血管肽，一种血管生成素-1 模拟物，可减少心肺转流期间大鼠肺血管渗漏并维持微循环灌注。

Vasculotide, an angiopoietin-1 mimetic, reduces pulmonary vascular leakage and preserves microcirculatory perfusion during cardiopulmonary bypass in rats.

机构信息

Department of Anaesthesiology, Experimental Laboratory for Vital Signs, Amsterdam Cardiovascular Sciences, VU University Medical Center, Amsterdam, The Netherlands; Department of Cardiothoracic Surgery and Amsterdam Cardiovascular Sciences, VU University Medical Center, Amsterdam, The Netherlands; Department of Physiology, Amsterdam Cardiovascular Sciences, VU University Medical Center, Amsterdam, The Netherlands.

Department of Pathology and Medical Biology, University Medical Center Groningen, Groningen, The Netherlands; Department of Critical Care Medicine, University Medical Center Groningen, Groningen, The Netherlands.

出版信息

Br J Anaesth. 2018 Nov;121(5):1041-1051. doi: 10.1016/j.bja.2018.05.049. Epub 2018 Jun 19.

DOI:10.1016/j.bja.2018.05.049

PMID:30336848

Abstract

BACKGROUND

Cardiopulmonary bypass (CPB) during cardiac surgery impairs microcirculatory perfusion and is paralleled by vascular leakage. The endothelial angiopoietin/Tie2 system controls microvascular leakage. This study investigated whether targeting Tie2 with the angiopoietin-1 mimetic vasculotide reduces vascular leakage and preserves microcirculatory perfusion in a rat CPB model.

METHODS

Rats were subjected to 75 min of CPB after treatment with vasculotide or phosphate buffered solution as control or underwent a sham procedure. Microcirculatory perfusion and leakage were assessed with intravital microscopy (n=10 per group) and Evans blue dye extravasation (n=13 per group), respectively. Angiopoietin-1, -2, and Tie2 protein and gene expression were determined in plasma, kidney, and lung.

RESULTS

CPB immediately impaired microcirculatory perfusion [5 (4-8) vs 10 (7-12) vessels per recording, P=0.002] in untreated CPB rats compared with sham, which persisted after weaning from CPB. CPB increased circulating angiopoeietin-1, -2, and soluble Tie2 concentrations and reduced Tie2 messenger ribonucleic acid (mRNA) expression in kidney and lung. Moreover, CPB increased Evans blue dye leakage in kidney [12 (8-25) vs 7 (1-12) μg g, P=0.04] and lung [and 23 (13-60) vs 6 (4-16) μg g, P=0.001] compared with sham. Vasculotide treatment preserved microcirculatory perfusion during and after CPB. Moreover, vasculotide treatment reduced Evans blue dye extravasation in lung compared with CPB control [18 (6-28) μg gvs 23 (13-60) μg g, P=0.04], but not in kidney [10 (3-23) vs 12 (8-25) μg g, P=0.38]. Vasculotide did not affect circulating or mRNA expression of angiopoietin-1, -2, and Tie2 concentrations compared with untreated CPB controls.

CONCLUSIONS

Treatment with the angiopoietin-1 mimetic vasculotide reduced pulmonary vascular leakage and preserved microcirculatory perfusion during CPB in a rat model.

摘要

背景

心脏手术中的体外循环（CPB）会损害微循环灌注，并伴有血管渗漏。内皮细胞血管生成素/Tie2 系统控制着微血管渗漏。本研究旨在探讨靶向 Tie2 的血管生成素-1 模拟肽 vasculotide 是否可以减少血管渗漏并维持 CPB 大鼠模型中的微循环灌注。

方法

大鼠接受 75 分钟 CPB 后，用 vasculotide 或磷酸盐缓冲液（对照）治疗，或行假手术。用活体显微镜（每组 10 只）和 Evans 蓝染料渗出（每组 13 只）分别评估微循环灌注和渗漏。测定血浆、肾脏和肺中血管生成素-1、-2 和 Tie2 蛋白和基因表达。

结果

与假手术相比，未经处理的 CPB 大鼠 CPB 后立即出现微循环灌注受损[5（4-8）比 10（7-12）个血管/记录，P=0.002]，CPB 后从 CPB 中恢复后仍持续存在。CPB 增加了循环血管生成素-1、-2 和可溶性 Tie2 浓度，并降低了肾脏和肺中的 Tie2 信使核糖核酸（mRNA）表达。此外，CPB 增加了肾脏[12（8-25）比 7（1-12）μg/g，P=0.04]和肺[23（13-60）比 6（4-16）μg/g，P=0.001]中的 Evans 蓝染料渗漏。Vasculotide 治疗在 CPB 期间和之后维持了微循环灌注。此外，与 CPB 对照组相比，Vasculotide 治疗降低了肺中的 Evans 蓝染料外渗[18（6-28）μg/g 比 23（13-60）μg/g，P=0.04]，但对肾脏无影响[10（3-23）比 12（8-25）μg/g，P=0.38]。与未处理的 CPB 对照组相比，Vasculotide 治疗并未影响循环或 mRNA 表达的血管生成素-1、-2 和 Tie2 浓度。