Ved, N;
Hulse, RP;
Bestall, SM;
Donaldson, LF;
Bainbridge, JW;
Bates, DO;
(2017)
Vascular endothelial growth factor-A165b ameliorates outer-retinal barrier and vascular dysfunction in the diabetic retina.
Clinical Science
, 131
(12)
pp. 1225-1243.
10.1042/CS20170102.
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Abstract
Diabetic retinopathy (DR) is one of the leading causes of blindness in the developed world. Characteristic features of DR are retinal neurodegeneration, pathological angiogenesis and breakdown of both the inner and outer retinal barriers of the retinal vasculature and retinal pigmented epithelial (RPE)–choroid respectively. Vascular endothelial growth factor (VEGF-A), a key regulator of angiogenesis and permeability, is the target of most pharmacological interventions of DR. VEGF-A can be alternatively spliced at exon 8 to form two families of isoforms, pro- and anti-angiogenic. VEGF-A165a is the most abundant pro-angiogenic isoform, is pro-inflammatory and a potent inducer of permeability. VEGF-A165b is anti-angiogenic, anti-inflammatory, cytoprotective and neuroprotective. In the diabetic eye, pro-angiogenic VEGF-A isoforms are up-regulated such that they overpower VEGF-A165b. We hypothesized that this imbalance may contribute to increased breakdown of the retinal barriers and by redressing this imbalance, the pathological angiogenesis, fluid extravasation and retinal neurodegeneration could be ameliorated. VEGF-A165b prevented VEGF-A165a and hyperglycaemia-induced tight junction (TJ) breakdown and subsequent increase in solute flux in RPE cells. In streptozotocin (STZ)-induced diabetes, there was an increase in Evans Blue extravasation after both 1 and 8 weeks of diabetes, which was reduced upon intravitreal and systemic delivery of recombinant human (rh)VEGF-A165b. Eight-week diabetic rats also showed an increase in retinal vessel density, which was prevented by VEGF-A165b. These results show rhVEGF-A165b reduces DR-associated blood–retina barrier (BRB) dysfunction, angiogenesis and neurodegeneration and may be a suitable therapeutic in treating DR.
| Type: | Article |
|---|---|
| Title: | Vascular endothelial growth factor-A165b ameliorates outer-retinal barrier and vascular dysfunction in the diabetic retina |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1042/CS20170102 |
| Publisher version: | http://doi.org/10.1042/CS20170102 |
| Language: | English |
| Additional information: | © 2017 The Author(s) This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution Licence 4.0 (CC-BY). |
| Keywords: | Science & Technology, Life Sciences & Biomedicine, Medicine, Research & Experimental, Research & Experimental Medicine, ANTI-VEGF THERAPY, SPLICE VARIANT, ANGIOGENIC ISOFORMS, GANGLION-CELLS, IN-VITRO, RETINOPATHY, VEGF(165)B, NEOVASCULARIZATION, PERMEABILITY, EXPRESSION |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1551919 |
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