PMID- 17960159
OWN - NLM
STAT- MEDLINE
DCOM- 20080411
LR  - 20211020
IS  - 1476-5462 (Electronic)
IS  - 0969-7128 (Print)
IS  - 0969-7128 (Linking)
VI  - 15
IP  - 1
DP  - 2008 Jan
TI  - Adeno-associated viral vector-mediated hypoxia-regulated VEGF gene transfer 
      promotes angiogenesis following focal cerebral ischemia in mice.
PG  - 30-9
AB  - 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 (tMCAO). Results show that HIF-1 was persistently 
      expressed in the ischemic brain. VEGF was overexpressed in the ischemic perifocal 
      region in AAVH9-VEGF-transduced mice. Double-labeled immunostaining showed that 
      VEGF expressed in neurons and astrocytes but not endothelial cells, suggesting 
      that adeno-associated virus (AAV) vectors transduced neurons and astrocytes 
      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 brain tissue.
FAU - Shen, F
AU  - Shen F
AD  - Department of Anesthesia and Perioperative Care, Center for Cerebrovascular 
      Research, University of California, San Francisco, CA 94110, USA.
FAU - Fan, Y
AU  - Fan Y
FAU - Su, H
AU  - Su H
FAU - Zhu, Y
AU  - Zhu Y
FAU - Chen, Y
AU  - Chen Y
FAU - Liu, W
AU  - Liu W
FAU - Young, W L
AU  - Young WL
FAU - Yang, G-Y
AU  - Yang GY
LA  - eng
GR  - P01 NS044145/NS/NINDS NIH HHS/United States
GR  - R01 NS027713/NS/NINDS NIH HHS/United States
GR  - P01 NS044155-05/NS/NINDS NIH HHS/United States
GR  - R01 NS027713-17/NS/NINDS NIH HHS/United States
GR  - R21 NS050668/NS/NINDS NIH HHS/United States
GR  - P01 NS044155/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20071025
PL  - England
TA  - Gene Ther
JT  - Gene therapy
JID - 9421525
RN  - 0 (3' Untranslated Regions)
RN  - 0 (Hypoxia-Inducible Factor 1)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 11096-26-7 (Erythropoietin)
SB  - IM
MH  - 3' Untranslated Regions
MH  - Animals
MH  - Astrocytes/chemistry
MH  - Brain Ischemia/metabolism/physiopathology/*therapy
MH  - Cerebrovascular Circulation
MH  - Dependovirus/*genetics
MH  - Erythropoietin/genetics
MH  - Gene Expression
MH  - Genetic Therapy/*methods
MH  - Genetic Vectors/*administration & dosage
MH  - Hypoxia/metabolism
MH  - Hypoxia-Inducible Factor 1/analysis/genetics
MH  - Immunohistochemistry
MH  - Mice
MH  - Neovascularization, Physiologic
MH  - Neurons/chemistry
MH  - Transduction, Genetic/*methods
MH  - Vascular Endothelial Growth Factor A/analysis/*genetics
PMC - PMC2586392
MID - NIHMS75426
EDAT- 2007/10/26 09:00
MHDA- 2008/04/12 09:00
PMCR- 2008/11/24
CRDT- 2007/10/26 09:00
PHST- 2007/10/26 09:00 [pubmed]
PHST- 2008/04/12 09:00 [medline]
PHST- 2007/10/26 09:00 [entrez]
PHST- 2008/11/24 00:00 [pmc-release]
AID - 3303048 [pii]
AID - 10.1038/sj.gt.3303048 [doi]
PST - ppublish
SO  - Gene Ther. 2008 Jan;15(1):30-9. doi: 10.1038/sj.gt.3303048. Epub 2007 Oct 25.