N A M Dekker1, M van Meurs2, A L I van Leeuwen1, H M Hofland3, P van Slyke4, A B A Vonk5, C Boer6, C E van den Brom7. 1. 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. 2. 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. 3. Department of Anaesthesiology, Experimental Laboratory for Vital Signs, Amsterdam Cardiovascular Sciences, VU University Medical Center, Amsterdam, The Netherlands; Department of Physiology, Amsterdam Cardiovascular Sciences, VU University Medical Center, Amsterdam, The Netherlands. 4. Vasomune Therapeutics, Toronto, ON, Canada. 5. Department of Cardiothoracic Surgery and Amsterdam Cardiovascular Sciences, VU University Medical Center, Amsterdam, The Netherlands. 6. Department of Anaesthesiology, Experimental Laboratory for Vital Signs, Amsterdam Cardiovascular Sciences, VU University Medical Center, Amsterdam, The Netherlands. 7. Department of Anaesthesiology, Experimental Laboratory for Vital Signs, Amsterdam Cardiovascular Sciences, VU University Medical Center, Amsterdam, The Netherlands; Department of Physiology, Amsterdam Cardiovascular Sciences, VU University Medical Center, Amsterdam, The Netherlands. Electronic address: c.vandenbrom@vumc.nl.
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-1, P=0.04] and lung [and 23 (13-60) vs 6 (4-16) μg g-1, 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 g-1vs 23 (13-60) μg g-1, P=0.04], but not in kidney [10 (3-23) vs 12 (8-25) μg g-1, 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.
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-1, P=0.04] and lung [and 23 (13-60) vs 6 (4-16) μg g-1, 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 g-1vs 23 (13-60) μg g-1, P=0.04], but not in kidney [10 (3-23) vs 12 (8-25) μg g-1, 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.
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