全身给予血管内皮生长因子后的位点特异性治疗性血管生成

Site-specific therapeutic angiogenesis after systemic administration of vascular endothelial growth factor.

作者信息

Bauters C, Asahara T, Zheng L P, Takeshita S, Bunting S, Ferrara N, Symes J F, Isner J M

机构信息

Department of Medicine (Cardiology), St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston.

出版信息

J Vasc Surg. 1995 Feb;21(2):314-24; discussion 324-5. doi: 10.1016/s0741-5214(95)70272-5.

DOI:10.1016/s0741-5214(95)70272-5

PMID:7531786

Abstract

PURPOSE

Recent experimental studies have established the feasibility of therapeutic angiogenesis; in all cases, this has been achieved with local administration of angiogenic growth factors. This study was designed to investigate the hypothesis that systemic administration of an angiogenic growth factor specifically mitogenic for endothelial cells--vascular endothelial growth factor (VEGF)--could augment collateral vessel development in a rabbit ischemic hindlimb model.

METHODS

Ten days after the ligation of the external iliac artery and excision of the common and superficial femoral arteries in one limb of New Zealand white rabbits, heparin (800 IU, n = 13), VEGF (1 mg, n = 3; 5 mg, n = 5), heparin (800 IU) + VEGF (1 mg, n = 5; 5 mg, n = 7), or saline solution (n = 8) was injected as a single bolus in a marginal ear vein. Collateral vessel formation and limb perfusion were assessed 10 and 30 days after treatment.

RESULTS

Animals in both VEGF-treated groups had a significantly higher (p < 0.01) increase in calf blood pressure ratio at day 10 (control, 0.44 +/- 0.02; heparin, 0.47 +/- 0.02; VEGF, 0.60 +/- 0.01; heparin+VEGF, 0.61 +/- 0.02) and day 30 (control, 0.49 +/- 0.05; heparin, 0.48 +/- 0.02; VEGF, 0.70 +/- 0.03; heparin+VEGF, 0.73 +/- 0.03). Both VEGF-treated groups had a significantly higher (p < 0.05) angiographic score at day 30 (control, 0.28 +/- 0.01; heparin, 0.28 +/- 0.01; VEGF, 0.37 +/- 0.01; heparin+VEGF, 0.38 +/- 0.02). Maximum flow reserve at day 30 in the ischemic limb was higher (p < 0.05) in VEGF-treated rabbits (control, 1.87 +/- 0.07; heparin, 1.92 +/- 0.08; VEGF, 2.42 +/- 0.16; heparin+VEGF, 2.33 +/- 0.12). Capillary density was higher (p < 0.01) in the ischemic muscles of VEGF-treated rabbits (control, 156 +/- 10/mm2; heparin, 178 +/- 8/mm2; VEGF, 230 +/- 10/mm2; heparin+VEGF, 233 +/- 8/mm2).

CONCLUSIONS

This series of in vivo experiments demonstrates that intravenous administration of VEGF, with or without heparin, results in both anatomic and physiologic evidence of enhanced collateral vessel formation in the rabbit ischemic hindlimb. Single-bolus systemic administration of VEGF may be a feasible therapeutic strategy in patients with lower-extremity ischemia.

摘要

目的

近期的实验研究证实了治疗性血管生成的可行性；在所有情况下，这都是通过局部给予血管生成生长因子实现的。本研究旨在探讨以下假说：全身给予对内皮细胞具有特异性促有丝分裂作用的血管生成生长因子——血管内皮生长因子（VEGF）——可促进兔缺血后肢模型中的侧支血管发育。

方法

在新西兰白兔一侧肢体的髂外动脉结扎及股总动脉和股浅动脉切除10天后，将肝素（800国际单位，n = 13）、VEGF（1毫克，n = 3；5毫克，n = 5）、肝素（800国际单位）+VEGF（1毫克，n = 5；5毫克，n = 7）或生理盐水（n = 8）作为单次推注注入耳缘静脉。在治疗后10天和30天评估侧支血管形成和肢体灌注情况。

结果

两个VEGF治疗组的动物在第10天（对照组，0.44±0.02；肝素组，0.47±0.02；VEGF组，0.60±0.01；肝素+VEGF组，0.61±0.02）和第30天（对照组，0.49±0.05；肝素组，0.48±0.02；VEGF组，0.70±0.03；肝素+VEGF组，0.73±0.03）的小腿血压比值升高均显著更高（p < 0.01）。两个VEGF治疗组在第30天的血管造影评分均显著更高（p < 0.05）（对照组，0.28±0.01；肝素组，0.28±0.01；VEGF组，0.37±0.01；肝素+VEGF组，0.38±0.02）。VEGF治疗的兔缺血肢体在第30天的最大血流储备更高（p < 0.05）（对照组，1.87±0.07；肝素组，1.92±0.08；VEGF组，2.42±0.16；肝素+VEGF组，2.33±0.12）。VEGF治疗的兔缺血肌肉中的毛细血管密度更高（p < 0.01）（对照组，156±10/mm²；肝素组，178±8/mm²；VEGF组，230±10/mm²；肝素+VEGF组，233±8/mm²）。