Recombinant adeno-associated virus serotype 1-vascular endothelial growth factor promotes neurogenesis and neuromigration in the subventricular zone and rescues neuronal function in ischemic rats.
OBJECTIVE
Vascular endothelial growth factor (VEGF) enhances neurogenesis in ischemic brains. However, in most circumstances, endogenous VEGF expression is limited and insufficient to prevent brain damage. We transferred the VEGF gene into brain tissue with recombinant adeno-associated virus serotype 1 (rAAV1) vectors and determined the effect of VEGF expression on neurogenesis and recovery of neurological function after brain ischemia.


METHODS
Two groups (n = 32) of Sprague Dawley rats received intraventricular injection of AAV1-VEGF or AAV1-lacZ. Twenty-one days after gene transfer, rats underwent transient middle cerebral artery occlusion, and neurological severity score was measured 1, 2, 3, 7, 14, and 21 days later. Immunostaining was used to identify the quantity and distribution of VEGF expression. Double-immunofluorescence for doublecortin and bromodeoxyuridine or neuronal nuclei was performed to detect neurogenesis and the migration of neural progenitor cells.


RESULTS
VEGF expression reduced the size of cerebral infarction and improved neurological function. It also enhanced the proliferation of neural progenitor cells in the subventricular zone and promoted their migration to the ischemic lesion. Neural precursors in the subgranular zone of the dentate gyrus were also increased; however, most of these cells did not move to the ischemic lesion and integrated with their region of origin.


CONCLUSIONS
rAAV1-mediated expression of VEGF in the rat brain reduces the size of the infarcted lesion and promotes recovery of neurological function, likely by enhancing neurogenesis in the subventricular zone and promoting neural precursor migration to brain tissue around the core of the ischemic lesion.
Li
Shi-Fang
SF
Department of Neurosurgery, The Affiliated Hospital of Medical College, Qingdao University, Qingdao, China.
Sun
Yun-Bo
YB
Meng
Qing-Hai
QH
Li
Shi-Ru
SR
Yao
Wei-Cheng
WC
Hu
Guo-Jie
GJ
Li
Zhao-Jian
ZJ
Wang
Ren-Zhi
RZ
D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D002454:Cell Differentiation / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D000089662:Doublecortin Protein; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics*; D008297:Male; D009410:Nerve Degeneration / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D055495:Neurogenesis / Q000235:genetics*; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000235:genetics; D020127:Recovery of Function / Q000235:genetics; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D013687:Telencephalon / Q000166:cytology / Q000378:metabolism; D014162:Transfection / Q000379:methods; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*
C000714848:Dcx protein, rat; D000089662:Doublecortin Protein; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A