Inhibition of VEGF receptor 2 increased cell death of dentate hilar neurons after traumatic brain injury.
Post-traumatic epilepsy, partly due to the loss of hilar neurons of the hippocampus, is a frequent long-term consequence of traumatic brain injury (TBI). We and others found that the levels of vascular endothelial growth factor (VEGF) that can act as a neuroprotectant increase after TBI. Here we tested whether VEGF and its receptor VEGFR2 are involved in mediating the death or survival of hilar neurons after injury. We demonstrated that VEGFR2 is expressed by most, if not all, hilar neurons and that these neurons are dying in large numbers as indicated by Fluoro-Jade B histology after fluid percussion TBI. To directly test the involvement of VEGFR2 and VEGF in the injury-induced apoptotic death of hilar neurons, we delivered SU5416, an inhibitor to VEGFR2, or recombinant VEGF into the ipsilateral cerebral ventricle of injured animals. We found that blocking VEGFR2 by SU5416 significantly increased the number of apoptotic (TUNEL-positive) cells in the hilus. Infusion of VEGF, however, failed to reduce the number of TUNEL-positive cells. Our results suggest that VEGFR2 is involved in mediating death or survival of hilar neurons after injury but delivering additional exogenous VEGF does not provide further protection from TBI-induced death of hilar neurons.
Lee
Cheol
C
Department of Anatomy, Physiology and Genetics, School of Medicine, USUHS, Bethesda, MD 20814, USA.
Agoston
Denes V
DV
D000818:Animals; D001930:Brain Injuries / Q000473:pathology*; D016923:Cell Death / Q000187:drug effects; D018891:Dentate Gyrus / Q000473:pathology*; D005452:Fluoresceins; D005456:Fluorescent Dyes; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007211:Indoles / Q000494:pharmacology; D007276:Injections, Intraventricular; D008297:Male; D009474:Neurons / Q000473:pathology*; D018696:Neuroprotective Agents; D009930:Organic Chemicals; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*
D005452:Fluoresceins; D005456:Fluorescent Dyes; D007211:Indoles; D018696:Neuroprotective Agents; D009930:Organic Chemicals; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D042461:Vascular Endothelial Growth Factor A; C435731:fluoro jade; C116890:Semaxinib; D040301:Vascular Endothelial Growth Factor Receptor-2