May 2006
Volume 47, Issue 13
ARVO Annual Meeting Abstract  |   May 2006
VEGF Has Both Direct and Indirect Neuroprotective Effects in Ischemic Retina
Author Affiliations & Notes
  • E. Ng
    Research, (OSI) Eyetech, Lexington, MA
  • K. Nishijima
    Research, (OSI) Eyetech, Lexington, MA
  • G.S. Robinson
    Research, (OSI) Eyetech, Lexington, MA
  • A.P. Adamis
    Research, (OSI) Eyetech, Lexington, MA
  • D.T. Shima
    Research, (OSI) Eyetech, Lexington, MA
  • Footnotes
    Commercial Relationships  E. Ng, (OSI) Eyetech, E; K. Nishijima, (OSI) Eyetech, E; G.S. Robinson, (OSI) Eyetech, E; A.P. Adamis, (OSI) Eyetech, E; D.T. Shima, (OSI) Eyetech, E.
  • Footnotes
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Investigative Ophthalmology & Visual Science May 2006, Vol.47, 4829. doi:
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      E. Ng, K. Nishijima, G.S. Robinson, A.P. Adamis, D.T. Shima; VEGF Has Both Direct and Indirect Neuroprotective Effects in Ischemic Retina . Invest. Ophthalmol. Vis. Sci. 2006;47(13):4829.

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      © ARVO (1962-2015); The Authors (2016-present)

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Purpose: : Vascular endothelial growth factor (VEGF) is speculated to have protective effect for neuronal cells against ischemic injury. However, as VEGF is known to increase blood flow, it is important to separate changes in blood flow from any direct neuronal effects. The aim of this study is to determine the mechanism of VEGF–mediated neuroprotection in the ischemic retina.

Methods: : Neuronal damage was induced by 60 min of retinal ischemia and reperfusion. Apoptotic cells in the retina were quantified by TUNEL staining 12 and 24 hr post reperfusion. VEGF was administrated intravitreally immediately following retinal ischemia and reperfusion, followed by TUNEL staining 24 hr later. An inhibitor of iNOS, 1400W (Cayman Chemical, MI), was used to decrease blood flow. Glial and endothelial cells were detected using anti–glutamine synthetase antibody (Chemicon, CA) and biotinylated isolectin B4 (Vector Lab, CA), respectively. VEGFR–2 (KDR) expression in the normal retina was determined using an anti–VEGFR–2 antibody (Santa Cruz, CA). To examine the direct neuroprotective effect of VEGF, retinal explants from early postnatal rat pups were cultured for 24 hr in the absence or presence of VEGF, and the number of apoptotic cells were quantified by TUNEL analysis.

Results: : Large numbers of apoptotic cells in the retina were detected at both 12 and 24 hr following ischemia–reperfusion injury. VEGF injection reduced this number by more than 80%. Moreover, inhibition of iNOS activity reduced the protective effect of VEGF injection by 50%, suggesting that increase blood flow plays a role in VEGF–mediated protection. By isolectin B4 and TUNEL double labeling, we determined that endothelial cells were not undergoing apoptosis in the ischemic retina. Similarly, based on glutamine synthetase and TUNEL double labeling, apoptosis of glial cells was not observed in the ischemic retina 12 and 24 hr post ischemia. The expression of VEGFR–2 in neuronal cells suggests that neuronal cells could potentially respond to VEGF directly. Exogenous VEGF addition to retinal explants reduced the number of apoptotic cells after 24 hr of culture, suggesting that VEGF could also play a direct neuroprotective role in the retina independent of changes in blood flow.

Conclusions: : Our data demonstrate that neuronal cells in the retina are highly susceptible to ischemic reperfusion injury, and that VEGF is effective at protecting these cells in the retina. Both VEGFR–2–mediated signaling in neuronal cells and increased blood flow to the injured tissue are implicated. The role of VEGF in normal retinal neuron survival is currently being explored.

Keywords: neuroprotection • vascular occlusion/vascular occlusive disease • growth factors/growth factor receptors 

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