Angiopoietin-2 is a potential mediator of endothelial barrier dysfunction following cardiopulmonary bypass
Open accessAbstract
Introduction Endothelial activation leading to vascular barrier dysfunction and organ failure is a well-recognized complication of cardiovascular surgery with cardiopulmonary bypass (CPB). The endothelial-specific angiopoietin-Tie2 ligand-receptor system has been identified as a non-redundant regulator of endothelial activation. Binding of angiopoietin-2 (Ang-2) to the Tie2 receptor antagonizes Tie2 signaling and renders the endothelial barrier responsive to pro-inflammatory cytokines. We aimed to study the time course and potential triggering factors of Ang-2 release after CPB, as well as the association of Ang-2 changes with surrogates of increased vascular permeability, organ dysfunction, and outcome.Methods Serum levels of Ang-2 from 25 adult patients (140 screened) were measured before and at 0, 12, and 24h following CPB procedure by in-house immuno-luminometric assay (ILMA), and compared with indices of organ dysfunction, duration of mechanical ventilation (MV), length of stay (LOS) in the intensive care unit (ICU), and hospital mortality. The effect of Ang-2 was studied in vitro by incubating high Ang-2 patient serum with endothelial cells (EC).Results Ang-2 levels steadily increased from 2.6 ± 2.4 ng/mL at 0 h up to 7.3 ± 4.6 ng/mL at 24h following CPB (P<0.001). The release of Ang-2 correlated with the duration of CPB, aortic cross-clamp time, and post-CPB lactate levels. Changes in Ang-2 during follow-up correlated with partial pressure of oxygen in arterial blood (PaO(2))/fraction of inspired oxygen (FiO(2)) ratio, alveolar-arterial oxygen tension difference (AaDO(2)), hemodynamics, fluid balance, and disease severity measures. Ang-2 levels at 12h predicted the duration of MV, ICU-LOS, and hospital mortality. High Ang-2 patient sera disrupted EC architecture in vitro, an effect reversed by treatment with the competitive Tie2 ligand angiopoietin-1 (Ang-1).Conclusions Collectively, our results suggest that Ang-2 is a putative mediator of endothelial barrier dysfunction after CPB. These findings suggest that targeting the Ang/Tie2 pathway may mitigate organ dysfunction and improve outcome in patients undergoing CPB.
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Cites
Vincent, J. L., Moreno, R., Takala, J., Willatts, S., De Mendonça, A., Bruining, H., Reinhart, C. K., Suter, P. M., & Thijs, L. G. (1996) · Intensive Care Medicine · doi:10.1007/bf01709751 · Cited by 11,674 · see citing works
Le Gall, J.-R. (1993) · JAMA: The Journal of the American Medical Association · doi:10.1001/jama.270.24.2957 · Cited by 7,773 · see citing works
Requisite Role of Angiopoietin-1, a Ligand for the TIE2 Receptor, during Embryonic Angiogenesis
Suri, C., Jones, P. F., Patan, S., Bartunkova, S., Maisonpierre, P. C., Davis, S. H., Sato, T. N., & Yancopoulos, G. D. (1996) · Cell · doi:10.1016/s0092-8674(00)81813-9 · Cited by 2,831 · see citing works
Isolation of Angiopoietin-1, a Ligand for the TIE2 Receptor, by Secretion-Trap Expression Cloning
Davis, S., Aldrich, T. H., Jones, P. F., Acheson, A., Compton, D. L., Jain, V., Ryan, T. E., Bruno, J., Radziejewski, C., Maisonpierre, P. C., et al. (1996) · Cell · doi:10.1016/s0092-8674(00)81812-7 · Cited by 1,989 · see citing works
Control of vascular morphogenesis and homeostasis through the angiopoietin–Tie system
Augustin, H. G., Koh, G. Y., Thurston, G., & Alitalo, K. K. (2009) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2639 · Cited by 1,460 · see citing works
Leakage-Resistant Blood Vessels in Mice Transgenically Overexpressing Angiopoietin-1
Thurston, G., Suri, C., Smith, K., McClain, J., Sato, T. T., Yancopoulos, G. D., & McDonald, D. M. (1999) · Science · doi:10.1126/science.286.5449.2511 · Cited by 1,350 · see citing works
The role of the endothelium in severe sepsis and multiple organ dysfunction syndrome
Aird, W. C. (2003) · Blood · doi:10.1182/blood-2002-06-1887 · Cited by 1,133 · see citing works
Acute Kidney Injury Is Associated With Increased Long-Term Mortality After Cardiothoracic Surgery
Hobson, C., Yavas, S., Segal, M. S., Schold, J. D., Tribble, C. G., Layon, A. J., & Bihorac, A. (2009) · Circulation · doi:10.1161/circulationaha.108.800011 · Cited by 1,015 · see citing works
Fiedler, U., Reiss, Y., Scharpfenecker, M., Grunow, V., Koidl, S., Thurston, G., Gale, N. W., Witzenrath, M., Rosseau, S., Suttorp, N., et al. (2006) · Nature Medicine · doi:10.1038/nm1351 · Cited by 933 · see citing works
Inflammatory Response to Cardiopulmonary Bypass
Wan, S., LeClerc, J.-L., & Vincent, J. (1997) · CHEST Journal · doi:10.1378/chest.112.3.676 · Cited by 893 · see citing works
Fiedler, U., Scharpfenecker, M., Koidl, S., Hegen, A., Grunow, V., Schmidt, J. M., Kriz, W., Thurston, G., & Augustin, H. G. (2004) · Blood · doi:10.1182/blood-2003-10-3685 · Cited by 742 · see citing works
Pulmonary Dysfunction After Cardiac Surgery
Ng, C. S. H., Wan, S., Yim, A. P. C., et al. (2002) · CHEST Journal · doi:10.1378/chest.121.4.1269 · Cited by 630 · see citing works
Excess Circulating Angiopoietin-2 May Contribute to Pulmonary Vascular Leak in Sepsis in Humans
Parikh, S. M., Mammoto, T., Schultz, A., Yuan, H.-T., Christiani, D., Karumanchi, S. A., & Sukhatme, V. P. (2006) · PLoS Medicine · doi:10.1371/journal.pmed.0030046 · Cited by 527 · see citing works
Self-citationSignaling and Functions of Angiopoietin-1 in Vascular Protection
Brindle, N. P. J., Saharinen, P., & Alitalo, K. K. (2006) · Circulation Research · doi:10.1161/01.res.0000218275.54089.12 · Cited by 485 · see citing works
Suppression of angiogenesis and tumor growth by selective inhibition of angiopoietin-2
Oliner, J. D., Min, H., Leal, J., Yu, D., Rao, S., You, E., Xiu, T., Kim, H. J., MEYER, S. R., Han, S. J., et al. (2004) · Cancer Cell · doi:10.1016/j.ccr.2004.09.030 · Cited by 471 · see citing works
Lung injury and acute respiratory distress syndrome after cardiopulmonary bypass
Asimakopoulos, G., Smith, P., Ratnatunga, C., & Taylor, K. M. (1999) · The Annals of Thoracic Surgery · doi:10.1016/s0003-4975(99)00781-x · Cited by 418 · see citing works
Tie2 Expression and Phosphorylation in Angiogenic and Quiescent Adult Tissues
Wong, A. L., Haroon, Z. A., Werner, S., Dewhirst, M. W., Greenberg, C. S., & Peters, K. G. (1997) · Circulation Research · doi:10.1161/01.res.81.4.567 · Cited by 417 · see citing works
Scharpfenecker, M., Fiedler, U., Reiss, Y., & Augustin, H. G. (2005) · Journal of Cell Science · doi:10.1242/jcs.01653 · Cited by 382 · see citing works
Endothelial Cell Injury in Cardiovascular Surgery: The Systemic Inflammatory Response
Boyle, E. M., Pohlman, T. H., Johnson, M., & Verrier, E. D. (1997) · The Annals of Thoracic Surgery · doi:10.1016/s0003-4975(96)01061-2 · Cited by 285 · see citing works
Endothelium as an organ system
Aird, W. C. (2004) · Critical Care Medicine · doi:10.1097/01.ccm.0000129669.21649.40 · Cited by 260 · see citing works
Angiopoietin-2 Causes Inflammation in Vivo by Promoting Vascular Leakage
Roviezzo, F., Tsigkos, S., Kotanidou, A. N., Bucci, M., Brancaleone, V., Cirino, G., & Papapetropoulos, A. (2005) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.105.086553 · Cited by 221 · see citing works
van der Heijden, M., Amerongen, G. P. V. N., Koolwijk, P., van Hinsbergh, V. W. M., & Groeneveld, A. B. J. (2008) · Thorax · doi:10.1136/thx.2007.087387 · Cited by 204 · see citing works
Protective Role of Angiopoietin-1 in Endotoxic Shock
Witzenbichler, B., Westermann, D., Knueppel, S., Schultheiss, H., & Tschöpe, C. (2004) · Circulation · doi:10.1161/01.cir.0000151287.08202.8e · Cited by 199 · see citing works
Fiedler, U., Krissl, T., Koidl, S., Weiss, C., Koblizek, T. I., Deutsch, U., Martiny‐Baron, G., Marmé, D., & Augustin, H. G. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m208550200 · Cited by 195 · see citing works
Angiopoietin-1 Requires p190 RhoGAP to Protect against Vascular Leakage in Vivo
Mammoto, T., Parikh, S. M., Mammoto, A., Gallagher, D. C., Chan, B., Mostoslavsky, G., Ingber, D. E., & Sukhatme, V. P. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m702169200 · Cited by 180 · see citing works
Self-citationKümpers, P., Lukasz, A. H., David, S., Horn, R., Hafer, C., Faulhaber‐Walter, R., Fliser, D., Haller, H. G., & Kielstein, J. T. (2008) · Critical Care · doi:10.1186/cc7130 · Cited by 162 · see citing works
Self-citationBench-to-bedside review: Angiopoietin signalling in critical illness – a future target?
van Meurs, M., Kümpers, P., Ligtenberg, J. J. M., Meertens, J. H. J. M., Molema, G., & Zijlstra, J. G. (2009) · Critical Care · doi:10.1186/cc7153 · Cited by 144 · see citing works
Self-citationKümpers, P., Gueler, F., David, S., Slyke, P. V., Dumont, D., Park, J.-K., Bockmeyer, C. L., Parikh, S. M., Pavenstädt, H. J., Haller, H. G., et al. (2011) · Critical Care · doi:10.1186/cc10523 · Cited by 141 · see citing works
Self-citationGallagher, D. C., Parikh, S. M., Balonov, K., Miller, A. C., Gautam, S., Talmor, D. S., & Sukhatme, V. P. (2008) · Shock · doi:10.1097/shk.0b013e31815dd92f · Cited by 133 · see citing works
Self-citationELEVATED SERUM ANGIOPOIETIN 2 LEVELS ARE ASSOCIATED WITH INCREASED MORTALITY IN SEPSIS
Siner, J. M., Bhandari, V., Engle, K. M., Elias, J. A., & Siegel, M. D. (2009) · Shock · doi:10.1097/shk.0b013e318188bd06 · Cited by 116 · see citing works
Time course of angiopoietin-2 release during experimental human endotoxemia and sepsis
Kümpers, P., van Meurs, M., David, S., Molema, G., Bijzet, J., Lukasz, A. H., Biertz, F., Haller, H. G., & Zijlstra, J. G. (2009) · Critical Care · doi:10.1186/cc7866 · Cited by 103 · see citing works
Self-citationThomas, M., Felcht, M., Kruse, K., Kretschmer, S., Deppermann, C., Biesdorf, A., Rohr, K., Benest, A. V., Fiedler, U., & Augustin, H. G. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.097543 · Cited by 101 · see citing works
Effects of a synthetic PEG-ylated Tie-2 agonist peptide on endotoxemic lung injury and mortality
David, S., Ghosh, C. C., Kümpers, P., Shushakova, N., Van Slyke, P., Khankin, E. V., Karumanchi, S. A., Dumont, D., & Parikh, S. M. (2011) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00459.2010 · Cited by 96 · see citing works
Self-citationDavid, S., Park, J.-K., van Meurs, M., Zijlstra, J. G., Koenecke, C., Schrimpf, C., Shushakova, N., Gueler, F., Haller, H. G., & Kümpers, P. (2011) · Cytokine · doi:10.1016/j.cyto.2011.04.005 · Cited by 95 · see citing works
Self-citationKümpers, P., Hafer, C., David, S., Hecker, H., Lukasz, A. H., Fliser, D., Haller, H. G., Kielstein, J. T., & Faulhaber‐Walter, R. (2009) · Intensive Care Medicine · doi:10.1007/s00134-009-1726-7 · Cited by 86 · see citing works
Self-citationLukasz, A. H., Hellpap, J., Horn, R., Kielstein, J. T., David, S., Haller, H. G., & Kümpers, P. (2008) · Critical Care · doi:10.1186/cc6966 · Cited by 85 · see citing works
Self-citationRegulation of angiopoietin expression by bacterial lipopolysaccharide
Mofarrahi, M., Nouh, T., Qureshi, S., Guillot, L., Mayaki, D., & Hussain, S. N. A. (2008) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00449.2007 · Cited by 60 · see citing works
Huang, Y. Q., Sauthoff, H., Herscovici, P., Pipiya, T., Cheng, J., Heitner, S., Szentirmai, O., Carter, B. S., & Hay, J. G. (2008) · Critical Care Medicine · doi:10.1097/01.ccm.0000297955.02633.a4 · Cited by 51 · see citing works
Keikkala, E., Wathén, K.-A., Alfthan, H. V., Ylikorkala, O., ANDERSSON, S. M., Stenman, U., & Vuorela, P. (2009) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2009-0715 · Cited by 50 · see citing works
Kümpers, P., Koenecke, C., Hecker, H., et al. (2008) · Blood · doi:10.1182/blood-2007-12-130021 · Cited by 44 · see citing works
Self-citationKinetics of Angiopoietin-2 in serum of multi-trauma patients: Correlation with patient severity
Giamarellos‐Bourboulis, E. J., Kanellakopoulou, K., Πελεκάνου, Α., Τσαγανός, Θ., & Kotzampassi, K. E. (2008) · Cytokine · doi:10.1016/j.cyto.2008.09.003 · Cited by 37 · see citing works
Plasma angiopoietin-2 levels increase in children following cardiopulmonary bypass
Giuliano, J. S., Lahni, P. M., Bigham, M. T., Manning, P. B., Nelson, D. P., Wong, H. R., & Wheeler, D. S. (2008) · Intensive Care Medicine · doi:10.1007/s00134-008-1174-9 · Cited by 35 · see citing works
Brudney, C. S., Gosling, P. J., & Manji, M. (2005) · Journal of Cardiothoracic and Vascular Anesthesia · doi:10.1053/j.jvca.2005.01.029 · Cited by 31 · see citing works
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- [35]Mammoto T Parikh SM Mammoto A Gallagher D Chan B Mostoslavsky G Angiopoietin-1 requires p190 RhoGAP to protect against vascular leakage in vivo J Biol Chem 2007 282 23910 23918 17562701
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- Authors
- Clajus, C., Lukasz, A., David, S., Hertel, B., Lichtinghagen, R., Parikh, S. M., Simon, A., Ismail, I., Haller, H., & Kümpers, P.
- Affiliations
- Medizinische Hochschule Hannover (DE)
- Beth Israel Deaconess Medical Center (US)
- University Hospital Münster (DE)
- Corresponding author
- Kümpers, Philipp
- Venue
- Cytokine
- Publisher
- Elsevier BV
- Published
- 2012-11
- Volume
- 60
- Issue
- 2
- Pages
- 352-359
- ISSN
- 1043-4666 (ISSN-L)
- PMC
- PMC4127984
- OpenAlex
- W2058504973
- Cited by
- 44
- References
- 43
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 1 · 2023: 14 · 2021: 4 · 2020: 3 · 2019: 2 · 2018: 6 · 2017: 1 · 2016: 3 · 2015: 2 · 2014: 5
- FWCI
- 2.29
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cytokine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01HL093234)
- Topics
- Health Sciences › Medicine › Surgery › Cardiac and Coronary Surgery Techniques
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Keywords
- angiopoietin-2, cardiopulmonary bypass, endothelial barrier dysfunction, Tie2 receptor, angiopoietin-1, vascular permeability, organ dysfunction, postoperative mortality, mechanical ventilation duration, endothelial activation, cardiac surgery complications
- MeSH terms
- Adult, Aged, Hypoxia, Capillaries, Cardiopulmonary Bypass, Endothelium, Female, Fluorescent Antibody Technique, Humans, Male, Respiration, Artificial, Treatment Outcome, Microscopy, Confocal, Angiopoietin-2, Endothelial Cells, Kaplan-Meier Estimate
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