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Vascular endothelial growth factor-angiopoietin chimera with improved properties for therapeutic angiogenesis

Vascular endothelial growth factor-angiopoietin chimera with improved properties for therapeutic angiogenesis

Authors :
Annamari Alitalo
Denis Tvorogov
Pipsa Saharinen
Kari Alitalo
Young Jun Koh
Andrey Anisimov
Petra Korpisalo
Seppo Ylä-Herttuala
Fabrizio Orsenigo
Gou Young Koh
Michael Jeltsch
Chulhee Choi
Eun Chun Han
Yuri An
Veli-Matti Leppänen
Salla Keskitalo
Tanja Holopainen
Tuomas Tammela
Elisabetta Dejana
Emilia I. Gaal
Anisimov, Andrey
Tvorogov, Denis
Alitalo, Annamari K
Leppanen, Veli-Matti
An, Yuri
Han, Eun Chun
Orsenigo, Fabrizio
Gaál, Emília Ilona
Holopainen, Tanja
Koh, Young Jun
Tammela, Tuomas
Korpisalo, Petra
Keskitalo, Sally
Jeltsch, Michael
Ylä-Herttuala, Seppo
Dejana, Elisabetta
Koh, Gou Young
Choi, Chulhee
Saharinen, Pipsa
Alitalo, Kari
Source :
Circulation
Publication Year :
2013

Abstract

Background— There is an unmet need for proangiogenic therapeutic molecules for the treatment of tissue ischemia in cardiovascular diseases. However, major inducers of angiogenesis such as vascular endothelial growth factor (VEGF/VEGF-A) have side effects that limit their therapeutic utility in vivo, especially at high concentrations. Angiopoietin-1 has been considered to be a blood vessel stabilization factor that can inhibit the intrinsic property of VEGF to promote vessel leakiness. In this study, we have designed and tested the angiogenic properties of chimeric molecules consisting of receptor-binding parts of VEGF and angiopoietin-1. We aimed at combining the activities of both factors into 1 molecule for easy delivery and expression in target tissues. Methods and Results— The VEGF–angiopoietin-1 (VA1) chimeric protein bound to both VEGF receptor-2 and Tie2 and induced the activation of both receptors. Detailed analysis of VA1 versus VEGF revealed differences in the kinetics of VEGF receptor-2 activation and endocytosis, downstream kinase activation, and VE-cadherin internalization. The delivery of a VA1 transgene into mouse skeletal muscle led to increased blood flow and enhanced angiogenesis. VA1 was also very efficient in rescuing ischemic limb perfusion. However, VA1 induced less plasma protein leakage and myeloid inflammatory cell recruitment than VEGF. Furthermore, angioma-like structures associated with VEGF expression were not observed with VA1. Conclusions— The VEGF–angiopoietin-1 chimera is a potent angiogenic factor that triggers a novel mode of VEGF receptor-2 activation, promoting less vessel leakiness, less tissue inflammation, and better perfusion in ischemic muscle than VEGF. These properties of VA1 make it an attractive therapeutic tool.

Details

ISSN :
15244539
Volume :
127
Issue :
4
Database :
OpenAIRE
Journal :
Circulation
Accession number :
edsair.doi.dedup.....c9e9dfde939956ba60c6a88f513a8fef