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The Journal of Neuroscience, November 29, 2006, 26(48):12439-12446; doi:10.1523/JNEUROSCI.0434-06.2006

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Neurobiology of Disease
Human Vascular Endothelial Growth Factor Protects Axotomized Retinal Ganglion Cells In Vivo by Activating ERK-1/2 and Akt Pathways

Ülkan Kilic,¹ Ertugrul Kilic,¹ Anne Järve,² Zeyun Guo,¹ Annett Spudich,¹ Katja Bieber,² Uxue Barzena,² Claudio L. Bassetti,¹ Hugo H. Marti,² and Dirk M. Hermann¹

¹Department of Neurology, University Hospital Zurich, CH-8091 Zurich, Switzerland, and ²Institute of Physiology and Pathophysiology, University of Heidelberg, D-69120 Heidelberg, Germany

Correspondence should be addressed to Dr. Dirk M. Hermann, Department of Neurology, University Hospital Zurich, Frauenklinikstrasse 26, CH-8091 Zurich, Switzerland. Email: dirk.hermann{at}usz.ch

Based on its trophic effects on neurons and vascular cells, vascular endothelial growth factor (VEGF) is a promising candidate for the treatment of neurodegenerative diseases. To evaluate the therapeutic potential of VEGF, we here examined effects of this growth factor on the degeneration of axotomized retinal ganglion cells (RGCs), which, as CNS-derived neurons, offer themselves in an excellent way to study neuroprotection in vivo. Making use of a transgenic mouse line that constitutively expresses human VEGF under a neuron-specific enolase promoter, we show that (1) the VEGF-transgenic retina overexpresses human VEGF, (2) RGCs carry the VEGF receptor-2, and (3) vascular networks in normal and axotomized VEGF-transgenic (tg) retinas do not differ from control animals. After axotomy, RGCs of VEGF-tg mice were protected against delayed degeneration, as compared with wild-type littermates. Western blots revealed increased phosphorylated ERK-1/2 and Akt and reduced phosphorylated p38 and activated caspase-3 levels in axotomized VEGF-transgenic retinas. Intravitreous injections of pharmacological ERK-1/2 (PD98059) or Akt (LY294002) inhibitors showed that VEGF exerts neuroprotection by dual activation of ERK-1/2 and Akt pathways. In view that axotomy-induced RGC death occurs slowly and considering that RGCs are CNS-derived neurons, we predict the clinical implementation of VEGF in neurodegenerative diseases of both brain and retina.

Key words: neurodegeneration; neuroprotection; neurotrophic; VEGF; signal transduction; mitogen activated protein kinase; phosphatidylinositol-3 kinase

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Received Jan. 31, 2006; revised Oct. 8, 2006; accepted Oct. 11, 2006.

Correspondence should be addressed to Dr. Dirk M. Hermann, Department of Neurology, University Hospital Zurich, Frauenklinikstrasse 26, CH-8091 Zurich, Switzerland. Email: dirk.hermann{at}usz.ch

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