Vascular endothelial growth factor-A is a survival factor for retinal neurons and a critical neuroprotectant during the adaptive response to ischemic injury.
Vascular endothelial growth factor-A (VEGF-A) has recently been recognized as an important neuroprotectant in the central nervous system. Given its position as an anti-angiogenic target in the treatment of human diseases, understanding the extent of VEGF's role in neural cell survival is paramount. Here, we used a model of ischemia-reperfusion injury and found that VEGF-A exposure resulted in a dose-dependent reduction in retinal neuron apoptosis. Although mechanistic studies suggested that VEGF-A-induced volumetric blood flow to the retina may be partially responsible for the neuroprotection, ex vivo retinal culture demonstrated a direct neuroprotective effect for VEGF-A. VEGF receptor-2 (VEGFR2) expression was detected in several neuronal cell layers of the retina, and functional analyses showed that VEGFR2 was involved in retinal neuroprotection. VEGF-A was also shown to be involved in the adaptive response to retinal ischemia. Ischemic preconditioning 24 hours before ischemia-reperfusion injury increased VEGF-A levels and substantially decreased the number of apoptotic retinal cells. The protective effect of ischemic preconditioning was reversed after VEGF-A inhibition. Finally, chronic inhibition of VEGF-A function in normal adult animals led to a significant loss of retinal ganglion cells yet had no observable effect on several vascular parameters. These findings have implications for both neural pathologies and ocular vascular diseases, such as diabetic retinopathy and age-related macular degeneration.
Nishijima
Kazuaki
K
R&D Consultants, Barnet, Herts, UK.
Ng
Yin-Shan
YS
Zhong
Lichun
L
Bradley
John
J
Schubert
William
W
Jo
Nobuo
N
Akita
Jo
J
Samuelsson
Steven J
SJ
Robinson
Gregory S
GS
Adamis
Anthony P
AP
Shima
David T
DT
D000328:Adult; D000818:Animals; D017209:Apoptosis; D001783:Blood Flow Velocity; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008268:Macular Degeneration; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000494:pharmacology; D009924:Organ Culture Techniques; D051381:Rats; D020318:Rats, Long-Evans; D015427:Reperfusion Injury / Q000378:metabolism* / Q000473:pathology; D012160:Retina / Q000187:drug effects / Q000502:physiology*; D012171:Retinal Vessels / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000502:physiology
D018696:Neuroprotective Agents; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2