Vascular endothelial growth factor-A165b ameliorates outer-retinal barrier and vascular dysfunction in the diabetic retina.
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.
Cancer Biology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham NG7 2UH, U.K.|Department of Genetics, UCL Institute of Ophthalmology, 11-43 Bath Street, London EC1V9EL, U.K.
Nikita
N
Ved
Cancer Biology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham NG7 2UH, U.K.
Richard P
RP
Hulse
Cancer Biology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham NG7 2UH, U.K.|School of Life Sciences, University of Nottingham, Nottingham NG7 2UH, U.K.
Samuel M
SM
Bestall
School of Life Sciences, University of Nottingham, Nottingham NG7 2UH, U.K.
Lucy F
LF
Donaldson
Department of Genetics, UCL Institute of Ophthalmology, 11-43 Bath Street, London EC1V9EL, U.K.
James W
JW
Bainbridge
Cancer Biology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham NG7 2UH, U.K. David.Bates@nottingham.ac.uk.
David O
DO
Bates
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001813:Blood-Retinal Barrier / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D019610:Cytoprotection; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000150:complications / Q000188:drug therapy*; D003930:Diabetic Retinopathy / Q000097:blood / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D058449:Intravitreal Injections; D009410:Nerve Degeneration; D010539:Permeability; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000008:administration & dosage; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015861:Retinal Neovascularization / Q000097:blood / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D055213:Retinal Pigment Epithelium / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D012171:Retinal Vessels / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D062725:Tight Junction Proteins / Q000378:metabolism; D019108:Tight Junctions / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000008:administration & dosage*
D020533:Angiogenesis Inhibitors; D001786:Blood Glucose; D011994:Recombinant Proteins; D062725:Tight Junction Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A
angiogenesis; diabetic retinopathy; vascular endothelial growth factor