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

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

  • Br J Anaesth. 2018 Nov;121(5):1041-1051. doi: 10.1016/j.bja.2018.05.049.
N A M Dekker 1,  M van Meurs 2,  A L I van Leeuwen 1,  H M Hofland 3,  P van Slyke 4,  A B A Vonk 5,  C Boer 6,  C E van den Brom 7
Affiliations

Affiliations

  • 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: [email protected].
PMID: 30336848 DOI: 10.1016/j.bja.2018.05.049
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.

Keywords

capillary permeability; cardiopulmonary bypass; microcirculation.

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