VEGF as a Survival Factor in Ex Vivo Models of Early Diabetic Retinopathy.
Growing evidence indicates neuroprotection as a therapeutic target in diabetic retinopathy (DR). We tested the hypothesis that VEGF is released and acts as a survival factor in the retina in early DR.



Ex vivo mouse retinal explants were exposed to stressors similar to those characterizing DR, that is, high glucose (HG), oxidative stress (OS), or advanced glycation end-products (AGE). Neuroprotection was provided using octreotide (OCT), a somatostatin analog, and pituitary adenylate cyclase activating peptide (PACAP), two well-documented neuroprotectants. Data were obtained with real-time RT-PCR, Western blot, ELISA, and immunohistochemistry.



Apoptosis was induced in the retinal explants by HG, OS, or AGE treatments. At the same time, explants also showed increased VEGF expression and release. The data revealed that VEGF is released shortly after exposure of the explants to stressors and before the level of cell death reaches its maximum. Retinal cell apoptosis was inhibited by OCT and PACAP. At the same time, OCT and PACAP also reduced VEGF expression and release. Vascular endothelial growth factor turned out to be a protective factor for the stressed retinal explants, because inhibiting VEGF with a VEGF trap further increased cell death.



These data show that protecting retinal neurons from diabetic stress also reduces VEGF expression and release, while inhibiting VEGF leads to exacerbation of apoptosis. These observations suggest that the retina in early DR releases VEGF as a prosurvival factor. Neuroprotective agents may decrease the need of VEGF production by the retina, therefore limiting the risk, in the long term, of pathologic angiogenesis.
Department of Biology, University of Pisa, Pisa, Italy.
Rosario
R
Amato
Department of Biology, University of Pisa, Pisa, Italy.
Martina
M
Biagioni
Department of Biology, University of Pisa, Pisa, Italy 2Interdepartmental Research Center Nutrafood "Nutraceuticals and Food for Health," University of Pisa, Pisa, Italy.
Maurizio
M
Cammalleri
Department of Biology, University of Pisa, Pisa, Italy 2Interdepartmental Research Center Nutrafood "Nutraceuticals and Food for Health," University of Pisa, Pisa, Italy.
Massimo
M
Dal Monte
Department of Biology, University of Pisa, Pisa, Italy 2Interdepartmental Research Center Nutrafood "Nutraceuticals and Food for Health," University of Pisa, Pisa, Italy.
Giovanni
G
Casini
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D016923:Cell Death / Q000502:physiology; D003930:Diabetic Retinopathy / Q000378:metabolism*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005947:Glucose / Q000494:pharmacology; D017127:Glycation End Products, Advanced; D007150:Immunohistochemistry; D051379:Mice; D018696:Neuroprotective Agents / Q000494:pharmacology; D015282:Octreotide / Q000494:pharmacology; D018384:Oxidative Stress / Q000502:physiology; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000494:pharmacology; D060888:Real-Time Polymerase Chain Reaction; D012160:Retina / Q000378:metabolism* / Q000473:pathology; D012171:Retinal Vessels / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
D017127:Glycation End Products, Advanced; D018696:Neuroprotective Agents; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D042461:Vascular Endothelial Growth Factor A; D005947:Glucose; D015282:Octreotide