TY - JOUR T1 - Vascular endothelial growth factor-angiopoietin chimera with improved properties for therapeutic angiogenesis JF - Circulation Y1 - 2013 A1 - Andrey Anisimov A1 - Denis Tvorogov A1 - Annamari Alitalo A1 - Veli-Matti Leppänen A1 - Y An A1 - EC Han A1 - F Orsenigo A1 - EI Gaál A1 - Tanja Holopainen A1 - YJ Koh A1 - Tuomas Tammela A1 - P Korpisalo A1 - Salla Keskitalo A1 - Michael Jeltsch A1 - Seppo Ylä-Herttuala A1 - Elisabetta Dejana A1 - GY Koh A1 - C Choi A1 - Pipsa Saharinen A1 - Kari Alitalo AB - 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. VL - 127 IS - 4 ER -