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1 Department of Surgery and Science, Kyushu University, Fukuoka, Japan
2 Department of Pathology, Kyushu University, Fukuoka, Japan
3 Department of Vascular Surgery, Nagoya University, Nagoya, Japan
4 Department of Surgery and Science, Kyushu University, Fukuoka, Japan; Department of Pathology, Kyushu University, Fukuoka, Japan
5 Department of Cardiovascular Medicine, Kyushu University, Fukuoka, Japan
6 DNAVEC Reseach Inc., Tsukuba, Japan
* To whom correspondence should be addressed. E-mail: yonemitu{at}pathol1.med.kyushu-u.ac.jp.
We previously demonstrated that sustained disturbance of endothelium-dependent vasorelaxation and poor distal runoff in ischemic limbs were critical factors affecting the neointimal development of autologous vein grafts (VGs). Also, we recently showed the superior therapeutic potential of basic fibroblast growth factor (bFGF/FGF-2) boosted by recombinant Sendai virus (SeV) for severe limb ischemia, compared to that of vascular endothelial growth factor. Here the effect of FGF-2 on neointimal hyperplasia of VGs was examined in a rabbit model of poor runoff limbs. Two weeks after initial surgery for the induction of poor runoff, SeV-expressing human FGF-2 (SeV-hFGF2) or that encoding firefly luciferase (109 pfu/head) was injected into the thigh and calf muscle. At that time, the femoral vein was implanted in the femoral artery in end-to-end manner in some groups. FGF-2 gene transferred limbs demonstrated significantly increased blood flow assessed not only by laser Doppler flow image but also by ultrasonic transit-time flowmeter (USTF). USTF also showed a significant increase of the blood flow ratio of the deep femoral artery/ external iliac artery, indicating that collateral flow was significantly restored in the thigh muscles (p<0.01). Reduction of neointimal hyperplasia was also observed in the VGs treated by SeV-hFGF2; these grafts demonstrated significant restoration of endothelium-dependent vasorelaxation. These findings thus extend the indications of therapeutic angiogenesis using SeV-hFGF2 to include not only limb salvage, but also prevention of late graft failure.
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