Published Online
on August 31, 2006

A more recent version of this article appeared on October 1, 2006

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Submitted on May 24, 2006
Revised on July 3, 2006
Accepted on July 24, 2006

Adeno-Associated Viral Vector-Mediated Hypoxia-Inducible Vascular Endothelial Growth Factor Gene Expression Attenuates Ischemic Brain Injury After Focal Cerebral Ischemia in Mice

Fanxia Shen MD; Hua Su MD; Yongfeng Fan MD, PhD; Yongmei Chen MD, PhD; Yiqian Zhu MD; Weizhong Liu MD; William L. Young MD; and Guo-Yuan Yang MD, PhD^*

From the Departments of Anesthesia and Perioperative Care (F.S., Y.F., Y.C., Y.Z., W.L., W.L.Y., G.-Y.Y.), Neurological Surgery (W.L.Y., G.-Y.Y.), Neurology (W.L.Y.), and Internal Medicine (H.S.), Center for Cerebrovascular Research, University of California, San Francisco, Calif; and the Department of Neurology (F.S., G.-Y.Y.), RuiJin Hospital, Jiaotong University, Shanghai, China.

^* To whom correspondence should be addressed. E-mail: gyyang{at}anesthesia.ucsf.edu.

Background and Purpose--Exogenous delivery of vascular endothelial growth factor gene (VEGF) may provide a useful approach to the treatment of brain ischemia. We investigated the use of a hypoxia-responsive element to control VEGF expression given for neuroprotection.

Methods--Three groups (n=36) of mice received AAVH9-VEGF, AAVH9-lacZ, or saline injection. Five days after gene transfer, the mice underwent 45 minutes of transient middle cerebral artery occlusion (tMCAO) followed by 1 to 7 days of reperfusion. Infarct volume was determined using cresyl violet staining; neuronal injury was examined using TUNEL, cleaved caspase-3, and fluoro-Jade B staining.

Results--Hypoxia-inducible factor-1 (HIF-1) was overexpressed after tMCAO in the ischemic hemisphere in the brain. Expression of lacZ, mediated by AAV-lacZ, was seen before and after tMCAO; however, AAVH9-lacZ-mediated lacZ expression was detected only after tMCAO. Infarct volume was smaller in the AAVH9-VEGF-transduced group compared with AAVH9-lacZ and saline groups (55% reduction, P<0.05) with reduced TUNEL (29±5% and 30±7% versus 12±3%, P<0.05), cleaved caspase-3 (20±3% and 21±5% versus 13±4%, P<0.05) and fluoro-Jade B (23±3% and 24±5% versus 12±5%, P<0.05) -positive neurons, respectively.

Conclusion--Exogenous expression of VEGF through AAVH9-VEGF gene transfer 5 days before the onset of ischemia provides neuroprotection. Hypoxia-responsive element is a viable strategy of restricting VEGF expression to areas of ischemia to minimize adverse effects of therapy on adjacent normal parenchyma.

Key words: adeno-associated virus • brain • hypoxia-responsive element • ischemia • neuroprotection • VEGF

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