02160nas a2200217   4500008004100000245017800041210006900219260001400288300001400302490000800316520140200324100002001726700001501746700002401761700002101785700002301806700002001829700002601849700001801875856004901893       2007                        eng d00aDistinct architecture of lymphatic vessels induced by chimeric vascular endothelial growth factor-C/vascular endothelial growth factor heparin-binding domain fusion proteins0 aDistinct architecture of lymphatic vessels induced by chimeric v  c2007/May/  a1468 - 750 v1003 aVascular 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.1 aTammela, Tuomas1 aHe, Yulong1 aLyytikkä, Johannes1 aJeltsch, Michael1 aMarkkanen, Johanna1 aPajusola, Katri1 aYlä-Herttuala, Seppo1 aAlitalo, Kari  uhttp://view.ncbi.nlm.nih.gov/pubmed/1747873302358nas a2200241   4500008004100000245016500041210006900206260001400275300001400289490000700303520155700310100001501867700001901882700002001901700002101921700002201942700002501964700002001989700001702009700002302026700001802049856004902067       2005                        eng d00aVascular endothelial cell growth factor receptor 3-mediated activation of lymphatic endothelium is crucial for tumor cell entry and spread via lymphatic vessels0 aVascular endothelial cell growth factor receptor 3mediated activ  c2005/Jun/  a4739 - 460 v653 aLymphangiogenic growth factors vascular endothelial growth factor (VEGF)-C and VEGF-D have been shown to promote lymphatic metastasis by inducing tumor-associated lymphangiogenesis. In this study, we have investigated how tumor cells gain access into lymphatic vessels and at what stage tumor cells initiate metastasis. We show that VEGF-C produced by tumor cells induced extensive lymphatic sprouting towards the tumor cells as well as dilation of the draining lymphatic vessels, suggesting an active role of lymphatic endothelial cells in lymphatic metastasis. A significant increase in lymphatic vessel growth occurred between 2 and 3 weeks after tumor xenotransplantation, and lymph node metastasis occurred at the same stage. These processes were blocked dose-dependently by inhibition of VEGF receptor 3 (VEGFR-3) signaling by systemic delivery of a soluble VEGFR-3-immunoglobulin (Ig) fusion protein via adenoviral or adeno-associated viral vectors. However, VEGFR-3-Ig did not suppress lymph node metastasis when the treatment was started at a later stage after the tumor cells had already spread out, suggesting that tumor cell entry into lymphatic vessels is a key step during tumor dissemination via the lymphatics. Whereas lymphangiogenesis and lymph node metastasis were significantly inhibited by VEGFR-3-Ig, some tumor cells were still detected in the lymph nodes in some of the treated mice. This indicates that complete blockade of lymphatic metastasis may require the targeting of both tumor lymphangiogenesis and tumor cell invasion.1 aHe, Yulong1 aRajantie, Iiro1 aPajusola, Katri1 aJeltsch, Michael1 aHolopainen, Tanja1 aYla-Herttuala, Seppo1 aHarding, Thomas1 aJooss, Karin1 aTakahashi, Takashi1 aAlitalo, Kari  uhttp://view.ncbi.nlm.nih.gov/pubmed/15930292