01477nas a2200133   4500008004100000022001400041245011000055210006900165260000900234300000900243490000600252520103100258856005401289       2013                        eng d  a1937-914500aThe basis for the distinct biological activities of vascular endothelial growth factor receptor-1 ligands0 abasis for the distinct biological activities of vascular endothe  c2013  ara520 v63 a<p>Vascular endothelial growth factors (VEGFs) regulate blood and lymphatic vessel development through VEGF receptors (VEGFRs). The VEGFR immunoglobulin homology domain 2 (D2) is critical for ligand binding, and D3 provides additional interaction sites. VEGF-B and placenta growth factor (PlGF) bind to VEGFR-1 with high affinity, but only PlGF is angiogenic in most tissues. We show that VEGF-B, unlike other VEGFs, did not require D3 interactions for high-affinity binding. VEGF-B with a PlGF-derived L1 loop (B-L1(P)) stimulated VEGFR-1 activity, whereas PlGF with a VEGF-B-derived L1 loop (P-L1(B)) did not. Unlike P-L1(B) and VEGF-B, B-L1(P) and PlGF were also angiogenic in mouse skeletal muscle. Furthermore, B-L1(P) also bound to VEGFR-2 and activated downstream signaling. These results establish a role for L1-mediated D3 interactions in VEGFR activation in endothelial cells and indicate that VEGF-B is a high-affinity VEGFR-1 ligand that, unlike PlGF, cannot efficiently induce signaling downstream of VEGFR-1.</p>  uhttps://www.jeltsch.org/Anisimov2013b?language=hu02406nas 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