death and decreased inward rectifying K + channel subtype 4.1 and aquaporin-4 expression. Recombinant VEGF-B restored Müller cell glutamine synthetase expression under hypoxic conditions and protected Müller cells from 4-HNE-induced damage by normalizing transient receptor potential vanilloid 4 channel expression and activity. CONCLUSIONS. Autocrine production of VEGF-B protects Müller cells under pathologic conditions.

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confidence: 99%

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confidence: 99%

“…VEGF-B, the most elusive member of the VEGF family, binds exclusively to VEGFR1, although its functions remain to be fully elucidated. 13 – 15 …”

mentioning

confidence: 99%

mentioning

confidence: 99%

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VEGF-B Is an Autocrine Gliotrophic Factor for Müller Cells under Pathologic Conditions

Llorián-Salvador

Barabás

Byrne

et al. 2020

Invest. Ophthalmol. Vis. Sci.

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“…Some authors have highlighted the crucial role of antioxidant expression in preventing toxic effects 31,32 . In this sense, Gpx1 is one of the most relevant antioxidant capable of reacting against oxidative stress as a therapeutic factor 33 . The role of Gpx1 is to modulate cellular oxidant stress responses 31 .…”

Section: Bxd84/rwwj Ri and Control Mice Do Not Show An Innate Changementioning

confidence: 99%

The BXD21/TyJ recombinant inbred strain as a model for innate inflammatory response in distinct brain regions

López-Granero

Ferrer

Santos

et al. 2020

Sci Rep

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Oxidative stress and inflammatory cytokines affect the human brain, increasing the risk for mood and cognitive disorders. Such risk might be selective to brain-specific regions. Here, we determined whether BXD recombinant inbred (RI) mice strains are more suitable than C57BL/6J mice for the understanding of the relationship between antioxidant response and inflammatory responses. We hypothesized that inflammatory responses could be independent of antioxidant response and be inherent to brain-specific regions. This hypothesis will be addressed by the analyses of mRNA expression. We explored, at 7-months-of-age, the innate activation of proinflammatory cytokines (tumor necrosis factor alpha (TNFα) and interleukin 6 (IL-6), as well as Kelch-like ECH-associating protein 1 (Keap1), nuclear factor erythroid 2 related factor 2 (Nrf2) and glutathione peroxidase 1 (Gpx1) mRNA in both male and female BXD84/RwwJ RI, BXD21/TyJ RI and control strain (C57BL/6J mice). We report that: (1) The cerebellum is more sensitive to antioxidant response in the BXD21/TyJ RI strain; (2) The cerebellum, hippocampus and striatum show increased levels of cytokines in the BXD21/TyJ RI strain; (3) The BXD RI strain has lower brain weight relative to control strain (C57BL/6 mice). In conclusion, our novel data show the utility of the BXD21/TyJ RI strain mice in offering mechanistic insight into Nrf2's role in the inflammatory system. Central nervous system (CNS) dysfunction is frequently accompanied by oxidative stress and inflammatory responses 1. Oxidative damage and inflammatory cytokines influence brain function and result in increased risk for mood, behavioral and cognitive disorders 2-4. Thus, the general hypothesis is that antioxidant defenses and inflammatory cytokines are key elements in CNS pathologies 5 and psychiatric disorders 3,4,6,7. Several studies have revealed the mechanism by which continued oxidative stress can lead to chronic inflammation, which, in turn, could mediate most chronic diseases 8. The disruption of the inflammatory and oxidative stress pathways is associated with multiple neurotoxic exposures 9-11. Oxidative stress acts activating a variety of transcription factors, including Nrf2. Upon oxidative stress generation, Nrf2 dissociates from Kelch-like ECH-associating protein 1 (Keap1), and translocates into the nucleus where it binds to the antioxidant response element (ARE), and initiates antioxidant gene transcription thus restoring cellular redox homeostasis 12-15. Activation of these transcription factors can lead to the expression of different genes, including those for inflammatory cytokines and anti-inflammatory molecules 8. Indeed, Nrf2 is essential for protection against oxidative stress and it has also been shown to attenuate inflammation 16. Consistent with these observations, published data have corroborated dysregulation of inflammatory and oxidative systems both in behavioral and psychiatric disorders as a consequence of altered Nrf2 pathway functioning 7,15. Neuroinflammatory processes are established...

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Peptides Derived from Vascular Endothelial Growth Factor B Show Potent Binding to Neuropilin‐1

et al. 2021

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Vascular endothelial growth factors (VEGFs) regulate significant pathways in angiogenesis, myocardial and neuronal protection, metabolism, and cancer progression. The VEGF-B growth factor is involved in cell survival, anti-apoptotic and antioxidant mechanisms, through binding to VEGF receptor 1 and neuropilin-1 (NRP1). We employed surface plasmon resonance technology and X-ray crystallography to analyse the molecular basis of the interaction between VEGF-B and the b1 domain of NRP1, and developed VEGF-B C-terminus derived peptides to be used as chemical tools for studying VEGF-B -NRP1 related pathways. Peptide lipidation was used as a means to stabilise the peptides. VEGF-B-derived peptides containing a C-terminal arginine show potent binding to NRP1-b1. Peptide lipidation increased binding residence time and improved plasma stability. A crystal structure of a peptide with NRP1 demonstrated that VEGF-B peptides bind at the canonical C-terminal arginine binding site. VEGF-B C-terminus imparts higher affinity for NRP1 than the corresponding VEGF-A 165 region. This tight binding may impact on the activity and selectivity of the fulllength protein. The VEGF-B 167 derived peptides were more effective than VEGF-A 165 peptides in blocking functional phosphorylation events. Blockers of VEGF-B function have potential applications in diabetes and non-alcoholic fatty liver disease.

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VEGF-B is a potent antioxidant

Cited by 48 publications

References 35 publications

VEGF-B Is an Autocrine Gliotrophic Factor for Müller Cells under Pathologic Conditions

VEGF-B Is an Autocrine Gliotrophic Factor for Müller Cells under Pathologic Conditions

The BXD21/TyJ recombinant inbred strain as a model for innate inflammatory response in distinct brain regions

Peptides Derived from Vascular Endothelial Growth Factor B Show Potent Binding to Neuropilin‐1

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