%0 Journal Article %J Duodecim Lääketieteellinen Aikakauskirja %D 2020 %T Lymphatics and the eye. [Finnish] %A Gucciardo, Erika %A Lehti, Timo A. %A Korhonen, Ani %A Salvén, Petri %A Lehti, Kaisa %A Jeltsch, Michael %A Loukovaara, Sirpa %B Duodecim Lääketieteellinen Aikakauskirja %V 136 %P 1777-1788 %8 2020/02/10/ %G eng %U https://www.duodecimlehti.fi/lehti/2020/16/duo15739 %N 16 %9 review %! Duodecim %& 1777 %R 10.5281/zenodo.4005517 %0 Journal Article %J Tissue Engineering Part B %D 2016 %T Lymphatic Vessels in Regenerative Medicine and Tissue Engineering %A Schaupper, Mira V. %A Jeltsch, Michael %A Rohringer, Sabrina %A Redl, Heinz %A Holnthoner, Wolfgang %X Once a DOI is available for this article, the final publication will be available from Mary Ann Liebert, Inc., publishers at http://dx.doi.org/10.1089/TEN.TEB.2016.0034. The postprint manuscript is available from here and for the next 30 days also from the publisher via this bit.ly shortcut: http://bit.ly/1VKjjMk. %B Tissue Engineering Part B %V 22 %P 1-13 %8 2016 %G eng %U http://online.liebertpub.com/doi/10.1089/ten.TEB.2016.0034 %N 5 %9 Review %R 10.1089/ten.TEB.2016.0034 %0 Conference Proceedings %B 41st European Societry of Lymphology (ESL) Congress %D 2015 %T Lymphangiogenesis in Health and Disease %A Jeltsch, Michael %X Despite the intensive research on the lymphangiogenic VEGF-C/VEGFR-3 signaling pathway in the last two decades, new and unexpected findings do not cease to be made. Diseases that involve the lymphatic system have helped to uncover mechanisms of its normal functioning and development. A recent example of new basic knowledge that resulted from the investigation of a human disease is Hennekam lymphangiectasia­ lymphedema syndrome (OMIM 235510). It is an autosomal recessive condition, which can co-segregate with mutations in the collagen- and calcium-binding EGF domains 1 (CCBEJ) or the protocadherin Fat 4 (FAT4) gene. Both CCBEI and the lymphangiogenic vascular endothelial growth factor C (VEGF-C) are necessary for the early lymphatic development, namely for the budding and migration of endothelial cells from the cardinal vein (CV) and for the formation of the early lymphatic structures. These processes fail in embryos deficient of either Ccbel or Vegfc. In Vegfc-deficient embryos pro-spective lymphatic endothelial cells fail to sprout from the CV, whereas in Ccbel-deficient embryos, the sprouting is abnormal and does not result in the formation of discrete lymphatic structures. The similar phenotypes of Ccbe- and Vegfc-deficient embryos result from the interaction of CCBEI with the VEGF-C growth factor signaling pathway, which is critical in embryonic and adult lymphangiogenesis. VEGF-C is synthesized as an inactive proprotein and needs to be processed by at least two distinct proteases to become fully active. The presence of CCBEI promotes VEGF-C by two independent mechanisms. The C-terminal domain of CCBEI boosts VEGF-C function via increased ADAMTS3-mediated proteolytic activation of VEGF-C, while the N-terminal domain of CCBEI concentrates pro-VEGF-C on endothelial cell-surfaces, where it can be activated in situ by cell-surface associated proteases. Both mechanisms lead to increased VEGFR-3 signaling and increased lymphangiogenesis. These results show that CCBEI is integral to lymphangiogenesis by increasing the levels of active VEGF-C at the endothelial cell surface. Because some forms of lymphedema appear to be treatable by increasing the amount of VEGFR-3 signaling, the first clinical trials designed around a pro-lymphangiogenic concept use VEGF-C. The goal in these trials is to enhance the integration of lymph nodes into the lymphatic vasculature after autologous transfer to treat postmastectomy lymphedema. On the other hand, VEGF-C­ induced lymphangiogenesis enhances tumor metastasis and VEGF-C-induced tumor angiogenesis in several mouse models. Blocking VEGF-C might be for these reasons an attractive adjuvant treatment to supplement current cancer treatment regimens that include anti­ angiogenic drugs. The right balance between pro- and anti-Iymphangiogenic stimuli might therefore differ between individuals and CCBEI is an attractive drug target to adjust pro- and anti-Iymphangiogenic stimuli by tuning the rate of VEGF-C activation. %B 41st European Societry of Lymphology (ESL) Congress %I European Group of Lymphology %C Lausanne, Switzerland %8 06/2015 %G eng %U http://www.eurolymphology.org/JOURNAL/VOL26-N72-2015/#p=10 %0 Journal Article %J Lymphologie in Forschung und Praxis %D 2013 %T The lymphangiogenic growth factors VEGF-C and VEGF-D. Part 1: Basic principles and embryonic development. [bilingual: English, German]. %A Krebs, Rainer %A Jeltsch, Michael %K growth factors %K Lymphangiogenesis %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 30 - 37 %8 05/2013 %G eng %U http://jeltsch.org/sites/jeltsch.org/files/JeltschMichael_Lymphforsch2013_30.pdf %N 1 %! Lymphforsch