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.

MRTF-A controls vessel growth and maturation by increasing the expression of CCN1 and CCN2

“…At the cellular level this response involves endothelial sprouting via CCN1 (CYR61) 29 and maturation-that is, pericyte investment-via CCN2 (CTGF) 24 resulting in a stable and functional vascular network that can carry collateral blood flow and improve conductance. Pericyte investment is crucial herein since Ang 2, by virtue of disrupting pericyte investment 38 , abolished the positive effects exerted by T 4-MRTF signalling (Fig. 3).…”

Gene control of tyrosine kinase TIE2 and vascular manifestations of infections

“…Angpt-1 protects against vascular leakage and death in experimental sepsis (15,16). Similar protective effects arise with blockade, deletion, or depletion of Angpt-2 (1,4,6,30). However, the importance of Tie2 has been diminished by the identification of integrin receptors for Angpt-1 (11-13) and, more recently, for Angpt-2 (3,31).…”

“…enhances Tie2 activation and counteracts leakage (1,6,(15)(16)(17). The role of TIE2 gene expression has not been fully investigated in this and related settings.…”

“…First, Tie2 phosphorylation is tightly controlled by the interplay of several proteins: a paralogous receptor, Tie1; a tyrosine phosphatase, vascular endothelial-protein tyrosine phosphatase (VE-PTP); and two secreted ligands, angiopoietin (Angpt)-1 and Angpt-2, the latter of which can act as an agonist, partial agonist, or antagonist depending upon context (1)(2)(3)(4)(5)(6). Second, unlike classic growth factor receptors, Tie2 is heavily expressed and phosphorylated throughout the quiescent adult vasculature (7), suggesting that Tie2 signaling has one or more roles in vascular maintenance.…”

Pericytes, mesenchymal stem cells and their contributions to tissue repair

“…Ang-2 is expressed by ECs, particularly during tissue regeneration (Hu et al, 2014); it binds competitively with Ang-1 for Tie-2 and acts as an opposing factor in pericyte-EC interactions. Furthermore, increased Ang-2 expression dissociates pericytes from vessels (Ziegler et al, 2013). It has been shown transgenic mice overexpressing Ang-2 develop dense vascular networks with drastically reduced pericyte numbers (Feng et al, 2007).…”