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

Background: Cardiopulmonary bypass (CPB) during cardiac surgery impairs microcirculatory perfusion and is paralleled by vascular leakage. The endothelial angiopoietin/Tie(2) system controls microvascular leakage. This study investigated whether targeting Tie(2) 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 Tie(2) 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 Tie(2) 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) mu g g(-1), P = 0.04] and lung [and 23 (13-60) vs 6 (4-16) mu g 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) mu g g(-1) vs 23 (13-60) mu g g(-1), P = 0.04], but not in kidney [10 (3-23) vs 12 (8-25) mu g g(-1), P = 0.38]. Vasculotide did not affect circulating or mRNA expression of angiopoietin-1, -2, and Tie(2) 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.