Intramuscular administration of vascular endothelial growth factor induces dose-dependent collateral artery augmentation in a rabbit model of chronic limb ischemia.
Intramuscular administration of vascular endothelial growth factor induces dose-dependent collateral artery augmentation in a rabbit model of chronic limb ischemia.
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发表时间：
1994-11
期刊：
影响因子：
37.8
通讯作者：
S. Takeshita;L. Q. Pu;L. Stein;A. Sniderman;S. Bunting;N. Ferrara;J. Isner;J. Symes;J. Symes
中科院分区：
文献类型：
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作者：
S. Takeshita;L. Q. Pu;L. Stein;A. Sniderman;S. Bunting;N. Ferrara;J. Isner;J. Symes;J. Symes
背景尽管手术和经皮血运重建技术取得了重大进展，但许多患有弥漫性周围血管疾病的患者仍无法实现肢体挽救和缺血性疼痛的缓解。血管内皮生长因子 (VEGF) 是一种肝素结合的内皮细胞特异性有丝分裂原。先前的研究表明，VEGF 是自然发生的生理和病理性血管生成的调节剂。在这项研究中，在慢性后肢缺血兔模型中研究了肌肉注射 VEGF 的治疗潜力。方法与结果采用结扎远端髂外动脉并完全切除股动脉的方法，使24只新西兰白兔后肢缺血。诱导肢体缺血十天后（第 0 天），每天将盐水（A 组，n = 7）或重组人 VEGF 的 165 个氨基酸亚型（B 组：200 微克，n = 6；C 组：500 微克，n = 7；D 组：1000 微克，n = 4）肌内注射到缺血肢体，持续 10 天。治疗开始后第30天的血管造影显示，缺血肢体中的侧支血管出现统计学上显着的剂量依赖性扩张（血管造影评分：A组，13.0+/-1.1；B组，21.2+/-1.8；C组，27.3+/-1.4；D组，31.5+/-2.5）。第 30 天，VEGF 组大腿肌肉毛细血管密度是对照组的 1.6 倍（每平方毫米 176 +/- 15.3 与 113 +/- 27.3，P < .05）。通过小腿收缩压比记录缺血肢体血流动力学缺陷的改善（A组，0.52+/-0.02；B组，0.67+/-0.02；C组，0.73+/-0.01；D组，0.82+/-0.03）。 VEGF 治疗组的“临床”改善（小腿肌肉萎缩和远端肢体坏死的发生率：A 组，85.7%；B 组，33.3%；C 组，14.3%；D 组，0%）高于对照组动物，同样呈剂量依赖性。结论 这些研究结果表明，在缺血兔后肢肌肉注射 VEGF 后，肢体灌注显着呈剂量依赖性增加，同时伴有侧枝循环形成增加的证据。因此，这项研究支持了这样的假设：施用 VEGF 刺激血管生成可能代表治疗动脉供血不足的新治疗方式。
BACKGROUND Despite major advances in both surgical and percutaneous revascularization techniques, limb salvage and relief of ischemic pain cannot be achieved in many patients with diffuse peripheral vascular disease. Vascular endothelial growth factor (VEGF) is a heparin-binding, endothelial cell-specific mitogen. Previous studies have suggested that VEGF is a regulator of naturally occurring physiological and pathological angiogenesis. In this study, the therapeutic potential of intramuscularly administered VEGF was investigated in a rabbit model of chronic hindlimb ischemia. METHODS AND RESULTS Ischemia was induced in the hindlimb of 24 New Zealand White rabbits by ligation of the distal external iliac artery and complete excision of the femoral artery. Ten days after the induction of limb ischemia (day 0), saline (group A, n = 7) or the 165-amino acid isoform of recombinant human VEGF (group B: 200 micrograms, n = 6; group C: 500 micrograms, n = 7; group D: 1000 micrograms, n = 4) was administered intramuscularly into the ischemic limb daily for 10 days. Angiography on day 30 after initiation of therapy revealed statistically significant dose-dependent augmentation of collateral vessels in the ischemic limb (angiographic score: group A, 13.0 +/- 1.1; group B, 21.2 +/- 1.8; group C, 27.3 +/- 1.4; group D, 31.5 +/- 2.5). Capillary density in the thigh muscles on day 30 was 1.6 times greater in VEGF groups versus controls (176 +/- 15.3 versus 113 +/- 27.3 per square millimeter, P < .05). Amelioration of the hemodynamic deficit in the ischemic limb was documented by calf systolic blood pressure ratio (group A, 0.52 +/- 0.02; group B, 0.67 +/- 0.02; group C, 0.73 +/- 0.01; group D, 0.82 +/- 0.03). "Clinical" improvement (incidence of calf muscle atrophy and distal limb necrosis: group A, 85.7%; group B, 33.3%; group C, 14.3%; group D, 0%) was greater in VEGF-treated than in control animals, again in a dose-dependent fashion. CONCLUSIONS These findings demonstrate a significant dose-dependent augmentation in limb perfusion accompanied by evidence of increased collateral formation after intramuscular administration of VEGF in ischemic rabbit hindlimbs. This study thus supports the hypothesis that administration of VEGF to stimulate angiogenesis may represent a new therapeutic modality in the management of arterial insufficiency.