Vascular Endothelial Growth Factor-Angiopoietin Chimera With Improved Properties for Therapeutic Angiogenesis

• Published in: Circulation (New York, N.Y.) N.Y.), 2013-01, Vol.127 (4), p.424-434
• Main Authors: ANISIMOV, Andrey, TVOROGOV, Denis, TAMMELA, Tuomas, KORPISALO, Petra, KESKITALO, Salla, JELTSCH, Michael, YLA-HERTTUALA, Seppo, DEJANA, Elisabetta, GOU YOUNG KOH, CHOI, Chulhee, SAHARINEN, Pipsa, ALITALO, Kari, ALITALO, Annamari, LEPPANEN, Veli-Matti, YURI AN, EUN CHUN HAN, ORSENIGO, Fabrizio, ILONA GAAL, Emilia, HOLOPAINEN, Tanja, YOUNG JUN KOH
• Format: Article
• Language: English
• Subjects: Adenoviridae - genetics; Angiopoietin-1 - genetics; Angiopoietin-1 - metabolism; Angiopoietin-1 - pharmacology; Animals; Biological and medical sciences; Blood and lymphatic vessels; Blood vessels and receptors; Capillary Permeability - physiology; Cardiology. Vascular system; Cell Line, Tumor; Disease Models, Animal; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Female; Fundamental and applied biological sciences. Psychology; Genetic Therapy - methods; HEK293 Cells; Hindlimb - blood supply; Human Umbilical Vein Endothelial Cells; Humans; Ischemia - drug therapy; Ischemia - genetics; Leukemia, Myeloid; Medical sciences; Mice; Mice, Inbred Strains; Muscle, Skeletal - blood supply; Neovascularization, Physiologic - physiology; Receptor Protein-Tyrosine Kinases - metabolism; Receptor, TIE-2; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - metabolism; Recombinant Fusion Proteins - pharmacology; Signal Transduction - physiology; Vascular Endothelial Growth Factor A - genetics; Vascular Endothelial Growth Factor A - metabolism; Vascular Endothelial Growth Factor A - pharmacology; Vascular Endothelial Growth Factor Receptor-1 - metabolism; Vascular Endothelial Growth Factor Receptor-2 - metabolism; Vertebrates: cardiovascular system
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/CIRCULATIONAHA.112.127472

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. 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. 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.