00451nas a2200109   4500008004100000245014500041210006900186260001600255300000900271490000600280856005500286       2017                        eng d00aEfficient activation of the lymphangiogenic growth factor VEGF-C requires the C-terminal domain of VEGF-C and the N-terminal domain of CCBE10 aEfficient activation of the lymphangiogenic growth factor VEGFC   c2017/07/07/  a49160 v7  uhttps://www.nature.com/articles/s41598-017-04982-101918nas a2200109   4500008004100000245007600041210006900117260001200186490000800198520151000206856009201716       2014                        eng d00aCCBE1 enhances lymphangiogenesis via ADAMTS3-mediated VEGF-C activation0 aCCBE1 enhances lymphangiogenesis via ADAMTS3mediated VEGFC activ  c05/20140 v1293 aBackground—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.  uhttp://circ.ahajournals.org/content/early/2014/02/19/CIRCULATIONAHA.113.002779.abstract01805nas a2200217   4500008004100000245007400041210006900115260001400184300001400198490000700212520115600219100002201375700002501397700002101422700002101443700001801464700001801482700002001500700001801520856004901538       2006                        eng d00aFunctional interaction of VEGF-C and VEGF-D with neuropilin receptors0 aFunctional interaction of VEGFC and VEGFD with neuropilin recept  c2006/Jul/  a1462 - 720 v203 aLymphatic vascular development is regulated by vascular endothelial growth factor receptor-3 (VEGFR-3), which is activated by its ligands VEGF-C and VEGF-D. Neuropilin-2 (NP2), known to be involved in neuronal development, has also been implicated to play a role in lymphangiogenesis. We aimed to elucidate the mechanism by which NP2 is involved in lymphatic endothelial cell signaling. By in vitro binding studies we found that both VEGF-C and VEGF-D interact with NP2, VEGF-C in a heparin-independent and VEGF-D in a heparin-dependent manner. We also mapped the domains of VEGF-C and NP2 required for their binding. The functional importance of the interaction of NP2 with the lymphangiogenic growth factors was demonstrated by cointernalization of NP2 along with VEGFR-3 in endocytic vesicles of lymphatic endothelial cells upon stimulation with VEGF-C or VEGF-D. NP2 also interacted with VEGFR-3 in coprecipitation studies. Our results show that NP2 is directly involved in an active signaling complex with the key regulators of lymphangiogenesis and thus suggest a mechanism by which NP2 functions in the development of the lymphatic vasculature.1 aKärpänen, Terhi1 aHeckman, Caroline, A1 aKeskitalo, Salla1 aJeltsch, Michael1 aOllila, Hanna1 aNeufeld, Gera1 aTamagnone, Luca1 aAlitalo, Kari  uhttp://view.ncbi.nlm.nih.gov/pubmed/16816121