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.
Br J Anaesth. 2018 Nov;121(5):1041-1051. doi: 10.1016/j.bja.2018.05.049. Epub 2018 Jun 19.
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.
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.
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.
Treatment with the angiopoietin-1 mimetic vasculotide reduced pulmonary vascular leakage and preserved microcirculatory perfusion during CPB in a rat model.
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。
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。
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。
在 CPB 大鼠模型中，血管生成素-1 模拟肽 vasculotide 的治疗可减少肺血管渗漏并维持微循环灌注。
