Human vascular endothelial growth factor protects axotomized retinal ganglion cells in vivo by activating ERK-1/2 and Akt pathways.
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.
Kilic
Ulkan
U
Department of Neurology, University Hospital Zurich, CH-8091 Zurich, Switzerland.
Kilic
Ertugrul
E
Järve
Anne
A
Guo
Zeyun
Z
Spudich
Annett
A
Bieber
Katja
K
Barzena
Uxue
U
Bassetti
Claudio L
CL
Marti
Hugo H
HH
Hermann
Dirk M
DM
D000818:Animals; D019771:Axotomy / Q000379:methods; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D012165:Retinal Ganglion Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology* / Q000502:physiology
D018696:Neuroprotective Agents; D042461:Vascular Endothelial Growth Factor A; D051058:Oncogene Protein v-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3