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  Angiopoietin 2 mediates microvascular and hemodynamic alterations in sepsis

Ziegler, T., Horstkotte, J., Schwab, C., Pfetsch, V., Weinmann, K., Dietzel, S., et al. (2013). Angiopoietin 2 mediates microvascular and hemodynamic alterations in sepsis. JOURNAL OF CLINICAL INVESTIGATION, 123(8), 3436-3445. doi:10.1172/JCI66549.

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 Creators:
Ziegler, Tilman1, Author
Horstkotte, Jan1, Author
Schwab, Claudia1, Author
Pfetsch, Vanessa1, Author
Weinmann, Karolina1, Author
Dietzel, Steffen1, Author
Rohwedder, Ina2, Author              
Hinkel, Rabea1, Author
Gross, Lisa1, Author
Lee, Seungmin1, Author
Hu, Junhao1, Author
Soehnlein, Oliver1, Author
Franz, Wolfgang M.1, Author
Sperandio, Markus1, Author
Pohl, Ulrich1, Author
Thomas, Markus1, Author
Weber, Christian1, Author
Augustin, Hellmut G.1, Author
Fässler, Reinhard2, Author              
Deutsch, Urban1, Author
Kupatt, Christian1, Author more..
Affiliations:
1external, ou_persistent22              
2Fässler, Reinhard / Molecular Medicine, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565147              

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Free keywords: ORGAN DYSFUNCTION SYNDROME; ENDOTHELIAL GROWTH-FACTOR; IN-VIVO; ANGIOGENESIS; CELLS; PERICYTES; TIE2; EXPRESSION; RECEPTOR; MICE
 Abstract: 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 carcliomyocyte-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.

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Language(s): eng - English
 Dates: 2013-08
 Publication Status: Published in print
 Pages: 10
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: ISI: 000322750500027
DOI: 10.1172/JCI66549
 Degree: -

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Title: JOURNAL OF CLINICAL INVESTIGATION
Source Genre: Journal
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Publ. Info: 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA : AMER SOC CLINICAL INVESTIGATION INC
Pages: - Volume / Issue: 123 (8) Sequence Number: - Start / End Page: 3436 - 3445 Identifier: ISSN: 0021-9738