ABSTRACT Uncontrolled expression of vascular endothelial growth factor (VEGF) _in vivo_ may cause unexpected side effects, such as brain hemangioma or tumor growth. Because hypoxia-inducible

factor-1 (HIF-1) is upregulated during cerebral ischemia and regulates gene expression by binding to a cis-acting hypoxia-responsive element (HRE), we therefore used a novel HRE,

originating in the 3′-end of the erythropoietin (Epo) gene, to control gene expression in the ischemic brain. A concatemer of nine copies (H9) of the consensus sequence of HRE was used to

mediate hypoxia induction. Three groups of adult CD-1 mice received AAVH9-VEGF, AAVH9-lacZ or saline injection, and then underwent 45 min of transient middle cerebral artery occlusion

predominantly. The total number of microvessels/enlarged microvessels was greatly increased in the AAVH9-VEGF-transduced mice (180±29/27±4) compared to the AAVH9-lacZ (118±19/14±3) or

saline-treated (119±20/14±2) mice after tMCAO (_P_<0.05). Cell proliferation examination demonstrated that these microvessels were newly formed. Regional cerebral blood flow recovery in

the AAVH9-VEGF-transduced mice was also better than in AAVH9-lacZ or saline-treated mice (_P_<0.05). Our data indicated that HRE is a novel trigger for the control of VEGF expression in

the ischemic brain. VEGF overexpression through AAVH9-VEGF gene transfer showed stable focal angiogenic effects in post-ischemic repair process, providing an opportunity to rebuild injured

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customer support SIMILAR CONTENT BEING VIEWED BY OTHERS DL-3-N-BUTYLPHTHALIDE PROMOTES ANGIOGENESIS IN ISCHEMIC STROKE MICE THROUGH UPREGULATING AUTOCRINE AND PARACRINE SONIC HEDGEHOG

Article 14 August 2023 ENDOTHELIAL CELLS REGULATE ASTROCYTE TO NEURAL PROGENITOR CELL TRANS-DIFFERENTIATION IN A MOUSE MODEL OF STROKE Article Open access 19 December 2022 VASCULAR

ENDOTHELIUM DEPLOYS CAVEOLIN-1 TO REGULATE OLIGODENDROGENESIS AFTER CHRONIC CEREBRAL ISCHEMIA IN MICE Article Open access 10 November 2022 ABBREVIATIONS * AAV: adeno-associated viral vector

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PubMed  Google Scholar  Download references ACKNOWLEDGEMENTS These studies were supported by NIH Grants: R01 NS027713 (WLY), R21 NS050668 (GYY) and P01 NS044145 (WLY, GYY). We thank Voltaire

Gungab for editorial assistance, and the staff of the Center for Cerebrovascular Research (http://avm.ucsf.edu/) for their collaborative support. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS

* Department of Anesthesia and Perioperative Care, Center for Cerebrovascular Research, University of California, San Francisco, CA, USA F Shen, Y Fan, Y Zhu, Y Chen, W Liu, W L Young &

 G-Y Yang * Department of Neurology, Rui-Jin Hospital, Jiaotong University, Shanghai, China F Shen & G-Y Yang * Department of Internal Medicine, University of California, San Francisco,

CA, USA H Su * Department of Neurological Surgery, University of California, San Francisco, CA, USA W L Young & G-Y Yang * Department of Neurology, University of California, San

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this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to G-Y Yang. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Shen, F., Fan, Y.,

Su, H. _et al._ Adeno-associated viral vector-mediated hypoxia-regulated VEGF gene transfer promotes angiogenesis following focal cerebral ischemia in mice. _Gene Ther_ 15, 30–39 (2008).

https://doi.org/10.1038/sj.gt.3303048 Download citation * Received: 16 April 2007 * Revised: 23 July 2007 * Accepted: 23 July 2007 * Published: 25 October 2007 * Issue Date: January 2008 *

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currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative KEYWORDS * adeno-associated viral vectors * angiogenesis *

hypoxia-responsive element * ischemia * VEGF