@article {428, title = {Die lymphangiogenen Wachstumsfaktoren VEGF-C und VEGF-D}, journal = {Lymphologie in Forschung und Praxis}, volume = {17}, year = {2013}, month = {06/2013}, pages = {30-37}, type = {Review}, chapter = {30}, abstract = {VEGF-C und VEGF-D sind die zwei zentralen Signalmolek{\"u}le, die f{\"u}r die Entwicklung und das Wachstum des Lymphgef{\"a}{\ss}systems verantwortlich sind. Beide geh{\"o}ren zur VEGF-Proteinfamilie, deren Mitglieder haupts{\"a}chlich im Wachstum von Blutgef{\"a}ssen (Angiogenese) und Lymphgef{\"a}ssen (Lymphangiogenese) ihre Funktionen haben. Die VEGF-Familie umfasst in S{\"a}ugetieren f{\"u}nf Mitglieder: VEGF, PlGF, VEGF-B, VEGF-C und VEGF-D. Benannt wurde diese Familie nach ihrem zuerst entdeckten Mitglied VEGF ({\quotedblbase}Vascular Endothelial Growth Factor{\textquotedblright}). 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 Vorg{\"a}ngermolek{\"u}le produziert, f{\"u}r deren Aktivierung ihre langen N- und C-terminalen Propeptide enzymatisch abgespalten werden m{\"u}ssen. Im Gegensatz zu den anderen VEGFs sind VEGF-C und VEGF-D direkte Stimulatoren f{\"u}r das Wachstum lymphatischer Gef{\"a}{\ss}e. Ihre lymphangiogene Wirkung enfalten VEGF-C und VEGF-D {\"u}ber 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 {\"U}berblick {\"u}ber die VEGF-Proteinfamilie und deren Rezeptoren mit dem Schwerpunkt auf den lymphangiogenen Mitgliedern VEGF-C und VEGF-D, {\"u}ber 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 ({\textquotedblleft}Vascular Endothelial Growth Factor{\textquotedblright}). 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. } } @article {443, title = {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].}, journal = {Lymphologie in Forschung und Praxis}, volume = {17}, year = {2013}, month = {11/2013}, pages = {96 - 104}, abstract = {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.}, keywords = {growth factors, Lymphangiogenesis, lymphedema, lymphogenic metastasis, VEGF-C, VEGF-D}, url = {http://jeltsch.org/sites/jeltsch.org/files/JeltschMichael_Lymphforsch2013_96.pdf}, author = {Krebs, Rainer and Jeltsch, Michael} } @article {444, title = {The lymphangiogenic growth factors VEGF-C and VEGF-D. Part 1: Basic principles and embryonic development. [bilingual: English, German].}, journal = {Lymphologie in Forschung und Praxis}, volume = {17}, year = {2013}, month = {05/2013}, pages = {30 - 37}, abstract = {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.}, keywords = {growth factors, Lymphangiogenesis, VEGF-C, VEGF-D}, url = {http://jeltsch.org/sites/jeltsch.org/files/JeltschMichael_Lymphforsch2013_30.pdf}, author = {Krebs, Rainer and Jeltsch, Michael} } @article {427, title = {Critical role of VEGF-C/VEGFR-3 signaling in innate and adaptive immune responses in experimental obliterative bronchiolitis.}, journal = {Am J Pathol}, volume = {181}, year = {2012}, month = {2012 Nov}, pages = {1607-20}, abstract = {

Chronic inflammation, a hallmark of obliterative bronchiolitis, is known to induce lymphangiogenesis. We therefore studied the role of lymphangiogenic vascular endothelial growth factor C (VEGF-C), its receptor VEGFR-3, and lymphangiogenesis during development of experimental obliterative bronchiolitis [ie, obliterative airway disease (OAD)] in rat tracheal allografts. The functional importance of VEGF-C was investigated by adenovirus-mediated overexpression of VEGF-C (AdVEGF-C), and by inhibition of VEGF-C activity with VEGFR-3-Ig (AdVEGFR-3-Ig). Analyses included histology, immunohistochemistry, and real-time RT-PCR 10 and 30 days after transplantation. In the course of OAD development, lymphangiogenesis was induced in the airway wall during the alloimmune response, which was reversed by cyclosporine A in a dose-dependent fashion. VEGF-C overexpression in tracheal allografts induced epithelial activation, neutrophil chemotaxis, and a shift toward a Th17 adaptive immune response, followed by enhanced lymphangiogenesis and the development of OAD. In contrast, inhibition of VEGF-C activity with VEGFR-3-Ig inhibited lymphangiogenesis and angiogenesis and reduced infiltration of CD4(+) T cells and the development of OAD. Lymphangiogenesis was linked to T-cell responses during the development of OAD, and VEGF-C/VEGFR-3 signaling modulated innate and adaptive immune responses in the development of OAD in rat tracheal allografts. Our results thus suggest VEGFR-3-signaling as a novel strategy to regulate T-cell responses in the development of obliterative bronchiolitis after lung transplantation.

}, keywords = {Adaptive Immunity, Animals, Bronchiolitis Obliterans, Chemotaxis, Cyclosporine, Dendritic Cells, Dose-Response Relationship, Drug, Down-Regulation, Epithelial Cells, Epithelium, Graft Rejection, Immunity, Innate, Immunoglobulins, Inflammation, Lymphangiogenesis, Macrophages, Neutrophils, Rats, Signal Transduction, Th17 Cells, Trachea, Transplantation, Homologous, Up-Regulation, Vascular Endothelial Growth Factor C, Vascular Endothelial Growth Factor Receptor-3}, issn = {1525-2191}, doi = {10.1016/j.ajpath.2012.07.021}, author = {Krebs, Rainer and Tikkanen, Jussi M and Ropponen, Jussi O and Jeltsch, Michael and Jokinen, Janne J and Yl{\"a}-Herttuala, Seppo and Nyk{\"a}nen, Antti I and Lemstr{\"o}m, Karl B} }