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Studies on the development of pharmacological inhibitors of Angiopoietin-2

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posted on 14.11.2019, 11:36 by Omeed J. A. AL-Dalawi
Blocking Angiopoietin-2 pathogenic effects mediated through Tie2 and other receptor is the main goal of this study. Angiopoietin-2 is a vascular growth factor that binds to the Tie2 receptor and is expressed mainly in endothelial cells. Several studies demonstrate the destabilizing effects of Ang2 in the vascular system of the human body. On the other hand, Ang1 has a stabilizing effect necessary for maintaining the integrity of the vessels. Increased levels of Ang2 can block the binding of the Ang1 to the Tie2 receptor and stimulate pathogenic signalling through Tie2 and β-integrin pathways. These effects can promote vessel destabilization through the induction of apoptosis, inflammation, and leakage.
Therefore, the aim of this study was to improve an Ang2 ligand-trap as a potential inhibitor for its regressive effects, and to investigate the possibility of Ang2 signalling through a Tie2 independent pathway. In order to inhibit Ang2 effects, a ligand-trap previously described was improved by mutagenesis and by pentamerization. The mutagenesis resulted in increased relative affinity 2-4 fold, while pentamerization improved the relative affinity of the current ligand-trap (R3-Fc) up to 18-fold using pentameric R3 design (R3-COMP). In addition, in this study the possibility that Ang2 signalling through Tie2 independent pathway was investigated for VE-cadherin and Tie1 cleavage. This study found Ang2 as a novel activator of VE-cadherin and Tie1 cleavage through an integrin pathway and by activation of ADAM10 and ADAM17 respectively. Furthermore, the study found Ang2 is required for the pro-cleavage effects of TNF-α.
In conclusion this study produced a higher affinity Ang2 ligand-trap and showed that Ang2 signals through integrins and this pathway can be inhibited to suppress Ang2 effects on VE-cadherin and Tie1 cleavage. Overall, these data provide a strategy for inhibition of Ang2 effects through Tie2, using a high affinity ligand-trap, as well as inhibition of integrin mediated effects by use of integrin blocking reagents.

Funding

Iraqi government/Ministry of Higher Education and Scientific Research

History

Supervisor(s)

Nicholas Brindle

Date of award

20/08/2019

Author affiliation

Department of Cardiovascular Sciences

Awarding institution

University of Leicester

Qualification level

Doctoral

Qualification name

PhD

Language

en

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