FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2892968416> ?p ?o ?g. }

• W2892968416 endingPage "5078" @default.
• W2892968416 startingPage "5077" @default.
• W2892968416 abstract "Peripheral neuropathy with chronic pain is a common sequela of diabetes, whose onset is mediated by the sensitization of both central and peripheral nociceptive neurons. While hyperglycaemia has been demonstrated to induce peripheral nerve sensitization, there is a paucity of research exploring this mechanism in the central nervous system, despite evidence that spinal sensory neurons in diabetic rodents also develop sensitization. The spinal cord is supported by a rich, interconnected network of blood vessels; given that hyperglycaemia induces vascular remodelling, it is possible that altered vascular function contributes to nociceptor sensitization. Vascular endothelial growth factor A (VEGF-A) is a necessary regulator of angiogenesis likely affected by hyperglycaemia, since it is overexpressed in the eyes of patients with diabetic retinopathy (Gupta et al. 2013). However, the VEGF-A gene codes for two different splice variant families: the pro-angiogenic VEGF-Axxxa family, and the putatively anti-angiogenic VEGF-Axxxb family. This description does not capture the full scope of VEGF-Axxxb's function, however; for example, administration of rh-VEGF-A165b is anti-nociceptive while rh-VEGF-A165a has the opposite effect (Hulse et al. 2014). Thus, there appears to be sub-splice variant family specificity of function that necessitates further investigation. In light of this evidence, in a recent issue of The Journal of Physiology, Ved et al. (2018) hypothesized that the loss of vascular integrity mediated by a disruption in the VEGF-A splice variant signalling cascade is central to the pain sensitization observed in diabetes. To demonstrate this, the authors used two murine models: ablation of β-cells in the pancreas of Sprague–Dawley rats using streptozotocin to induce type 1 diabetes (T1D), and tamoxifen-induced, Tie2CreERT2-dependent knockout of VEGFR2 in the endothelial cells of Tie2CreERT2 × vegfr2fl/fl mice. The T1D rats demonstrated a reduced pinch force threshold for limb withdrawal as measured using von Frey filaments and a mechanical pincher, and a reduced latency to withdrawal from heat as measured by the Hargreaves test. These findings confirmed pain sensitization in diabetes. The T1D rat spinal cords exhibited reduced vascular integrity, as measured by quantifying CD31- and IB4-labelled endothelial cells, proxy metrics for blood vessel number and volume. Additionally, Evans blue dye extravasation revealed reduced vascular permeability in the spinal cord but no difference in solute flux in the brain. This indicated selective reduction of functional blood vessels in the spinal cord. To establish the role of VEGF-A, they performed immunoblot analysis of overall VEGF-A expression. They found that diabetic rats had no difference in pan-VEGF-A expression but significantly reduced VEGF-A165b expression. This suggests that there might be specific loss of cytoprotective splice variants with overcompensation of other VEGF-A isoforms. This corroborates clinical data demonstrating increased VEGF-A expression seen in retinopathic patients (Gupta et al. 2013). Administration of rh-VEGF-A165b to T1D rats and spinal endothelial cells cultured in hyperglycaemic media rescued the reduced vascularity phenotype. This supports the role of hyperglycaemia as an underlying cytotoxic factor inducing vascular breakdown. Rh-VEGF-A165b also reversed the diabetic neuropathic pain phenotype, with molecular evidence demonstrating reduced apoptosis in sensory neurons (reduced number of cells with co-localization of NeuN and apoptosis marker CC3). Finally, it reversed the increased baseline sensory neuron activation in the dorsal horn of the spinal cord, as measured by c-fos; interestingly, this difference was observed without any provocative testing typically used to induce c-fos expression. Given the above findings, the authors sought to establish whether the induction of vascular breakdown by VEGFR2 knockout recapitulates the neuropathic effects seen in diabetes. The VEGFR2ECKO mice (tamoxifen-treated, Tie2CreERT2-positive vegfr2fl/fl) had reduced endothelial junctional marker expression (VE-cadherin and CD31) as well as reduced vessel number and volume. However, this effect was only observed in blood vessels around 4 μm in diameter, which contrasts with the size subgroup analysis results from diabetic rats, where vessels of size 4–6 μm were unaffected. Additionally, vessel integrity was highly variable between different diameters for both diabetic and knockout experiments across all test groups. This suggests that susceptibility to vascular breakdown varies based on vessel size and that hyperglycaemia might impair angiogenesis by receptors besides VEGFR2, although the disagreement between the two sets of results could be attributed to differences in vessel anatomy between rats and mice. Given the multiplicity of roles assumed by the VEGF-signalling cascade, the impaired vascular integrity was expected in the knockouts, but the pain sensitization is a highly novel finding. The tight correlation between impaired vascular integrity and pain sensitization provides compelling evidence for hyperglycaemia-induced sensitization occurring through impaired VEGF signalling. While the results from VEGFR2 knockout are significant, the current method uses a tamoxifen-inducible Cre model, where Cre recombinase is activated via i.p. injection of tamoxifen. Notably, tamoxifen is a potent angiogenesis modulator (McNamara et al. 2001), and this effect is recapitulated in the present study: in vegfr2fl/fl mice treated with tamoxifen, the vascular volume was significantly reduced compared to the vehicle-treated Tie2CreERT2× vegfr2fl/fl mice (Fig. 8 in Ved et al. 2018). While the study controls for the anti-angiogenetic effects by using a tamoxifen-positive control and demonstrates that the VEGFR2ECKO mice have a comparatively reduced vascular volume, the combined anti-angiogenic effects of tamoxifen and VEGFR2 could have debilitating effects on blood vessel health that complicate the results. The authors demonstrate that the VEGF-A/VEGFR2 signalling pathway is disrupted in diabetic rodents and that it mediates the development of neuropathic pain. However, the heterogeneity of the VEGF-A gene's splice variants and their diversity of function necessitates a closer analysis of specific roles. Future research establishing the neuroprotective role of VEGF-A165b will involve administering it to VEGFR2ECKO mice to confirm that its neuroprotective effect is mediated by the VEGFR2 receptor and not a different target. Additionally, the necessity of the VEGF-A165b splice transcript for neuroprotection could be determined by the specific knockdown or knockout of the VEGF-A165b transcript, via shRNA technology. Previous research from this group found that in a nerve injury model, VEGF-Axxxb administration reduced pain sensitization, whereas VEGF-Axxxa increased it (Hulse et al. 2014). If these results can be repeated in a diabetic neuropathic pain model, this would point towards a novel therapy for neuropathic pain that is conserved across different aetiologies. Additionally, the VEGFR2 knockout achieved in the transgenic mice is systemic. It would be interesting to achieve site-specific VEGFR2 knockout from the spinal cord instead; if the vascular breakdown of local vessels in the spinal cord is sufficient to affect the activation of sensory neurons, this would help identify a specific drug delivery site for the treatment of chronic diabetic neuropathic pain. This could be achieved by transfecting a vegfr2fl/fl mouse with AAV-dependent Cre in the lumbar spinal cord. This paper is pioneering in that it identifies a direct relationship between vascular degeneration and the development of neuropathic pain. The authors, however, concede that the spinal cord nociceptive response to hyperglycaemia was not studied. Determining the mechanism connecting hyperglycaemia and altered VEGF signalling and connecting vascular integrity and pain sensitization is a clear topic of future research. Furthermore, longitudinal observation of blood vessel health in diabetic rodents is needed to assess the transition from pain sensitization to the development of diabetic chronic pain, and if VEGF disruption is responsible for more than its immediate pain sensitization effects. As the authors conclude, the effect of vascular breakdown on neuropathic pain could be mediated either directly via the involvement of vasculature in nociceptive signalling, or indirectly as reduced nutrient and oxygen supply, resulting in the increased apoptosis seen, or a combination of both. Previous studies have identified VEGF as a potent modulator of nociceptive signalling. Importantly, other disorders with chronic neuropathic pain, such as multiple sclerosis, have also been linked to disturbances in the VEGF signalling system (Rasol et al. 2016). Furthermore, VEGF-A165b administration has been shown to reduce nociceptive measures suggesting that there could be a commonality of vascular disruption (that can be rescued by VEGF-A165b) in the development of neuropathic pain across disorders (Hulse et al. 2014). The development of a drug that mimics VEGF-A165b's neuroprotective and anti-nociceptive role could very well be the key to targeting neuropathic pain, in diabetes and beyond. None declared. Both authors have read and approved the final version of this manuscript and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed. None." @default.
• W2892968416 created "2018-10-05" @default.
• W2892968416 creator A5049710310 @default.
• W2892968416 creator A5056489444 @default.
• W2892968416 date "2018-09-19" @default.
• W2892968416 modified "2023-10-14" @default.
• W2892968416 title "VEGF-A₁₆₅ b to the rescue: vascular integrity and pain sensitization" @default.
• W2892968416 cites W2026983478 @default.
• W2892968416 cites W2040168311 @default.
• W2892968416 cites W2040883058 @default.
• W2892968416 cites W2275546737 @default.
• W2892968416 cites W2803126293 @default.
• W2892968416 doi "https://doi.org/10.1113/jp276902" @default.
• W2892968416 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/6209758" @default.
• W2892968416 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/30156272" @default.
• W2892968416 hasPublicationYear "2018" @default.
• W2892968416 type Work @default.
• W2892968416 sameAs 2892968416 @default.
• W2892968416 citedByCount "1" @default.
• W2892968416 countsByYear W28929684162022 @default.
• W2892968416 crossrefType "journal-article" @default.
• W2892968416 hasAuthorship W2892968416A5049710310 @default.
• W2892968416 hasAuthorship W2892968416A5056489444 @default.
• W2892968416 hasBestOaLocation W28929684161 @default.
• W2892968416 hasConcept C203014093 @default.
• W2892968416 hasConcept C2776217527 @default.
• W2892968416 hasConcept C71924100 @default.
• W2892968416 hasConceptScore W2892968416C203014093 @default.
• W2892968416 hasConceptScore W2892968416C2776217527 @default.
• W2892968416 hasConceptScore W2892968416C71924100 @default.
• W2892968416 hasIssue "21" @default.
• W2892968416 hasLocation W28929684161 @default.
• W2892968416 hasLocation W28929684162 @default.
• W2892968416 hasLocation W28929684163 @default.
• W2892968416 hasOpenAccess W2892968416 @default.
• W2892968416 hasPrimaryLocation W28929684161 @default.
• W2892968416 hasRelatedWork W1506200166 @default.
• W2892968416 hasRelatedWork W1995515455 @default.
• W2892968416 hasRelatedWork W2048182022 @default.
• W2892968416 hasRelatedWork W2080531066 @default.
• W2892968416 hasRelatedWork W2604872355 @default.
• W2892968416 hasRelatedWork W2748952813 @default.
• W2892968416 hasRelatedWork W2899084033 @default.
• W2892968416 hasRelatedWork W3031052312 @default.
• W2892968416 hasRelatedWork W3032375762 @default.
• W2892968416 hasRelatedWork W3108674512 @default.
• W2892968416 hasVolume "596" @default.
• W2892968416 isParatext "false" @default.
• W2892968416 isRetracted "false" @default.
• W2892968416 magId "2892968416" @default.
• W2892968416 workType "article" @default.