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Letter

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

Ru-Yuan Zhang, Dong Min, Jun Wu, Lei Li, Hong-Ping Qu and Yao-Qing Tang*

Author Affiliations

Department of Critical Care Medicine, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China

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Critical Care 2012, 16:466  doi:10.1186/cc11844


See related research by Alfieri et al., http://ccforum.com/content/16/5/R182


The electronic version of this article is the complete one and can be found online at: http://ccforum.com/content/16/6/466


Published:27 November 2012

© 2012 BioMed Central Ltd

Letter

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.

Abbreviations

Ang: angiopoietin.

Competing interests

The authors declare that they have no competing interests.

Acknowledgements

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

References

  1. Alfieri A, Watson JJ, Kammerer RA, Tasab M, Progias P, Reeves K, Brown NJ, Brookes ZL: Angiopoietin-1 variant reduces LPS-induced microvascular dysfunction in a murine model of sepsis.

    Crit Care 2012, 16:R182. PubMed Abstract | BioMed Central Full Text OpenURL

  2. Dejana E, Orsenigo F, Lampugnani MG: The role of adherens junctions and VE-cadherin in the control of vascular permeability.

    J Cell Sci 2008, 121:2115-2122. PubMed Abstract | Publisher Full Text OpenURL

  3. Potter MD, Barbero S, Cheresh DA: Tyrosine phosphorylation of VE-cadherin prevents binding of p120- and beta-catenin and maintains the cellular mesenchymal state.

    J Biol Chem 2005, 280:31906-31912. PubMed Abstract | Publisher Full Text OpenURL

  4. Gamble JR, Drew J, Trezise L, Underwood A, Parsons M, Kasminkas L, Rudge J, Yancopoulos G, Vadas MA: Angiopoietin-1 is an antipermeability and anti-inflammatory agent in vitro and targets cell junctions.

    Circ Res 2000, 87:603-607. PubMed Abstract | Publisher Full Text OpenURL

  5. Lee SW, Won JY, Lee HY, Lee HJ, Youn SW, Lee JY, Cho CH, Cho HJ, Oh S, Chae IH, Kim HS: Angiopoietin-1 protects heart against ischemia/reperfusion injury through VE-cadherin dephosphorylation and myocardiac integrinbeta1/ERK/caspase-9 phosphorylation cascade.

    Mol Med 2011, 17:1095-1106. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  6. Harris SE, Nelson WJ: VE-cadherin: at the front, center, and sides of endothelial cell organization and function.

    Curr Opin Cell Biol 2012, 22:651-658. OpenURL

  7. Orrington-Myers J, Gao X, Kouklis P, Broman M, Rahman A, Vogel SM, Malik AB: Regulation of lung neutrophil recruitment by VE-cadherin.

    Am J Physiol Lung Cell Mol Physiol 2006, 291:L764-L771. PubMed Abstract | Publisher Full Text OpenURL

  8. Sprague AH, Khalil RA: Inflammatory cytokines in vascular dysfunction and vascular disease.

    Biochem Pharmacol 2009, 78:539-552. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL