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/2093797402406nas a2200229   4500008004100000245009500041210006900136260001400205300001400219490000800233520168800241100002101929700002201950700002101972700002001993700002302013700002602036700002102062700002602083700001802109856004902127       2009                        eng d00aActivated forms of VEGF-C and VEGF-D provide improved vascular function in skeletal muscle0 aActivated forms of VEGFC and VEGFD provide improved vascular fun  c2009/Jun/  a1302 - 120 v1043 aThe therapeutic potential of vascular endothelial growth factor (VEGF)-C and VEGF-D in skeletal muscle has been of considerable interest as these factors have both angiogenic and lymphangiogenic activities. Previous studies have mainly used adenoviral gene delivery for short-term expression of VEGF-C and VEGF-D in pig, rabbit, and mouse skeletal muscles. Here we have used the activated mature forms of VEGF-C and VEGF-D expressed via recombinant adeno-associated virus (rAAV), which provides stable, long-lasting transgene expression in various tissues including skeletal muscle. Mouse tibialis anterior muscle was transduced with rAAV encoding human or mouse VEGF-C or VEGF-D. Two weeks later, immunohistochemical analysis showed increased numbers of both blood and lymph vessels, and Doppler ultrasound analysis indicated increased blood vessel perfusion. The lymphatic vessels further increased at the 4-week time point were functional, as shown by FITC-lectin uptake and transport. Furthermore, receptor activation and arteriogenic activity were increased by an alanine substitution mutant of human VEGF-C (C137A) having an increased dimer stability and by a chimeric CAC growth factor that contained the VEGF receptor-binding domain flanked by VEGF-C propeptides, but only the latter promoted significantly more blood vessel perfusion when compared to the other growth factors studied. We conclude that long-term expression of VEGF-C and VEGF-D in skeletal muscle results in the generation of new functional blood and lymphatic vessels. The therapeutic value of intramuscular lymph vessels in draining tissue edema and lymphedema can now be evaluated using this model system.1 aAnisimov, Andrey1 aAlitalo, Annamari1 aKorpisalo, Petra1 aSoronen, Jarkko1 aKaijalainen, Seppo1 aLeppänen, Veli-Matti1 aJeltsch, Michael1 aYlä-Herttuala, Seppo1 aAlitalo, Kari  uhttp://view.ncbi.nlm.nih.gov/pubmed/19443835