Mending Leaky Blood Vessels: The Angiopoietin-Tie2 Pathway in Sepsis

Sepsis is a systemic inflammatory response to infection. A common end-feature, these patients regularly suffer from is the so-called multiple organ dysfunction syndrome, an often fatal consequence of organ hypoperfusion, coagulopathy, immune dysregulation, and mitochondrial dysfunction. Microvascular dysfunction critically contributes to the morbidity and mortality of this disease. The angiopoietin (Angpt)/Tie2 system consists of the transmembrane endothelial tyrosine kinase Tie2 and its circulating ligands (Angpt-1, -2, and -3/4). The balance between the canonical agonist Angpt-1 and its competitive inhibitor, Angpt-2, regulates basal endothelial barrier function and the leakage and vascular inflammation that develop in response to pathogens and cytokines. Here we summarize recent work in mice and men to highlight the therapeutic potential in this pathway to prevent or even reverse microvascular dysfunction in this deadly disease.

[1]  M. van Meurs,et al.  Pleiotropic effects of angiopoietin-2 deficiency do not protect mice against endotoxin-induced acute kidney injury. , 2013, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[2]  R. Homer,et al.  Increased hyperoxia-induced lung injury in nitric oxide synthase 2 null mice is mediated via angiopoietin 2. , 2012, American journal of respiratory cell and molecular biology.

[3]  N. Shapiro,et al.  Angiopoietin-2 may contribute to multiple organ dysfunction and death in sepsis* , 2012, Critical care medicine.

[4]  M. Bauer,et al.  Angiopoietin-2 Enhances Survival in Experimental Sepsis Induced by Multidrug-Resistant Pseudomonas aeruginosa , 2012, Journal of Pharmacology and Experimental Therapeutics.

[5]  U. Knaus,et al.  Impaired function of the Tie-2 receptor contributes to vascular leakage and lethality in anthrax , 2012, Proceedings of the National Academy of Sciences.

[6]  M. Felcht,et al.  Angiopoietin-2 differentially regulates angiogenesis through TIE2 and integrin signaling. , 2012, The Journal of clinical investigation.

[7]  Andrew Rhodes,et al.  Drotrecogin alfa (activated) in adults with septic shock. , 2012, The New England journal of medicine.

[8]  H. Pavenstädt,et al.  The synthetic Tie2 agonist peptide vasculotide protects against vascular leakage and reduces mortality in murine abdominal sepsis , 2011, Critical care.

[9]  M. Bhasin,et al.  PGC-1α promotes recovery after acute kidney injury during systemic inflammation in mice. , 2011, The Journal of clinical investigation.

[10]  J. Zijlstra,et al.  Acute administration of recombinant Angiopoietin-1 ameliorates multiple-organ dysfunction syndrome and improves survival in murine sepsis. , 2011, Cytokine.

[11]  D. Dumont,et al.  Effects of a synthetic PEG-ylated Tie-2 agonist peptide on endotoxemic lung injury and mortality. , 2011, American journal of physiology. Lung cellular and molecular physiology.

[12]  D. McDonald,et al.  Angiopoietin-2-driven vascular remodeling in airway inflammation. , 2010, The American journal of pathology.

[13]  王林,et al.  Acute Respiratory Distress Syndrome Network , 2010 .

[14]  D. Fliser,et al.  Angiopoietin-2 in patients requiring renal replacement therapy in the ICU: relation to acute kidney injury, multiple organ dysfunction syndrome and outcome , 2010, Intensive Care Medicine.

[15]  K. Jang,et al.  COMP-angiopoietin-1 decreases lipopolysaccharide-induced acute kidney injury. , 2009, Kidney international.

[16]  B. Jeon,et al.  COMP-Ang1 ameliorates leukocyte adhesion and reinforces endothelial tight junctions during endotoxemia. , 2009, Biochemical and biophysical research communications.

[17]  S. Karumanchi,et al.  Angiopoietin 2 Is a Partial Agonist/Antagonist of Tie2 Signaling in the Endothelium , 2009, Molecular and Cellular Biology.

[18]  D. Fliser,et al.  Excess circulating angiopoietin-2 is a strong predictor of mortality in critically ill medical patients , 2008, Critical care.

[19]  H. Haller,et al.  Circulating angiopoietin-1 and angiopoietin-2 in critically ill patients: development and clinical application of two new immunoassays , 2008, Critical care.

[20]  David B Hoyt.  Faculty Opinions recommendation of Prevention of LPS-induced acute lung injury in mice by mesenchymal stem cells overexpressing angiopoietin 1. , 2008 .

[21]  D. Ingber,et al.  Angiopoietin-1 Requires p190 RhoGAP to Protect against Vascular Leakage in Vivo* , 2007, Journal of Biological Chemistry.

[22]  J. Sunderram,et al.  Rapid increase in hospitalization and mortality rates for severe sepsis in the United States: A trend analysis from 1993 to 2003* , 2007, Critical care medicine.

[23]  G. Yancopoulos,et al.  Angiopoietin-2 functions as an autocrine protective factor in stressed endothelial cells , 2006, Proceedings of the National Academy of Sciences.

[24]  H. Augustin,et al.  Angiopoietin-2 sensitizes endothelial cells to TNF-α and has a crucial role in the induction of inflammation , 2006, Nature Medicine.

[25]  D. Christiani,et al.  Excess Circulating Angiopoietin-2 May Contribute to Pulmonary Vascular Leak in Sepsis in Humans , 2006, PLoS medicine.

[26]  Z. Brookes,et al.  Angiopoietin-1 increases arteriolar vasoconstriction to phenylephrine during sepsis , 2005, Regulatory Peptides.

[27]  B. Witzenbichler,et al.  Protective Role of Angiopoietin-1 in Endotoxic Shock , 2005, Circulation.

[28]  R. Henkelman,et al.  Angiopoietin-1 causes reversible degradation of the portal microcirculation in mice: implications for treatment of liver disease. , 2004, The American journal of pathology.

[29]  R. Schrier,et al.  Acute renal failure and sepsis. , 2004, The New England journal of medicine.

[30]  Patrick England,et al.  A short synthetic peptide inhibits signal transduction, migration and angiogenesis mediated by Tie2 receptor , 2004, EMBO reports.

[31]  D. Mannino,et al.  The epidemiology of sepsis in the United States from 1979 through 2000. , 2003, The New England journal of medicine.

[32]  P. Campochiaro,et al.  Angiopoietin-2 is required for postnatal angiogenesis and lymphatic patterning, and only the latter role is rescued by Angiopoietin-1. , 2002, Developmental cell.

[33]  D. Annane,et al.  Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. , 2002, JAMA.

[34]  E. Ivers,et al.  Early Goal-Directed Therapy in the Treatment of Severe Sepsis and Septic Shock , 2001 .

[35]  G. V. Berghe,et al.  Intensive insulin therapy in critically ill patients. , 2001, The New England journal of medicine.

[36]  G. Bernard,et al.  Safety and dose relationship of recombinant human activated protein C for coagulopathy in severe sepsis , 2001, Critical care medicine.

[37]  D. Schoenfeld,et al.  Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. , 2000, The New England journal of medicine.

[38]  N. Glazer,et al.  Angiopoietin-1 protects the adult vasculature against plasma leakage , 2000, Nature Medicine.

[39]  Thomas N. Sato,et al.  Leakage-resistant blood vessels in mice transgenically overexpressing angiopoietin-1. , 1999, Science.

[40]  Thomas N. Sato,et al.  Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. , 1997, Science.

[41]  G. Zimmerman,et al.  The acute respiratory distress syndrome. , 1996, The Journal of clinical investigation.

[42]  B. Bistrian,et al.  Intensive insulin therapy in critically ill patients. , 2002, The New England journal of medicine.