02729nas a2200349   4500008004100000245015500041210006900196260001400265300001400279490000800293520163900301100001501940700002001955700002201975700002101997700002002018700002002038700002102058700001902079700002102098700002102119700002102140700002302161700002202184700002602206700001902232700001902251700002302270700001902293700001802312856004902330       2010                        eng d00aVascular endothelial growth factor-B acts as a coronary growth factor in transgenic rats without inducing angiogenesis, vascular leak, or inflammation0 aVascular endothelial growth factorB acts as a coronary growth fa  c2010/Oct/  a1725 - 330 v1223 aBACKGROUND: Vascular endothelial growth factor-B (VEGF-B) binds to VEGF receptor-1 and neuropilin-1 and is abundantly expressed in the heart, skeletal muscle, and brown fat. The biological function of VEGF-B is incompletely understood. METHODS AND RESULTS: Unlike placenta growth factor, which binds to the same receptors, adeno-associated viral delivery of VEGF-B to mouse skeletal or heart muscle induced very little angiogenesis, vascular permeability, or inflammation. As previously reported for the VEGF-B(167) isoform, transgenic mice and rats expressing both isoforms of VEGF-B in the myocardium developed cardiac hypertrophy yet maintained systolic function. Deletion of the VEGF receptor-1 tyrosine kinase domain or the arterial endothelial Bmx tyrosine kinase inhibited hypertrophy, whereas loss of VEGF-B interaction with neuropilin-1 had no effect. Surprisingly, in rats, the heart-specific VEGF-B transgene induced impressive growth of the epicardial coronary vessels and their branches, with large arteries also seen deep inside the subendocardial myocardium. However, VEGF-B, unlike other VEGF family members, did not induce significant capillary angiogenesis, increased permeability, or inflammatory cell recruitment. CONCLUSIONS: VEGF-B appears to be a coronary growth factor in rats but not in mice. The signals for the VEGF-B-induced cardiac hypertrophy are mediated at least in part via the endothelium. Because cardiomyocyte damage in myocardial ischemia begins in the subendocardial myocardium, the VEGF-B-induced increased arterial supply to this area could have therapeutic potential in ischemic heart disease.1 aBry, Maija1 aKivelä, Riikka1 aHolopainen, Tanja1 aAnisimov, Andrey1 aTammela, Tuomas1 aSoronen, Jarkko1 aSilvola, Johanna1 aSaraste, Antti1 aJeltsch, Michael1 aKorpisalo, Petra1 aCarmeliet, Peter1 aLemström, Karl, B1 aShibuya, Masabumi1 aYlä-Herttuala, Seppo1 aAlhonen, Leena1 aMervaala, Eero1 aAndersson, Leif, C1 aKnuuti, Juhani1 aAlitalo, Kari  uhttp://view.ncbi.nlm.nih.gov/pubmed/2093797402358nas 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