Painful Understanding of VEGF

Llorián-Salvador, María; González-Rodríguez, Sara

doi:10.3389/fphar.2018.01267

Cited by 32 publications

(29 citation statements)

References 41 publications

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“… 16 In addition, VEGF-A has a complicated role in nociception with both pro- and antialgesic findings reported in the literature. 17 , 18 These disparate effects are thought to be due to variation in tissue specific expression levels of two key VEGF-A splice variants and their differential effects on sensory neurons. 17 , 19 Alternative splicing produces isoforms of varying length, indicated as VEGF-A xxx , where xxx refers to the length of the mature protein.…”

Section: Introductionmentioning

confidence: 99%

“… 17 , 19 Alternative splicing produces isoforms of varying length, indicated as VEGF-A xxx , where xxx refers to the length of the mature protein. 19 The most well-studied pain-related isoforms result from alternative splicing of exon 8 with VEGF-A 165 a generally found to be pronociceptive and VEGF-A 165 b found to be antinociceptive, 17 , 18 with one exception. 20 This alternative splicing is dependent on serine-arginine rich protein kinase 1 (SRPK1) which mediates the phosphorylation of serine-arginine rich splice factor (SRSF1).…”

Section: Introductionmentioning

confidence: 99%

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Novel Compounds Targeting Neuropilin Receptor 1 with Potential To Interfere with SARS-CoV-2 Virus Entry

Perez‐Miller

Pátek

Moutal

et al. 2021

ACS Chem. Neurosci.

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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 confirmed 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 physicochemical properties. Using 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 all tested compounds inhibited VEGF-A triggered VEGFR2 phosphorylation. Further, 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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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Novel Compounds Targeting Neuropilin Receptor 1 with Potential To Interfere with SARS-CoV-2 Virus Entry

Perez‐Miller

Pátek

Moutal

et al. 2021

ACS Chem. Neurosci.

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“…[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. 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.…”

mentioning

confidence: 99%

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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“…The fact that VEGF induces pro-inflammatory cytokines may explain why bevacizumab 0.05% eye drops can improve OSDI scores in dry eye patients, i.e., by inhibiting VEGF-A, itself, and other pain-associated cytokines, including IL-1β, IL-17 and IL-18. [20] However, the complete details of the molecular inflammatory mechanisms are still unknown [19].…”

Section: Plos Onementioning

confidence: 99%

Efficacy of topical bevacizumab 0.05% eye drops in dry eye disease: A double-masked, randomized trial

et al. 2020

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The objective of this double-masked, placebo-controlled, randomized trial was to assess the efficacy and safety of bevacizumab 0.05% eye drops in dry eye patients. This study included Dry Eye Workshop Study (DEWS) Grade 3-4 dry eye participants (n = 31) whose tear break-up time (TBUT) was �5 seconds(s). Participants were randomized to undergo treatment with either bevacizumab 0.05% eye drops (n = 19) or placebo (n = 12). The primary outcome was TBUT, and the proportion of responders (increase of �3s in TBUT at week 12), ocular surface disease index (OSDI) score, Schirmer test, and Oxford scheme grade were secondary outcomes. All outcomes were measured at 1-, 4-and 12 weeks. TBUT in bevacizumab group differed significantly from TBUT in placebo group within 12 weeks (P = 0.001). Moreover, the improvement of TBUT in bevacizumab group versus placebo group at 4-and 12 weeks differed significantly from that difference at baseline (P = 0.002 and P = 0.003, respectively). The proportion of participants achieving increase of 3 seconds or more of TBUT at week 12 in the bevacizumab group was significantly greater than that in the placebo group (P = 0.02). Oxford scheme grade at 1-, 4-and 12 weeks differed significantly from the values at baseline in bevacizumab group (P = 0.001, P = 0.01, and P = 0.03, respectively). OSDI scores at 1-, 4-and 12-week follow-ups were significantly lower than that at baseline in bevacizumab group (P<0.001 at each follow-up). Schirmer test were not significantly different within or between groups (the lowest P = 0.92). No adverse events occurred in this study. Patients treated with bevacizumab 0.05% eye drops showed significant improvement in tear film stability, corneal staining and symptoms.

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Painful Understanding of VEGF

Cited by 32 publications

References 41 publications

Novel Compounds Targeting Neuropilin Receptor 1 with Potential To Interfere with SARS-CoV-2 Virus Entry

Novel Compounds Targeting Neuropilin Receptor 1 with Potential To Interfere with SARS-CoV-2 Virus Entry

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

Efficacy of topical bevacizumab 0.05% eye drops in dry eye disease: A double-masked, randomized trial

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