Attenuation of brain response to vascular endothelial growth factor-mediated angiogenesis and neurogenesis in aged mice.
OBJECTIVE
Alterations of neuroangiogenic response play important roles in the development of aging-related neurodisorders and affect gene-based therapies. We tested brain response to vascular endothelial growth factor (VEGF) in aged mice.


METHODS
Adeno-associated viral vector (AAV)-VEGF, an adeno-associated viral vector expressing VEGF, was injected into the brain of 3-, 12-, and 24-month-old mice. AAV-LacZ-injected mice were used as controls (n=6). Before euthanasia at 6 weeks after vector injection, the mice were intraperitoneally injected with 5-bromodeoxyuridine for 3 consecutive days. The vascular density and the number of neuroprogenitors were analyzed.


RESULTS
Injection of AAV-VEGF increased the vascular density in the brain of 3-, 12-, and 24-month-old mice by 22%+/-7% (AAV-VEGF: 320+/-15 per 10x field versus AAV-LacZ: 263+/-8, P<0.05), 20%+/-8 (AAV-VEGF: 300+/-9 versus AAV-LacZ: 250+/-11, P<0.05), and 7%+/-16% (AAV-VEGF: 257+/-27 versus AAV-LacZ: 236+/-13, P=0.283), respectively. There were more VEGF receptor-positive neuroprogenitors in the subventricular zone of AAV-VEGF-injected 3- (22+/-2) and 12-month-old mice (21+/-5) than that of 24-month-old mice (7+/-1). More 5-bromodeoxyuridine-positive endothelial cells and neuroprogenitors were detected around the injection site and subventricular zone of 3- (13+/-4) and 12-month-old mice (14+/-5) than that of 24-month-old mice (1+/-1). VEGF receptor 2 was upregulated in AAV-VEGF-injected brains of 3- and 12-month-old mice, but not in 24-month-old mice.


CONCLUSIONS
The angiogenic and neurogenic response to VEGF stimulation is attenuated in the aged mouse brain, which may be due to reduced VEGF receptor activity.
Gao
Peng
P
Department of Anesthesia and Perioperative Care, University of California, Center for Cerebrovascular Research, San Francisco, Calif 94110, USA.
Shen
Fanxia
F
Gabriel
Rodney Allanigue
RA
Law
David
D
Yang
Ethan Yibo
EY
Yang
Ethan
E
Yang
Guo-Yuan
GY
Young
William L
WL
Su
Hua
H
D000375:Aging / Q000235:genetics / Q000473:pathology / Q000502:physiology*; D000818:Animals; D001923:Brain Chemistry / Q000235:genetics / Q000502:physiology*; D000229:Dependovirus / Q000235:genetics; D005786:Gene Expression Regulation / Q000502:physiology; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000008:administration & dosage; D051379:Mice; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic / Q000235:genetics / Q000502:physiology*; D055495:Neurogenesis / Q000235:genetics / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000008:administration & dosage* / Q000096:biosynthesis / Q000235:genetics
D042461:Vascular Endothelial Growth Factor A