Angiopoietin 2 mediates microvascular and hemodynamic alterations in sepsis
Data(s) |
01/08/2013
|
---|---|
Resumo |
Septic shock is characterized by increased vascular permeability and hypotension despite increased cardiac output. Numerous vasoactive cytokines are upregulated during sepsis, including angiopoietin 2 (ANG2), which increases vascular permeability. Here we report that mice engineered to inducibly overexpress ANG2 in the endothelium developed sepsis-like hemodynamic alterations, including systemic hypotension, increased cardiac output, and dilatory cardiomyopathy. Conversely, mice with cardiomyocyte-restricted ANG2 overexpression failed to develop hemodynamic alterations. Interestingly, the hemodynamic alterations associated with endothelial-specific overexpression of ANG2 and the loss of capillary-associated pericytes were reversed by intravenous injections of adeno-associated viruses (AAVs) transducing cDNA for angiopoietin 1, a TIE2 ligand that antagonizes ANG2, or AAVs encoding PDGFB, a chemoattractant for pericytes. To confirm the role of ANG2 in sepsis, we i.p. injected LPS into C57BL/6J mice, which rapidly developed hypotension, acute pericyte loss, and increased vascular permeability. Importantly, ANG2 antibody treatment attenuated LPS-induced hemodynamic alterations and reduced the mortality rate at 36 hours from 95% to 61%. These data indicate that ANG2-mediated microvascular disintegration contributes to septic shock and that inhibition of the ANG2/TIE2 interaction during sepsis is a potential therapeutic target. |
Formato |
application/pdf |
Identificador |
http://boris.unibe.ch/49789/1/Ziegler_JCI66549.pdf Ziegler, Tilman; Horstkotte, Jan; Schwab, Claudia; Pfetsch, Vanessa; Weinmann, Karolina; Dietzel, Steffen; Rohwedder, Ina; Hinkel, Rabea; Gross, Lisa; Lee, Seungmin; Hu, Junhao; Soehnlein, Oliver; Franz, Wolfgang M.; Sperandio, Markus; Pohl, Ulrich; Thomas, Markus; Weber, Christian; Augustin, Hellmut G.; Fässler, Reinhard; Deutsch, Urban; ... (2013). Angiopoietin 2 mediates microvascular and hemodynamic alterations in sepsis. Journal of clinical investigation, 123(8), pp. 3436-3445. American Society for Clinical Investigation 10.1172/JCI66549 <http://dx.doi.org/10.1172/JCI66549> doi:10.7892/boris.49789 info:doi:10.1172/JCI66549 info:pmid:23863629 urn:issn:0021-9738 |
Idioma(s) |
eng |
Publicador |
American Society for Clinical Investigation |
Relação |
http://boris.unibe.ch/49789/ |
Direitos |
info:eu-repo/semantics/openAccess |
Fonte |
Ziegler, Tilman; Horstkotte, Jan; Schwab, Claudia; Pfetsch, Vanessa; Weinmann, Karolina; Dietzel, Steffen; Rohwedder, Ina; Hinkel, Rabea; Gross, Lisa; Lee, Seungmin; Hu, Junhao; Soehnlein, Oliver; Franz, Wolfgang M.; Sperandio, Markus; Pohl, Ulrich; Thomas, Markus; Weber, Christian; Augustin, Hellmut G.; Fässler, Reinhard; Deutsch, Urban; ... (2013). Angiopoietin 2 mediates microvascular and hemodynamic alterations in sepsis. Journal of clinical investigation, 123(8), pp. 3436-3445. American Society for Clinical Investigation 10.1172/JCI66549 <http://dx.doi.org/10.1172/JCI66549> |
Palavras-Chave | #610 Medicine & health |
Tipo |
info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion PeerReviewed |