Open Access

Unraveling the mechanisms involved in endothelial barrier protective effects of angiopoietin-1 variant MAT.Ang-1

  • Ru-Yuan Zhang1,
  • Dong Min1,
  • Jun Wu1,
  • Lei Li1,
  • Hong-Ping Qu1 and
  • Yao-Qing Tang1Email author
Critical Care201216:466

DOI: 10.1186/cc11844

Published: 27 November 2012

With great interest we read the recent article by Alfieri and colleagues [1], demonstrating that angiopoietin (Ang)-1 variant MAT.Ang-1 improved endotoxemiainduced microvascular dysfunction and microvascular hyperpermeability. The authors suggested that MAT. Ang-1-induced recovery of microcirculatory tissue perfusion during sepsis is due to preservation of endothelial barrier integrity. To further elucidate the mechanism, they investigated the possibility of involvement of VE-cadherin, a major adherens junctions protein responsible for microvascular leakage in inflammation. They found, however, while there was no change in overall expression of VE-cadherin, MAT.Ang-1 increased VE-cadherin phosphorylation in the treated mice, which appears unable to explain the observed endothelial barrier protective effects of MAT.Ang-1.

The work by Dejana and co-workers [2] highlights the critical role of VE-cadherin for maintenance of endothelial barrier function. It is generally accepted that the tyrosine phosphorylation of VE-cadherin and other components of adherens junctions induced by permeability-increasing agents is associated with weak junctions and impaired barrier function via regulating VE-cadherin member localization [2]. Recently, among the nine tyrosines in the cytoplasmic tail of VE-cadherin, Potter and colleagues [3] revealed that tyrosine phosphorylation of VE-cadherin at two critical tyrosines, Tyr-658 and Tyr-731, was sufficient to disrupt VE-cadherin-mediated cell-cell junctions, leading to inhibition of cell barrier function.

Previous studies have shown that Ang-1 restores the endothelial barrier function via phosphorylation-dependent redistribution of VE-cadherin [4, 5]. While in the present study the total amount of VE-cadherin was not changed, intriguingly MAT.Ang-1 increases VE-cadherin phosphorylation (at Y658) in sepsis. This is unexpected because the endothelial barrier protective effects of MAT.Ang-1 do not seem to be consistent with its effect on an important cellular junction molecule involved in endothelial cell integrity, namely VE-cadherin; however, other mechanisms of action cannot be ruled out. Nevertheless, further studies are needed to investigate the mechanisms by which this novel Ang-1 variant rescues the endothelial barrier function.

Authors' response

Alessio Alfieri, Nicola J Brown and Zoe L Brookes

We appreciate the interest and insightful comments made by Zhang and colleagues concerning our recent research article. The functional in vivo studies presented in our manuscript demonstrated that MAT.Ang-1 reduced macromolecular leak and improved tissue perfusion without significantly changing the diameter of microvessels, thus suggesting that the protective effects induced by MAT.Ang-1 depend on preserving the endothelial barrier integrity. In addition to the well-recognized role in controlling vascular permeability, VE-cadherin and associated junctional proteins form part of complex signaling cascades regulating important cellular functions [6]. In particular, as discussed in our manuscript, disassembly of the VE-cadherin complex triggers an intracellular negative signal reducing transendothelial leukocyte migration in mice 6 hours after challenge with lipopolysaccharide [7]. Therefore, an increase in VE-cadherin phosphorylation paralleled by reduced interleukin-1β protein expression may be a mechanism by which MAT.Ang-1 induces protection against microvascular stasis in sepsis. Furthermore, lipopolysaccharide-induced endotoxemia increases the expression of several inflammatory cytokines (for example, tumor necrosis factor-α), which in turn cause macromolecular leak [8]. Therefore, in vivo a complex mechanistic scenario develops in sepsis with regards to the endothelial barrier function, which is difficult to unravel. The elegant studies referenced by Zhang and colleagues concerning Ang-1 and VE-cadherin phosphorylation report in vitro findings, whereas all our results are from septic mice in vivo with or without MAT.Ang-1 post-treatment. Nevertheless, we agree that further investigations are required before making firm conclusions on the effects of MAT.Ang-1 on the endothelium in sepsis - for instance, studies aimed at providing a complete in vivo time-course of the expression, localization and phosphorylation of endothelial junctional proteins would be extremely informative.






This work was supported by the National Natural Science Foundation of China (NSFC, Grant No. 81071534).

Authors’ Affiliations

Department of Critical Care Medicine, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine


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