Bettina Hesse
University Hospital Muenster, Germany
Title: Angiopoietin-2 mediates endothelial glycocalyx damage
Biography
Biography: Bettina Hesse
Abstract
The endothelial glycocalyx (eGC), a carbohydrate-rich layer mainly consisting of heparan sulfates (HS), lines the luminal side of the vascular endothelium. It provides a first vasoprotective barrier against vascular leakage and leukocyte adhesion in sepsis and vascular inflammation. The eGC is damaged in sepsis and thereby leads to defects in vascular permeability. Angiopoietin-2 (Angpt-2), an antagonist of the endothelium-stabilizing receptor tyrosine kinase Tie2 secreted by endothelial cells upon inflammatory stimulation, promotes vascular permeability through cellular contraction and junctional disintegration. Since the eGC damage and Angpt-2 are both involved in mechanisms influencing vascular permeability we hypothesize that Angpt-2 might also mediate the breakdown of the eGC. Using confocal and atomic force microscopy, we show that exogenous Angpt-2 induces a rapid loss of the eGC in endothelial cells and aortic endothelium in vitro. Glycocalyx deterioration involves the specific loss of its main constituent HS, paralleled by the secretion of the HS-specific heparanase. Corresponding in vivo experiments revealed that exogenous Angpt-2 leads to heparanase-dependent eGC breakdown, which contributes to plasma leakage and leukocyte recruitment in vivo. In summary, our data reveal a novel and crucial role for Angpt-2 in the regulation of the eGC. The results advance our understanding of the Angpt/Tie2 ligand-receptor system as a shared and concurrent gatekeeper of both layers of the vascular double barrier: the endothelial cell and the eGC.