title: Vascular endothelial growth factor is involved in mediating increased de novo hippocampal neurogenesis in response to traumatic brain injury.
abstract: Stimulating the endogenous repair process after traumatic brain injury (TBI) can be an important approach in neuroregenerative medicine. Vascular endothelial growth factor (VEGF) is one of the molecules that can increase de novo hippocampal neurogenesis. Here, we tested whether VEGF signaling through Flk1 (VEGF receptor 2) is involved in the neurogenic process after experimental TBI. We found that Flk1 is expressed both by neuroblasts in the subgranular layer (SGL) and by maturing granule neurons in the adult dentate gyrus (DG) of the hippocampus. After lateral fluid percussion TBI (LFP-TBI) in the rat, we detected elevated VEGF levels and also increased numbers of de novo neurons in the ipsilateral DG. To test the involvement of VEGF and Flk1 in the neurogenic process directly, we delivered recombinant VEGF or SU5416, an inhibitor to Flk1, into the ipsilateral cerebral ventricle of injured animals. We found that VEGF infusion significantly increased the number of BrdU+/Prox1+ new neurons, decreased the number of TUNEL+ cells, but did not change the number of BrdU+ newborn cells per se. Infusion with SU5416 caused no significant changes. Our results suggest that (a) VEGF is a part of the molecular signaling network that mediates de novo hippocampal neurogenesis after TBI; (b) VEGF predominantly mediates survival of de novo granule neurons rather than proliferation of neuroblasts in the injured brain; and (c) additional VEGF receptor(s) and/or other molecular mechanism(s) are also involved in mediating increased neurogenesis following injury.
authors.affiliation: Neuroscience Program, Department of Anatomy, Physiology and Genetics, School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814, USA.
authors.forename: Cheol
authors.initials: C
authors.lastname: Lee
authors.forename: Denes V
authors.initials: DV
authors.lastname: Agoston
mesh_terms: D000818:Animals; D015415:Biomarkers; D001930:Brain Injuries / Q000378:metabolism* / Q000503:physiopathology; D001973:Bromodeoxyuridine; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D000089622:Doublecortin Domain Proteins; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D020287:In Situ Nick-End Labeling; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use; D015918:Infusion Pumps, Implantable; D008297:Male; D008869:Microtubule-Associated Proteins / Q000032:analysis / Q000378:metabolism; D009416:Nerve Regeneration / Q000187:drug effects / Q000502:physiology*; D055495:Neurogenesis / Q000187:drug effects / Q000502:physiology*; D009479:Neuropeptides / Q000032:analysis / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology*; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism* / Q000494:pharmacology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D015415:Biomarkers; D000089622:Doublecortin Domain Proteins; D007211:Indoles; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D042461:Vascular Endothelial Growth Factor A; C116890:Semaxinib; D040301:Vascular Endothelial Growth Factor Receptor-2; D001973:Bromodeoxyuridine