02383nas a2200277   4500008004100000022001400041245009400055210006900149260001200218490000600230520155100236653001201787653001001799653002801809653001901837653002201856653001501878653002701893653002301920653001901943653001101962100002201973700001801995700002102013856007102034       2018                        eng d  a2296-418500aBiology of Vascular Endothelial Growth Factor C in the Morphogenesis of Lymphatic Vessels0 aBiology of Vascular Endothelial Growth Factor C in the Morphogen  c02/20180 v63 aBecause 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.10aADAMTS310aCCBE110agrowth factor signaling10agrowth factors10aLymphatic Vessels10alymphedema10aproteolytic processing10aTissue Engineering10aVEGF receptors10aVEGF-C1 aRauniyar, Khushbu1 aJha, Sawan, K1 aJeltsch, Michael  uhttps://www.frontiersin.org/articles/10.3389/fbioe.2018.00007/full02825nas a2200361   4500008004100000245011400041210006900155260001200224300001200236490000800248520180400256100002102060700002002081700002202101700002602123700001002149700001202159700001602171700001402187700002202201700001202223700002002235700001702255700002102272700002102293700002602314700002302340700001202363700001202375700002102387700001802408856003702426       2013                        eng d00aVascular endothelial growth factor-angiopoietin chimera with improved properties for therapeutic angiogenesis0 aVascular endothelial growth factorangiopoietin chimera with impr  c01/2013  a424-4340 v1273 aBACKGROUND:

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.1 aAnisimov, Andrey1 aTvorogov, Denis1 aAlitalo, Annamari1 aLeppänen, Veli-Matti1 aAn, Y1 aHan, EC1 aOrsenigo, F1 aGaál, EI1 aHolopainen, Tanja1 aKoh, YJ1 aTammela, Tuomas1 aKorpisalo, P1 aKeskitalo, Salla1 aJeltsch, Michael1 aYlä-Herttuala, Seppo1 aDejana, Elisabetta1 aKoh, GY1 aChoi, C1 aSaharinen, Pipsa1 aAlitalo, Kari  uhttps://jeltsch.org/Anisimov2013