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(Stroke. 2009;40:3596.)
© 2009 American Heart Association, Inc.

Original Contributions

Attenuation of Brain Response to Vascular Endothelial Growth Factor-Mediated Angiogenesis and Neurogenesis in Aged Mice

Peng Gao, PhD, MD; Fanxia Shen, MD; Rodney Allanigue Gabriel, BS; David Law, MD; Ethan Yang, MS; Guo-Yuan Yang, PhD, MD; William L. Young, MD Hua Su, MD

From the Center for Cerebrovascular Research (P.G., F.S., R.A.G., D.L., E.Y., G.-Y.Y., W.L.Y., H.S.), Department of Anesthesia and Perioperative Care and the Departments of Neurological Surgery (W.L.Y.) and Neurology (W.L.Y.), University of California, San Francisco, Calif.

Correspondence to Hua Su, MD, University of California, San Francisco, Department of Anesthesia and Perioperative Care, 1001 Potrero Avenue, Room 3C-38, San Francisco, CA 94110. E-mail hua.su{at}ucsf.edu

Background and Purpose— 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.

Conclusion— The angiogenic and neurogenic response to VEGF stimulation is attenuated in the aged mouse brain, which may be due to reduced VEGF receptor activity.

Key Words: aging • angiogenesis • brain • neurogenesis • VEGF