Ameliorating role of Tie2 activation in vascular diseases

Abstract

Part I. Amelioration of Sepsis by Tie2 Activation Induced Vascular Protection

Protection of endothelial integrity has been recognized as a front line approach to mitigate sepsis progression, yet no effective agent for preserving endothelial integrity is available. Here I show that the activation of endothelial receptor Tie2 protects vasculature from septic dam-age and provides survival benefit in an experimental sepsis model using a unique anti-angiopoietin-2 (Ang2) antibody named as ABTAA (Ang2 Binding and Tie2 Activating Anti-body). Upon binding to Ang2, ABTAA renders clustering of Ang2, assembling an AB-TAA/Ang2 complex that can subsequently bind and activate Tie2. Compared with a conven-tional Ang2 blocking antibody, ABTAA was highly effective in delaying sepsis progression by strengthening the endothelial glycocalyx

reducing cytokine storms, vascular leakage, and rarefaction

and mitigating organ damages. Together, my data establishes the ameliorative role of Tie2 activation in sepsis progression, proposing a therapeutic avenue for sepsis amidst the unavailability of sepsis-specific treatments.

Part II. Amelioration of post-ischemic cardiac remodeling through Ang-Tie2 signaling

Although acute mortality of myocardial infarction (MI) remarkably reduced by primary PCI, about 10% of MI survivors die in 18 months and 25% of survivor suffer from heart failure as a sequelae of MI. Although, prompt recanalization is the most important goal in rescuing MI patient, restoration of blood flow per se contributes to cardiomyocyte death by inducing oxi-dative stress and inflammation, called “lethal reperfusion injury”. In this study, utilizing genet-ically modified mice and anti-angiopoietin-2 (Ang2) antibody, I show that endothelial cell de-rived Ang2 plays a crucial role in augmenting post-ischemic adverse cardiac remodeling. Ang2 was expressed in the endothelial cells of infarction border zone and ischemia-reperfusion (I/R) area 2 days after ischemia. Endothelial cell specific deletion of Ang2 markedly reduced vascu-lar leakage, adhesion molecule expression, neutrophil infiltration, increased pericyte coverage and effective perfusion. Consequently EC-specific deletion of Ang2 significantly ameliorated cardiac hypoxia and infarct progression. Similar findings were observed by administration of anti-Ang2 antibody. My data elucidated the ameliorating role of Ang2 in post-ischemic cardi-ac remodeling, and presents a noble approach to mitigate the injury by Ang2 neutralization.