TY - JOUR T1 - Biology of Vascular Endothelial Growth Factor C in the Morphogenesis of Lymphatic Vessels JF - Frontiers in Biotechnology and Bioengineering Y1 - 2018 A1 - Khushbu Rauniyar A1 - Sawan K Jha A1 - Michael Jeltsch KW - ADAMTS3 KW - CCBE1 KW - growth factor signaling KW - growth factors KW - Lymphatic Vessels KW - lymphedema KW - proteolytic processing KW - Tissue Engineering KW - VEGF receptors KW - VEGF-C AB - Because virtually all tissues contain blood vessels, the importance of hemevascularization has been long recognized in regenerative medicine and tissue engineering. However, the lymphatic vasculature has only recently become a subject of interest. Central to the task of growing a lymphatic network are lymphatic endothelial cells (LECs), which constitute the innermost layer of all lymphatic vessels. The central molecule that directs proliferation and migration of LECs during embryogenesis is Vascular Endothelial Growth Factor-C (VEGF-C). VEGF-C is, therefore, an important ingredient for LEC culture and attempts to (re)generate lymphatic vessels and networks. During its biosynthesis, VEGF-C undergoes a stepwise proteolytic processing, during which its properties and affinities for its interaction partners change. Many of these fundamental aspects of VEGF-C biosynthesis have only recently been uncovered. So far, most - if not all - applications of VEGF-C do not discriminate between different forms of VEGF-C. However, for lymphatic regeneration and engineering purposes, it appears mandatory to understand these differences, since they relate e.g. to such important aspects as biodistribution and receptor activation potential. In this review, we discuss the molecular biology of VEGF-C as it relates to the growth of LECs and lymphatic vessels. However, the properties of VEGF-C are similarly relevant for the cardiovascular system, since both old and recent data show that VEGF-C can have a profound effect on the blood vasculature. VL - 6 UR - https://www.frontiersin.org/articles/10.3389/fbioe.2018.00007/full ER - 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 -