Adenoviral delivery of soluble VEGF receptor 1 (sFlt-1) inhibits experimental autoimmune encephalomyelitis in dark Agouti (DA) rats

• Published in: Life sciences (1973) Vol. 83; no. 11; pp. 404 - 412
• Main Authors: Zhu, Can-Sheng, Hu, Xue-Qiang, Xiong, Zhao-Jun, Lu, Zheng-Qi, Zhou, Guo-Yu, Wang, Dun-Jing
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 12.09.2008
• Subjects: Adenoviridae - genetics; Animals; Blotting, Western; Brain Chemistry - genetics; Cell Line; Cell Movement; Encephalomyelitis, Autoimmune, Experimental - genetics; Encephalomyelitis, Autoimmune, Experimental - pathology; Encephalomyelitis, Autoimmune, Experimental - therapy; Enzyme-Linked Immunosorbent Assay; Experimental autoimmune encephalomyelitis; Fluorescent Antibody Technique; Gene therapy; Genetic Therapy; Genetic Vectors - genetics; Immunohistochemistry; Inflammation; Kinetics; Male; Rats; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - biosynthesis; RNA, Messenger - genetics; sFlt-1(1-3) gene; Spinal Cord - metabolism; Transfection; Vascular Endothelial Growth Factor A - biosynthesis; Vascular Endothelial Growth Factor Receptor-1 - genetics; Vascular Endothelial Growth Factor Receptor-1 - physiology; Experimental autoimmune encephalomyelitis; Inflammation; Gene therapy; sFlt-1(1-3) gene
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/j.lfs.2008.07.009

Previous studies have shown that vascular endothelial growth factor (VEGF) expression is up-regulated in both multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), a model for MS, and may exacerbate the disease. However, it remains unknown whether anti-VEGF modalities could serve as a potential treatment for such central nervous system (CNS) autoimmune diseases. We constructed a recombinant adenoviral vector carrying FLAG-tagged sFlt-1(1-3) (the first three extracellular domains of Flt-1, the hVEGF receptor-1). Intramuscular transfection of the recombinant adenoviral vector suppressed VEGF-induced inflammatory cell infiltration in matrigel plugs. When given intracerebrally to EAE rats, recombinant sFlt-1(1-3) adenoviral vector significantly reduced disease severity compared to untreated rats. sFlt-1(1-3) gene transfer blocked VEGF and greatly reduced the number of cells that express VEGF and ED1-positive cells in CNS in EAE rats. This study demonstrates that sFlt-1(1-3) gene transfer into the brain ameliorates the severity of EAE by inhibiting monocyte recruitment in the CNS of dark Agouti rats.