%0 Journal Article %J Circulation %D 2014 %T CCBE1 enhances lymphangiogenesis via ADAMTS3-mediated VEGF-C activation %A Jeltsch, Michael %A Jha, Sawan Kumar %A Tvorogov, Denis %A Anisimov, Andrey %A Leppänen, Veli-Matti %A Holopainen, Tanja %A Kivelä, Riikka %A Ortega, Sagrario %A Kärpänen, Terhi %A Alitalo, Kari %K ADAMTS3 %K angiogenesis %K CCBE1 %K endothelium %K growth factors and cytokines %K Hennekam Syndrome %K metalloproteinase %K vasculature %K VEGF-C %X Background—Hennekam lymphangiectasia-lymphedema syndrome (OMIM 235510) is a rare autosomal recessive disease, which is associated with mutations in the collagen- and calcium-binding EGF domains 1 (CCBE1) gene. Because of the striking phenotypic similarity of embryos lacking either the Ccbe1 gene or the lymphangiogenic growth factor Vegfc gene, we searched for CCBE1 interactions with the VEGF-C growth factor signaling pathway, which is critical in embryonic and adult lymphangiogenesis. Methods and Results—By analyzing VEGF-C produced by CCBE1-transfected cells, we found that while CCBE1 itself does not process VEGF-C, it promotes proteolytic cleavage of the otherwise poorly active 29/31-kDa form of VEGF-C by the A disintegrin and metalloprotease with thrombospondin motifs-3 (ADAMTS3) protease, resulting in the mature 21/23-kDa form of VEGF-C, which induces increased VEGF-C receptor signaling. Adeno-associated viral vector (AAV) mediated transduction of CCBE1 into mouse skeletal muscle enhanced lymphangiogenesis and angiogenesis induced by AAV-VEGF-C. Conclusions—These results identify ADAMTS3 as a VEGF-C activating protease and reveal a novel type of regulation of a vascular growth factor by a protein that enhances its proteolytic cleavage and activation. The results suggest CCBE1 is a potential therapeutic tool for the modulation of lymphangiogenesis and angiogenesis in a variety of diseases that involve the lymphatic system, such as lymphedema or lymphatic metastasis. %B Circulation %V 129 %8 05/2014 %G eng %U http://circ.ahajournals.org/content/early/2014/02/19/CIRCULATIONAHA.113.002779.abstract %N 19 %& 1962-1971 %R http://dx.doi.org/10.1161/CIRCULATIONAHA.113.002779 %0 Journal Article %J Am J Pathol %D 2012 %T Critical role of VEGF-C/VEGFR-3 signaling in innate and adaptive immune responses in experimental obliterative bronchiolitis. %A Krebs, Rainer %A Tikkanen, Jussi M %A Ropponen, Jussi O %A Jeltsch, Michael %A Jokinen, Janne J %A Ylä-Herttuala, Seppo %A Nykänen, Antti I %A Lemström, Karl B %K Adaptive Immunity %K Animals %K Bronchiolitis Obliterans %K Chemotaxis %K Cyclosporine %K Dendritic Cells %K Dose-Response Relationship, Drug %K Down-Regulation %K Epithelial Cells %K Epithelium %K Graft Rejection %K Immunity, Innate %K Immunoglobulins %K Inflammation %K Lymphangiogenesis %K Macrophages %K Neutrophils %K Rats %K Signal Transduction %K Th17 Cells %K Trachea %K Transplantation, Homologous %K Up-Regulation %K Vascular Endothelial Growth Factor C %K Vascular Endothelial Growth Factor Receptor-3 %X

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.

%B Am J Pathol %V 181 %P 1607-20 %8 2012 Nov %G eng %N 5 %R 10.1016/j.ajpath.2012.07.021 %0 Journal Article %J Genes Dev %D 2010 %T Claudin-like protein 24 interacts with the VEGFR-2 and VEGFR-3 pathways and regulates lymphatic vessel development %A Saharinen, Pipsa %A Helotera, Hanna %A Miettinen, Juho %A Norrmen, Camilla %A D'Amico, Gabriela %A Jeltsch, Michael %A Langenberg, Tobias %A Vandevelde, Wouter %A Ny, Annelii %A Dewerchin, Mieke %A Carmeliet, Peter %A Alitalo, Kari %X The Claudin-like protein of 24 kDa (CLP24) is a hypoxia-regulated transmembrane protein of unknown function. We show here that clp24 knockdown in Danio rerio and Xenopus laevis results in defective lymphatic development. Targeted disruption of Clp24 in mice led to enlarged lymphatic vessels having an abnormal smooth muscle cell coating. We also show that the Clp24(-/-) phenotype was further aggravated in the Vegfr2(+/LacZ) or Vegfr3(+/LacZ) backgrounds and that CLP24 interacts with vascular endothelial growth factor receptor-2 (VEGFR-2) and VEGFR-3 and attenuates the transcription factor CREB phosphorylation via these receptors. Our results indicate that CLP24 is a novel regulator of VEGFR-2 and VEGFR-3 signaling pathways and of normal lymphatic vessel structure. %B Genes Dev %V 24 %P 875 - 80 %8 2010/May/ %G eng %U http://view.ncbi.nlm.nih.gov/pubmed/20439428 %N 9 %! Genes & Development %0 Journal Article %J Curr Opin Biotechnol %D 1999 %T Current biology of VEGF-B and VEGF-C %A Olofsson, B %A Jeltsch, M %A Eriksson, U %A Alitalo, K %X Endothelial growth factors and their receptors may provide important therapeutic tools for the treatment of pathological conditions characterised by defective or aberrant angiogenesis. Vascular endothelial growth factor (VEGF) is pivotal for vasculogenesis and for angiogenesis in normal and pathological conditions. VEGF-B and VEGF-C provide this gene family with additional functions, for example, VEGF-C also regulates lymphangiogenesis. %B Curr Opin Biotechnol %V 10 %P 528 - 35 %8 1999/Dec/ %G eng %U http://view.ncbi.nlm.nih.gov/pubmed/10600689 %N 6 %! Current Opinion in Biotechnology