Therapeutic angiogenesis induced by human recombinant hepatocyte growth factor in rabbit hind limb ischemia model as cytokine supplement therapy

被引:240
作者
Morishita, R
Nakamura, S
Hayashi, S
Taniyama, Y
Moriguchi, A
Nagano, T
Taiji, M
Noguchi, H
Takeshita, S
Matsumoto, K
Nakamura, T
Higaki, J
Ogihara, T
机构
[1] Osaka Univ, Sch Med, Dept Geriatr Med, Suita, Osaka 565, Japan
[2] Sumitomo Pharmaceut Co Ltd, Osaka, Japan
[3] Teikyo Univ, Dept Internal Med 2, Tokyo, Japan
[4] Osaka Univ, Sch Med, Biomed Res Ctr, Dept Oncol,Div Biochem, Suita, Osaka 565, Japan
关键词
arterial occlusive diseases; cell; endothelial; angiogenesis; cell hypoxia; hepatocyte growth factor;
D O I
10.1161/01.HYP.33.6.1379
中图分类号
R6 [外科学];
学科分类号
1002 ; 100210 ;
摘要
Hepatocyte growth factor (HGF) exclusively stimulates the growth of endothelial cells without replication of vascular smooth muscle cells and acts as a survival factor against endothelial cell death. Therefore we hypothesized that a decrease in local vascular HGF might be related to the pathogenesis of peripheral arterial disease. We initially evaluated vascular HGF concentration in the vessels of patients with arteriosclerosis obliterans. Consistent with in vitro findings that hypoxia downregulated vascular HGF production, vascular HGF concentration in the diseased segments of vessels from patients with arteriosclerosis obliterans was significantly decreased as compared with disease-free segments from the same patients (P<0.05), accompanied by a marked reduction in HGF mRNA. On the other hand, a novel therapeutic strategy for ischemic diseases that uses angiogenic growth factors to expedite and/or augment collateral artery development has recently been proposed. Thus in view of the decreased endogenous vascular HGF, rhHGF (500 mu g/animal) was intra-arterially administered through the internal iliac artery of rabbits in which the femoral artery was excised to induce unilateral hind limb ischemia, to evaluate the angiogenic activity of HGF, which could potentially have a beneficial effect in hypoxia. Administration of rhHGF twice on days 10 and 12 after surgery produced significant augmentation of collateral vessel development on day 30 in the ischemic model as assessed by angiography (P<0.01). Serial angiograms revealed progressive linear extension of collateral arteries from the origin stem artery to the distal point of the reconstituted parent vessel in HGF-treated animals. In addition, we examined the feasibility of intravenous administration of rhHGF in a moderate ischemia model. Importantly, intravenous administration of rhHGF also resulted in a significant increase in angiographic score as compared with vehicle (P<0.01), Overall, a decrease in vascular HGF might be related to the pathogenesis of peripheral arterial disease. In the presence of decreased endogenous HGF, administration of rhHGF induced therapeutic angiogenesis in the rabbit ischemic hind limb model, as potential cytokine supplement therapy for peripheral arterial disease.
引用
收藏
页码:1379 / 1384
页数:6
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