The angiopoietin-Tie2 signaling axis in the vascular leakage of systemic inflammation

Abstract

The ability of small blood vessels to undergo rapid, reversible morphological changes is essential for the adaptive response to tissue injury or local infection. A canonical feature of this response is transient hyperpermeability. However, when leakiness is profound or persistent, adverse consequences accrue to the host, including organ dysfunction and shock. A growing body of literature identifies the Tie2 receptor, a transmembrane tyrosine kinase highly enriched in the endothelium, as an important regulator of vascular barrier function in health and in disease. The principal ligands of Tie2, Angiopoietins 1 and 2, exert opposite effects on this receptor in the context of inflammation. This review will focus on recent studies that have illuminated novel aspects of the exquisitely controlled Tie2 signaling axis while proposing unanswered questions and future directions for this field of study.

Keywords:

• Angiopoietin
• anthrax
• ARDS
• barrier function
• endothelium
• inflammation
• lung injury
• malaria
• respiratory distress
• sepsis
• Tie1
• Tie2
• vascular leakage
• VE-PTP

Abbreviations:

• Angpt, angiopoietin
• PI3K, phosphatidylinositol-3-kinase
• MAPK, mitogen-activated protein kinase
• VEGF, vascular endothelial growth factor
• EC, endothelial cell
• siRNA, small interfering RNA
• VE-cadherin, vascular endothelial cadherin
• VE-PTP, vascular endothelial protein tyrosine phosphatase

Disclosure of Potential Conflicts of Interest

S.M.P. advises Vasomune Therapeutics and Eunoia Biotech and is listed as an inventor on disclosures and patents related to Angiopoietins held by Beth Israel Deaconess Medical Center.

Acknowledgments

The authors would like to thank Drs. Chandra Ghosh (Boston, USA) and Sascha David (Hannover, Germany) for critical review and helpful advice with this manuscript.

Funding

Research in S.M.P's laboratory is supported by the National Institutes of Health (R01-HL093234 and R01-DK095072) and the American Diabetes Association.