Vascular endothelial growth factor-A165b ameliorates outer-retinal barrier and vascular dysfunction in the diabetic retina

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.

Diabetes‐induced microvascular complications at the level of the spinal cord: a contributing factor in diabetic neuropathic pain

“…; Ved et al . ) but also prevented diabetic neuropathic pain behaviours (mechanical allodynia, Fig. A ; and heat hyperalgesia, Fig.…”

“…The VEGF‐A xxx b isoforms, however, do not stimulate angiogenesis or increase solute flux in diabetes, and in fact they can reverse it in rodent models of diabetic retinopathy (Ved et al . ). Despite these opposing profiles both families are cytoprotective for endothelial cells and neurons (Beazley‐Long et al .…”

“…This is an interesting comparison with most other vascular beds [including eyes (Ved et al . ) and the peripheral nerves (Hulse et al . )], where diabetes results in increased solute flux, probably through increased vascular permeability (Poduslo & Curran, ).…”

Retinal pigment epithelium in the pathogenesis of age‐related macular degeneration and photobiomodulation as a potential therapy?

“…However, this resistance is plastic, as permeability of the tight junctions can change in the presence of diffusible factors produced from the neural retina . One such factor is vascular endothelial growth factor (VEGF) which has been implicated in the breakdown of the outer blood‐retinal barrier in diabetic macular oedema . Hypoxia and hyperglycaemia may upregulate hypoxia inducible factor 1 alpha and therefore VEGF expression, resulting in altered tight junction proteins .…”

“…18 One such factor is vascular endothelial growth factor (VEGF) which has been implicated in the breakdown of the outer blood-retinal barrier in diabetic macular oedema. 19,20 Hypoxia and hyperglycaemia may upregulate hypoxia inducible factor 1 alpha and therefore VEGF expression, resulting in altered tight junction proteins. [20][21][22] During the development of the RPE, tight junctions tend to be leaky, but these become progressively less permeable due to secretion of these diffusible factors from the neural retina.…”