基因传递对慢性灌注不足时侧支循环发育的影响：血管生成素-1与血管内皮生长因子的不同作用

Effects of gene delivery on collateral development in chronic hypoperfusion: diverse effects of angiopoietin-1 versus vascular endothelial growth factor.

作者信息

Zhou Yi Fu, Stabile Eugenio, Walker Jill, Shou Matie, Baffour Richard, Yu Zuxi, Rott David, Yancopoulos George D, Rudge John S, Epstein Stephen E

机构信息

Vascular Biology Laboratory, Cardiovascular Research Institute, MedStar Research Institute, Washington Hospital Center, Washington, DC 20010, USA.

出版信息

J Am Coll Cardiol. 2004 Aug 18;44(4):897-903. doi: 10.1016/j.jacc.2004.05.046.

DOI:10.1016/j.jacc.2004.05.046

PMID:15312878

Abstract

OBJECTIVES

The aim of this research was to test the effects of vascular endothelial growth factor (VEGF)/angiopoietin-1 (Ang-1) on adult hypoperfused tissues.

BACKGROUND

Angiopoietin-1 and VEGF act separately and synergistically in vascular development during embryogenesis. However, little is known regarding their relative roles in collateral development after chronic arterial obstruction and tissue ischemia in the adult.

METHODS

Central and caudal ear arteries of 32 rabbits were ligated to induce ischemia. At two months, when flow was about 65% of pre-ligation values, we injected intradermally 10(9) plaque-forming unit adenovirus with the following transgenes: Ang-1, VEGF, or a combination of both. Ear perfusion was followed up for four weeks, and vessel leakage was assessed by Evens Blue test.

RESULTS

Before injection, flow was 65% of baseline, and endogenous VEGF levels in ischemic tissue were increased. Adenovirus-encoding VEGF gene (Ad.VEGF) at one week caused a visible inflammatory response associated with a 24% flow increase (p = 0.018). Adenovirus-encoding Ang-1 gene (Ad.Ang-1) increased flow 22% (p = 0.004) with no visible inflammation; Ad.VEGF caused three times as much vessel leakage as Ad.Ang-1 (142.5 +/- 38 vs. 49.5 +/- 9.8 ng Evens Blue/mg tissue; p < 0.001). However, at four weeks, compared with baseline, VEGF decreased flow 18% (p = 0.004), whereas Ang-1 increased tissue perfusion 26% (p < 0.001). This effect was abolished when Ad.Ang-1 was injected with soluble VEGF receptor [Ad.Flt(1-3)-Fc], which blocks VEGF-dependent signaling. Exogenous Ang-1 did not increase perfusion in a normally perfused ear, in which endogenous VEGF is not expressed.

CONCLUSIONS

Exogenous Ang-1 enhances perfusion in hypoperfused tissues only in the presence of increased levels of endogenous VEGF. Overexpression of VEGF, however, after causing an inflammatory response, does not improve collateral blood flow.

摘要

目的

本研究旨在测试血管内皮生长因子（VEGF）/血管生成素-1（Ang-1）对成年低灌注组织的影响。

背景

血管生成素-1和VEGF在胚胎发育过程中的血管生成中分别发挥作用且具有协同作用。然而，关于它们在成年慢性动脉阻塞和组织缺血后侧支循环发育中的相对作用，人们了解甚少。

方法

结扎32只兔子的中耳动脉和尾耳动脉以诱导缺血。两个月后，当血流量约为结扎前值的65%时，我们皮内注射10⁹个噬斑形成单位携带以下转基因的腺病毒：Ang-1、VEGF或两者的组合。对耳部灌注进行四周的随访，并通过伊文思蓝试验评估血管渗漏情况。

结果

注射前，血流量为基线的65%，缺血组织中的内源性VEGF水平升高。编码VEGF基因的腺病毒（Ad.VEGF）在一周时引起明显的炎症反应，血流量增加24%（p = 0.018）。编码Ang-1基因的腺病毒（Ad.Ang-1）使血流量增加22%（p = 0.004），且无明显炎症；Ad.VEGF引起的血管渗漏是Ad.Ang-1的三倍（伊文思蓝142.5±38对49.5±9.8 ng/毫克组织；p < 0.001）。然而，在四周时，与基线相比，VEGF使血流量降低18%（p = 0.004），而Ang-1使组织灌注增加26%（p < 0.001）。当Ad.Ang-1与可溶性VEGF受体[Ad.Flt(1 - 3)-Fc]一起注射时，这种作用被消除，可溶性VEGF受体可阻断VEGF依赖的信号传导。外源性Ang-1在正常灌注的耳部（其中不表达内源性VEGF）中不会增加灌注。