title: Angiopoietin 2 mediates microvascular and hemodynamic alterations in sepsis.
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 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.
authors.forename: Tilman
authors.initials: T
authors.lastname: Ziegler
authors.forename: Jan
authors.initials: J
authors.lastname: Horstkotte
authors.forename: Claudia
authors.initials: C
authors.lastname: Schwab
authors.forename: Vanessa
authors.initials: V
authors.lastname: Pfetsch
authors.forename: Karolina
authors.initials: K
authors.lastname: Weinmann
authors.forename: Steffen
authors.initials: S
authors.lastname: Dietzel
authors.forename: Ina
authors.initials: I
authors.lastname: Rohwedder
authors.forename: Rabea
authors.initials: R
authors.lastname: Hinkel
authors.forename: Lisa
authors.initials: L
authors.lastname: Gross
authors.forename: Seungmin
authors.initials: S
authors.lastname: Lee
authors.forename: Junhao
authors.initials: J
authors.lastname: Hu
authors.forename: Oliver
authors.initials: O
authors.lastname: Soehnlein
authors.forename: Wolfgang M
authors.initials: WM
authors.lastname: Franz
authors.forename: Markus
authors.initials: M
authors.lastname: Sperandio
authors.forename: Ulrich
authors.initials: U
authors.lastname: Pohl
authors.forename: Markus
authors.initials: M
authors.lastname: Thomas
authors.forename: Christian
authors.initials: C
authors.lastname: Weber
authors.forename: Hellmut G
authors.initials: HG
authors.lastname: Augustin
authors.forename: Reinhard
authors.initials: R
authors.lastname: Fässler
authors.forename: Urban
authors.initials: U
authors.lastname: Deutsch
authors.forename: Christian
authors.initials: C
authors.lastname: Kupatt