Role of VEGF-A in chronic pain

Hulse, Richard P.

doi:10.18632/oncotarget.14615

Cited by 26 publications

(43 citation statements)

References 6 publications

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“…40 Splice variants of isoform VEGF-A were shown to have antinociceptive potential. [41][42][43] We did observe an increase in VEGF-B and decrease in VEGF-A in the DED cohort, suggesting their aberrant levels may contribute to ocular discomfort in these patients. IL-2, a key immunoregulatory cytokine, is known to render antinociceptive response by its engagement of opioid receptors.…”

Section: Discussionmentioning

confidence: 63%

Dysregulated Tear Fluid Nociception-Associated Factors, Corneal Dendritic Cell Density, and Vitamin D Levels in Evaporative Dry Eye

Khamar

Nair

Shetty

et al. 2019

Invest. Ophthalmol. Vis. Sci.

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Citation: Khamar P, Nair AP, Shetty R, et al. Dysregulated tear fluid nociception-associated factors, corneal dendritic cell density, and vitamin D levels in evaporative dry eye. Invest Ophthalmol Vis Sci. 2019;60:2532-2542. https://doi.org/10.1167 PURPOSE. The purpose of this study was to study the status and association among tear-soluble factors, corneal dendritic cell density, vitamin D, and signs and symptoms in dry eye disease (DED). METHODS.A total of 33 control subjects and 47 evaporative dry eye patients were included in the study. DED diagnosis and classification was based on the 2017 Report of the Tear Film & Ocular Surface Society International Dry Eye Workshop (TFOS DEWS II). DED workup, including tear film break-up time (TBUT), Schirmer's test I (STI), corneal and conjunctival staining, ocular surface disease index (OSDI) scoring, and in vivo confocal microscopy (to assess corneal dendritic cell density [cDCD] and subbasal nerve plexus [SBNP] features) was performed in the study subjects. Tear fluid using Schirmer's strip and serum were collected from the subjects. Multiplex ELISA or single analyte ELISA was performed to measure 34 tearsoluble factors levels including vitamin D.RESULTS. Significantly higher OSDI discomfort score, lower TBUT, and lower STI were observed in DED patients. cDCD was significantly higher in DED patients. No significant difference was observed in SBNP features. Tear fluid IL-1b, IL-17A, MMP9, MMP10, MMP9/ TIMP ratio, and VEGF-B were significantly higher in DED patients. Significantly lower tear fluid IL-2, IP-10, NPY, VEGF-A, and vitamin D was observed in DED patients. These dysregulated tear factors showed significant associations with DED signs and symptoms.CONCLUSIONS. Altered tear fluid soluble factors with potential to modulate nociception exhibited a distinct association with ocular surface discomfort status, TBUT, STI, and cDCD. This implies a functional relationship between the various tear-soluble factors and dry eye pathogenesis, indicating new molecular targets for designing targeted therapies.

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Section: Discussionmentioning

confidence: 63%

Dysregulated Tear Fluid Nociception-Associated Factors, Corneal Dendritic Cell Density, and Vitamin D Levels in Evaporative Dry Eye

Khamar

Nair

Shetty

et al. 2019

Invest. Ophthalmol. Vis. Sci.

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“…Anti-VEGF drugs are also used to attenuate neovascularisation in age-related macular degeneration and diabetic macular oedema (Ferrara, 2004 ; Kim and D'Amore, 2012 ). However, in recent years, the role of the VEGF family in neuroprotection and nociception has received increased attention (Beazley-Long et al, 2013 , 2018 ; Hulse et al, 2014 , 2015 , 2016 ; Selvaraj et al, 2015 ; Hulse, 2017 ; Lai et al, 2017 ). The involvement of VEGF in the pathophysiology of pain is not fully understood, however, the association between this growth factor and some of the main hallmarks of painful diseases warrants the investigation of VEGF as a therapeutic target for pain treatment.…”

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confidence: 99%

Painful Understanding of VEGF

Llorián-Salvador

González-Rodríguez

2018

Front. Pharmacol.

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“…VEGF-A is a selective endothelial cell mitogen that promotes angiogenesis, primarily via interaction with the VEGF receptor VEGFR2, also known as kinase insert domain-containing receptor (KDR) 16 . Alternative splicing of the VEGF-A gene produces several isoforms of the mature protein containing between 121 and 206 amino acid residues, with VEGF-A 165 being pro-nociceptive 17 via sensitization of transient receptor potential (TRP) channels 18 and ATP-gated purinergic P2X 2/3 receptors 19 on dorsal root ganglion (DRG) neurons. This alternative splicing is dependent on serine-arginine rich protein kinase 1 (SRPK1) which mediates the phosphorylation of serine-arginine rich splice factor (SRSF1) 17,20,21 .…”

Section: Introductionmentioning

confidence: 99%

“…Alternative splicing of the VEGF-A gene produces several isoforms of the mature protein containing between 121 and 206 amino acid residues, with VEGF-A 165 being pro-nociceptive 17 via sensitization of transient receptor potential (TRP) channels 18 and ATP-gated purinergic P2X 2/3 receptors 19 on dorsal root ganglion (DRG) neurons. This alternative splicing is dependent on serine-arginine rich protein kinase 1 (SRPK1) which mediates the phosphorylation of serine-arginine rich splice factor (SRSF1) 17,20,21 . VEGF binding to VEGFR2, a co-receptor for NRP-1, is associated with receptor dimerization and activation that triggers downstream signaling pathways including phosphatidylinositol 3-kinase (PI3-K)/Akt and phospholipase C gamma/extracellular signal-regulated kinase (PLCg/ERK) 16 .…”

Section: Introductionmentioning

confidence: 99%

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In silico identification and validation of inhibitors of the interaction between neuropilin receptor 1 and SARS-CoV-2 Spike protein

Perez‐Miller

Pátek²,

Moutal

et al. 2020

Preprint

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Neuropilin-1 (NRP-1) is a multifunctional transmembrane receptor for ligands that affect developmental axonal growth and angiogenesis. In addition to a role in cancer, NRP-1 is a reported entry point for several viruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causal agent of coronavirus disease 2019 (COVID-19). The furin cleavage product of SARS-CoV-2 Spike protein takes advantage of the vascular endothelial growth factor A (VEGF-A) binding site on NRP-1 which accommodates a polybasic stretch ending in a C-terminal arginine. This site has long been a focus of drug discovery efforts for cancer therapeutics. We recently showed that interruption of the VEGF-A/NRP-1 signaling pathway ameliorates neuropathic pain and hypothesize that interference of this pathway by SARS-CoV-2 spike protein interferes with pain signaling. Here, we report hits from a small molecule and natural product screen of nearly 0.5 million compounds targeting the VEGF-A binding site on NRP-1. We identified nine chemical series with lead- or drug-like physico-chemical properties. Using an ELISA, we demonstrate that six compounds disrupt VEGF-A-NRP-1 binding more effectively than EG00229, a known NRP-1 inhibitor. Secondary validation in cells revealed that almost all tested compounds inhibited VEGF-A triggered VEGFR2 phosphorylation. Two compounds displayed robust inhibition of a recombinant vesicular stomatitis virus protein that utilizes the SARS-CoV-2 Spike for entry and fusion. These compounds represent a first step in a renewed effort to develop small molecule inhibitors of the VEGF-A/NRP-1 signaling for the treatment of neuropathic pain and cancer with the added potential of inhibiting SARS-CoV-2 virus entry.

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Role of VEGF-A in chronic pain

Cited by 26 publications

References 6 publications

Dysregulated Tear Fluid Nociception-Associated Factors, Corneal Dendritic Cell Density, and Vitamin D Levels in Evaporative Dry Eye

Dysregulated Tear Fluid Nociception-Associated Factors, Corneal Dendritic Cell Density, and Vitamin D Levels in Evaporative Dry Eye

Painful Understanding of VEGF

In silico identification and validation of inhibitors of the interaction between neuropilin receptor 1 and SARS-CoV-2 Spike protein

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