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The Endothelial Receptor Tyrosine Kinase Tie2 is Essential for Vascular Integrity Dependent/Independent of Inflammation
Author(s) -
Ghosh Chandra,
David Sascha,
Milam Katelyn,
Mukherjee Aditi,
Santel Ansgar,
Lu Shulin,
Yano Kiichiro,
Dumont Daniel,
Parikh Samir
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.lb99
Subject(s) - angiopoietin receptor , receptor tyrosine kinase , medicine , inflammation , extravasation , receptor , tyrosine kinase , sepsis , pharmacology , immunology
Endothelial Receptor Tyrosine Kinase Tie2, and its two principal ligands Angiopoietin1&2 (Angpt‐1&2), play an important role in heath and diseases. Its agonistic ligand Angpt‐1 mainly expressed in perivascular cells whereas Angpt‐2, stored in Weible –Palade‐Bodies, compete with Angpt‐1 and function as partial agonist/antagonist. However, the consequence of the loss of Tie2 and potential contribution to vascular dysfunction in health and disease has not been investigated so far. In the present study we found mice with one copy of Tie2 gene a) are more vulnerable to death in murine sepsis models, endotoxemia (83% vs. 42%, P < 0.05) and Cecal Ligation and Perforation (CLP) (76% vs. 32%, P < 0.05); b) has enhanced vascular leak as measured by Evans's blue extravasation assay. Similarly,siRNA mediated knock‐down of Tie2 results in enhanced vascular leak in lungs with perturbed downstream signaling of Tie2. In vitro by using shRNA ‐lentiparticles we found Angpt‐1 induced prevention of Lipo‐polysaccharide (LPS) ‐mediated vascular barrier dysunction in Tie2 dependent fashion. Above all, the effect of reduced Tie2 expression in‐vivo and in‐vitro is independent of changes to the inflammatory milieu. In conclusion, our study demonstrates a novel inflammation independent role for Tie2 mediating endothelial vascular function in sepsis. Further studies are underway to investigate the upstream and downstream regulators of Tie2 and reveal the diagnostic and therapeutic implication of this important pathway.