Postischemic gene transfer of soluble Flt-1 protects against brain ischemia with marked attenuation of blood-brain barrier permeability

Yasuhiro Kumai, Hiroaki Ooboshi, Setsuro Ibayashi, Eiichi Ishikawa, Hiroshi Sugimori, Masahiro Kamouchi, Takanari Kitazono, Kensuke Egashira, Mitsuo Iida

研究成果: ジャーナルへの寄稿記事

37 引用 (Scopus)

抄録

Brain edema is a major and often mortal complication of brain ischemia. Vascular endothelial growth factor (VEGF) is also known as a potent vascular permeability factor and may play detrimental roles at the acute stage of brain infarction. Our goal in this study was to explore protective effects of gene transfer of soluble flt-1 (sFlt-1), a natural inhibitor of VEGF, on focal brain ischemia. Adenoviral vector encoding sFlt-1 or β-galactosidase as control was injected into the lateral ventricle 90 mins after photochemical distal middle cerebral artery occlusion in male spontaneously hypertensive rats. The transduced sFlt-1 was released to the cerebrospinal fluid from the ventricular wall and significantly increased 6 h, 1 and 7 days after sFlt-1 transfection. One day after brain ischemia, sFlt-1 gene transfer significantly reduced infarct volume (by 35%), brain edema (by 35%), and blood-brain barrier permeability (Evans blue extravasation; by 69%) with diminished phosphorylation of focal adhesion kinase (FAKtyr397 and FAKtyr861) in the ischemic vessels. Seven days after ischemia, sFlt-1 gene transfer also significantly attenuated infarct volume (by 29%) and monocyte/macrophage infiltration (by 27%), although there were no reductions in angiogenesis by sFlt-1 overexpression. These results suggest that sFlt-1 gene therapy targeting brain edema in acute stage of brain ischemia may be useful for brain infarction.

元の言語英語
ページ(範囲)1152-1160
ページ数9
ジャーナルJournal of Cerebral Blood Flow and Metabolism
27
発行部数6
DOI
出版物ステータス出版済み - 6 1 2007

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Brain Ischemia
Blood-Brain Barrier
Permeability
Brain Edema
Vascular Endothelial Growth Factor A
Brain Infarction
Genes
Galactosidases
Focal Adhesion Protein-Tyrosine Kinases
Evans Blue
Gene Targeting
Lateral Ventricles
Middle Cerebral Artery Infarction
Inbred SHR Rats
Genetic Therapy
Transfection
Cerebrospinal Fluid
Monocytes
Ischemia
Macrophages

All Science Journal Classification (ASJC) codes

  • Neurology
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine

これを引用

Postischemic gene transfer of soluble Flt-1 protects against brain ischemia with marked attenuation of blood-brain barrier permeability. / Kumai, Yasuhiro; Ooboshi, Hiroaki; Ibayashi, Setsuro; Ishikawa, Eiichi; Sugimori, Hiroshi; Kamouchi, Masahiro; Kitazono, Takanari; Egashira, Kensuke; Iida, Mitsuo.

:: Journal of Cerebral Blood Flow and Metabolism, 巻 27, 番号 6, 01.06.2007, p. 1152-1160.

研究成果: ジャーナルへの寄稿記事

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abstract = "Brain edema is a major and often mortal complication of brain ischemia. Vascular endothelial growth factor (VEGF) is also known as a potent vascular permeability factor and may play detrimental roles at the acute stage of brain infarction. Our goal in this study was to explore protective effects of gene transfer of soluble flt-1 (sFlt-1), a natural inhibitor of VEGF, on focal brain ischemia. Adenoviral vector encoding sFlt-1 or β-galactosidase as control was injected into the lateral ventricle 90 mins after photochemical distal middle cerebral artery occlusion in male spontaneously hypertensive rats. The transduced sFlt-1 was released to the cerebrospinal fluid from the ventricular wall and significantly increased 6 h, 1 and 7 days after sFlt-1 transfection. One day after brain ischemia, sFlt-1 gene transfer significantly reduced infarct volume (by 35{\%}), brain edema (by 35{\%}), and blood-brain barrier permeability (Evans blue extravasation; by 69{\%}) with diminished phosphorylation of focal adhesion kinase (FAKtyr397 and FAKtyr861) in the ischemic vessels. Seven days after ischemia, sFlt-1 gene transfer also significantly attenuated infarct volume (by 29{\%}) and monocyte/macrophage infiltration (by 27{\%}), although there were no reductions in angiogenesis by sFlt-1 overexpression. These results suggest that sFlt-1 gene therapy targeting brain edema in acute stage of brain ischemia may be useful for brain infarction.",
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