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腺病毒介导的血管内皮生长因子基因转移所诱导的挽救性血管生成可预防缺血性血管闭塞。

Salvage angiogenesis induced by adenovirus-mediated gene transfer of vascular endothelial growth factor protects against ischemic vascular occlusion.

作者信息

Mack C A, Magovern C J, Budenbender K T, Patel S R, Schwarz E A, Zanzonico P, Ferris B, Sanborn T, Isom P, Ferris B, Sanborn T, Isom O W, Crystal R G, Rosengart T K

机构信息

Department of Cardiothoracic Surgery, The New York Hospital-Cornell Medical Center, NY 10021, USA.

出版信息

J Vasc Surg. 1998 Apr;27(4):699-709. doi: 10.1016/s0741-5214(98)70236-8.

Abstract

PURPOSE

Vascular endothelial growth factor (VEGF) is a potent stimulator of angiogenesis, and transgene expression from adenovirus vectors can provide in vivo delivery of proteins. On the basis of this knowledge, we hypothesized that local administration of a replication-deficient adenovirus vector expressing complementary DNA for VEGF (AdVEGF) would induce collateral vessel formation in the setting of ischemia that could protect against subsequent acute vascular occlusion.

METHODS

Hindlimb ischemia was induced in Sprague-Dawley rats by means of unilateral ligation of the common iliac artery immediately followed by administration of 4 x 10(9)-plaque-forming units VEGF, the control vector AdNull, or phosphate-buffered saline solution into the iliofemoral adipose tissue and thigh muscles. Untreated rats with common iliac ligation were used as an additional control group.

RESULTS

Local VEGF expression was observed for 5 days in AdVEGF-treated rats but not in controls. Three weeks after ligation and vector administration, the ipsilateral femoral artery was ligated for a model of an acute vascular occlusion in the setting of preexisting ischemia. Blood flow to the ischemic hindlimb relative to the contralateral hindlimb evaluated with color microspheres demonstrated significantly increased blood flow in the AdVEGF-treated rats compared with each control group (p < 0.0001). Relative blood flow assessed by means of 99mTc-sestamibi radionuclide scans also demonstrated increased blood flow to the ligated hindlimb of AdVEGF-treated rats compared with each control group (p < 0.002). AdVEGF-treated rats also demonstrated increased vascularity in the ligated limb compared with each control group as assessed by means of angiography (p < 0.0001) and histologic quantification of blood vessels less than 80 microm diameter in local adipose tissue and capillaries per muscle fiber (p < 0.0002). AdVEGF treatment prevented a rise in femoral venous lactate femoral venous concentrations 1 hour after femoral artery ligation in control rats (p < 0.04).

CONCLUSIONS

An adenovirus vector expressing VEGF complementary DNA is capable of stimulating an angiogenic response that protects against acute vascular occlusion in the setting of preexisting ischemia, suggesting that in vivo gene transfer of VEGF complementary DNA might be useful in prophylaxis of advancing arterial occlusive disease.

摘要

目的

血管内皮生长因子(VEGF)是一种强大的血管生成刺激因子,腺病毒载体的转基因表达可实现蛋白质的体内递送。基于这一认识,我们推测局部给予表达VEGF互补DNA的复制缺陷型腺病毒载体(AdVEGF)会在缺血情况下诱导侧支血管形成,从而预防随后的急性血管闭塞。

方法

通过单侧结扎髂总动脉诱导Sprague-Dawley大鼠后肢缺血,随后立即将4×10⁹空斑形成单位的VEGF、对照载体AdNull或磷酸盐缓冲盐溶液注入髂股脂肪组织和大腿肌肉。未治疗的髂总动脉结扎大鼠用作额外的对照组。

结果

在AdVEGF治疗的大鼠中观察到局部VEGF表达持续5天,而对照组未观察到。结扎和给予载体3周后,对同侧股动脉进行结扎,以建立先前存在缺血情况下的急性血管闭塞模型。用彩色微球评估缺血后肢相对于对侧后肢的血流,结果显示与各对照组相比,AdVEGF治疗的大鼠血流显著增加(p<0.0001)。通过99mTc-甲氧基异丁基异腈放射性核素扫描评估的相对血流也显示,与各对照组相比,AdVEGF治疗的大鼠结扎后肢的血流增加(p<0.002)。通过血管造影评估(p<0.0001)以及对局部脂肪组织中直径小于80μm的血管和每根肌纤维中的毛细血管进行组织学定量分析(p<0.0002),结果显示与各对照组相比,AdVEGF治疗的大鼠结扎肢体的血管增多。AdVEGF治疗可防止对照大鼠股动脉结扎1小时后股静脉乳酸浓度升高(p<0.04)。

结论

表达VEGF互补DNA的腺病毒载体能够刺激血管生成反应,在先前存在缺血的情况下预防急性血管闭塞,这表明VEGF互补DNA的体内基因转移可能对预防进展性动脉闭塞性疾病有用。

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