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

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 beta-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.

• Authors: Yasuhiro Kumai, Hiroaki Ooboshi, Setsuro Ibayashi, Eiichi Ishikawa, Hiroshi Sugimori, Masahiro Kamouchi, Takanari Kitazono, Kensuke Egashira, Mitsuo Iida
• Journal: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism (J Cereb Blood Flow Metab) Vol. 27 Issue 6 Pg. 1152-60 (Jun 2007) ISSN: 0271-678X [Print] United States
• PMID: 17077813 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Vascular Endothelial Growth Factor A
• Flt1 protein, rat
• Vascular Endothelial Growth Factor Receptor-1

Topics

• Animals
• Blood-Brain Barrier (metabolism)
• Brain Ischemia (prevention & control, therapy)
• Chemotaxis
• Genetic Therapy (methods)
• Male
• Monocytes (physiology)
• Neovascularization, Physiologic (drug effects)
• Permeability
• Pharmacokinetics
• Rats
• Rats, Inbred SHR
• Transduction, Genetic (methods)
• Vascular Endothelial Growth Factor A (antagonists & inhibitors)
• Vascular Endothelial Growth Factor Receptor-1 (administration & dosage)