%0 Journal Article %J Lymphologie in Forschung und Praxis %D 2013 %T Die lymphangiogenen Wachstumsfaktoren VEGF-C und VEGF-D %A Krebs, Rainer %A Jeltsch, Michael %K Lymphangiogenese %K VEGF-C %K VEGF-D %K Wachstumsfaktoren %X VEGF-C und VEGF-D sind die zwei zentralen Signalmoleküle, die für die Entwicklung und das Wachstum des Lymphgefäßsystems verantwortlich sind. Beide gehören zur VEGF-Proteinfamilie, deren Mitglieder hauptsächlich im Wachstum von Blutgefässen (Angiogenese) und Lymphgefässen (Lymphangiogenese) ihre Funktionen haben. Die VEGF-Familie umfasst in Säugetieren fünf Mitglieder: VEGF, PlGF, VEGF-B, VEGF-C und VEGF-D. Benannt wurde diese Familie nach ihrem zuerst entdeckten Mitglied VEGF („Vascular Endothelial Growth Factor”). VEGF-C und VEGF-D bilden funktionell und strukturell eine Untergruppe innerhalb der VEGF-Familie. Sie unterscheiden sich von den anderen VEGFs durch ihre besondere Biosynthese: sie werden als inaktive Vorgängermoleküle produziert, für deren Aktivierung ihre langen N- und C-terminalen Propeptide enzymatisch abgespalten werden müssen. Im Gegensatz zu den anderen VEGFs sind VEGF-C und VEGF-D direkte Stimulatoren für das Wachstum lymphatischer Gefäße. Ihre lymphangiogene Wirkung enfalten VEGF-C und VEGF-D über den VEGF-Rezeptor-3 (VEGFR-3), der im erwachsenen Organismus fast nur auf den Endothelzellen der Lymphvaskulatur zu finden ist. In diesem Artikel geben wir einen Überblick über die VEGF-Proteinfamilie und deren Rezeptoren mit dem Schwerpunkt auf den lymphangiogenen Mitgliedern VEGF-C und VEGF-D, über ihre Biosynthese und ihre Rolle in der Embryonalentwicklung. VEGF-C and VEGF-D are the two central signaling molecules that stimulate the development and the growth of lymphatic system. Both belong to the VEGF protein family which plays important roles in the growth of blood vessels (angiogenesis) and lymphatic vessels (lymphangiogenesis). In mammals the VEGF family comprises five members: VEGF, PlGF, VEGF-B, VEGF-C and VEGF-D. The family was named after its first discovered member VEGF (“Vascular Endothelial Growth Factor”). VEGF-C and VEGF-D form functionally and structurally a subgroup within this family. They differ from the other VEGFs by their peculiar biosynthesis: they are produced as inactive precursors and need to be activated by proteolytic removal of their long N- and C-terminal propeptides. Unlike the other VEGFs, VEGF-C and VEGF-D are direct stimulators of lymphatic growth. They exert their lymphangiogenic function via VEGF receptor 3, which is expressed in the adult organism almost exclusively on lymphatic endothelial cells. In this review we give an overview of the VEGF protein family and their receptors with the emphasis on the lymphangiogenic VEGF-C and VEGF-D, and we discuss their biosynthesis and their role in embryonic lymphangiogenesis. %B Lymphologie in Forschung und Praxis %V 17 %P 30-37 %8 06/2013 %G eng %N 1 %9 Review %& 30 %0 Journal Article %J Lymphologie in Forschung und Praxis %D 2013 %T Die lymphangiogenic growth factors VEGF-C and VEGF-D. Part 2: The role of VEGF-C and VEGF-D in diseases of the lymphatic system. [bilingual: English, German]. %A Krebs, Rainer %A Jeltsch, Michael %K growth factors %K Lymphangiogenesis %K lymphedema %K lymphogenic metastasis %K VEGF-C %K VEGF-D %X VEGF-C and VEGF-D are the two central signaling molecules that stimulate the develop- ment and growth of the lymphatic system. Both belong to the vascular endothelial growth factor (VEGF) protein family, which plays important roles in the growth of blood vessels (angiogenesis) and lymphatic vessels (lymphangiogenesis). In mammals, the VEGF family comprises five members: VEGF-A, PlGF, VEGF-B, VEGF-C and VEGF-D. The family was named after VEGF-A, the first member to be discovered. VEGF-C and VEGF-D form a subgroup within this family in terms of function and structure. Their distinctive biosynthesis differentiates them from the other VEGFs: they are produced as inactive precursors and need to be activated by proteolytic removal of their long N- and C-terminal propeptides. Unlike the other VEGFs, VEGF-C and VEGF-D are direct stimulators of lymphatic vessel growth. They exert their lymphangiogenic function via VEGF receptor 3, which is expressed in the adult organism almost exclusively on lymphatic endothelial cells. In this review, we provide an overview of the VEGF protein family and their receptors. We focus on the lymphangiogenic VEGF-C and VEGF-D, discussing their biosynthesis and their role in embryonic lymphangiogenesis. %B Lymphologie in Forschung und Praxis %V 17 %P 96 - 104 %8 11/2013 %G eng %U http://jeltsch.org/sites/jeltsch.org/files/JeltschMichael_Lymphforsch2013_96.pdf %N 2 %! Lymphforsch %0 Journal Article %J Circ Res %D 2007 %T Distinct architecture of lymphatic vessels induced by chimeric vascular endothelial growth factor-C/vascular endothelial growth factor heparin-binding domain fusion proteins %A Tammela, Tuomas %A He, Yulong %A Lyytikkä, Johannes %A Jeltsch, Michael %A Markkanen, Johanna %A Pajusola, Katri %A Ylä-Herttuala, Seppo %A Alitalo, Kari %X Vascular endothelial growth factor (VEGF)-C and VEGF-D are composed of the receptor-binding VEGF homology domain and a carboxy-terminal silk homology domain that requires proteolytic cleavage for growth factor activation. Here, we explored whether the C-terminal heparin-binding domain of the VEGF(165) or VEGF(189) isoform also containing neuropilin-binding sequences could substitute for the silk homology domain of VEGF-C. Such VEGF-C/VEGF-heparin-binding domain chimeras were produced and shown to activate VEGF-C receptors, and, when expressed in tissues via adenovirus or adeno-associated virus vectors, stimulated lymphangiogenesis in vivo. However, both chimeras induced a distinctly different pattern of lymphatic vessels when compared with VEGF-C. Whereas VEGF-C-induced vessels were initially a dense network of small diameter vessels, the lymphatic vessels induced by the chimeric growth factors tended to form directly along tissue borders, along basement membranes that are rich in heparan sulfate. For example, in skeletal muscle, the chimeras induced formation of lumenized lymphatic vessels more efficiently than wild-type VEGF-C. We conclude that the matrix-binding domain of VEGF can target VEGF-C activity to heparin-rich basement membrane structures. These properties may prove useful for tissue engineering and attempts to regenerate lymphatic vessels in lymphedema patients. %B Circ Res %V 100 %P 1468 - 75 %8 2007/May/ %G eng %U http://view.ncbi.nlm.nih.gov/pubmed/17478733 %N 10 %! Circulation Research