VEGF receptor-2 (Flk-1) overexpression in mice counteracts focal epileptic seizures.
Vascular endothelial growth factor (VEGF) was first described as an angiogenic agent, but has recently also been shown to exert various neurotrophic and neuroprotective effects in the nervous system. These effects of VEGF are mainly mediated by its receptor, VEGFR-2, which is also referred to as the fetal liver kinase receptor 1 (Flk-1). VEGF is up-regulated in neurons and glial cells after epileptic seizures and counteracts seizure-induced neurodegeneration. In vitro, VEGF administration suppresses ictal and interictal epileptiform activity caused by AP4 and 0 Mg(2+) via Flk-1 receptor. We therefore explored whether increased VEGF signaling through Flk-1 overexpression may regulate epileptogenesis and ictogenesis in vivo. To this extent, we used transgenic mice overexpressing Flk-1 postnatally in neurons. Intriguingly, Flk-1 overexpressing mice were characterized by an elevated threshold for seizure induction and a decreased duration of focal afterdischarges, indicating anti-ictal action. On the other hand, the kindling progression in these mice was similar to wild-type controls. No significant effects on blood vessels or glia cells, as assessed by Glut1 and GFAP immunohistochemistry, were detected. These results suggest that increased VEGF signaling via overexpression of Flk-1 receptors may directly affect seizure activity even without altering angiogenesis. Thus, Flk-1 could be considered as a novel target for developing future gene therapy strategies against ictal epileptic activity.
Experimental Epilepsy Group, Wallenberg Neuroscience Center, BMC A-11, Lund University Hospital, Lund, Sweden.
Litsa
L
Nikitidou
Irene
I
Kanter-Schlifke
Joke
J
Dhondt
Peter
P
Carmeliet
Diether
D
Lambrechts
Mérab
M
Kokaia
D000818:Animals; D005260:Female; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D006624:Hippocampus / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D051379:Mice; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D060888:Real-Time Polymerase Chain Reaction; D012640:Seizures / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*
D051272:Glucose Transporter Type 1; C495678:Slc2a1 protein, mouse; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2