1. Vascular endothelial growth factor-angiopoietin chimera with improved properties for therapeutic angiogenesis
- Author
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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, and Alitalo, Kari
- Subjects
Vascular Endothelial Growth Factor A ,capillary permeability ,Angiogenesis ,Vascular permeability ,Neovascularization ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Ischemia ,0303 health sciences ,biology ,gene therapy ,Angiopoietin receptor ,Receptor, TIE-2 ,3. Good health ,Hindlimb ,Vascular endothelial growth factor ,medicine.anatomical_structure ,Leukemia, Myeloid ,030220 oncology & carcinogenesis ,Female ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,vascular endothelium ,Blood vessel ,Signal Transduction ,Recombinant Fusion Proteins ,Neovascularization, Physiologic ,angiogenesis inducers ,Mice, Inbred Strains ,ischemia ,Adenoviridae ,Angiopoietin ,Capillary Permeability ,03 medical and health sciences ,Physiology (medical) ,Cell Line, Tumor ,medicine ,Angiopoietin-1 ,Human Umbilical Vein Endothelial Cells ,Animals ,Humans ,Therapeutic angiogenesis ,Muscle, Skeletal ,030304 developmental biology ,Vascular Endothelial Growth Factor Receptor-1 ,business.industry ,Receptor Protein-Tyrosine Kinases ,Genetic Therapy ,Vascular Endothelial Growth Factor Receptor-2 ,Disease Models, Animal ,HEK293 Cells ,chemistry ,Immunology ,Cancer research ,biology.protein ,business - 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.
- Published
- 2013