01909nas a2200229   4500008004100000245010400041210006900145260001400214300001200228490000700240520124400247100001401491700001601505700001501521700001201536700001601548700001301564700001701577700002101594700001501615856004901630       2001                        eng d00aAdenoviral expression of vascular endothelial growth factor-C induces lymphangiogenesis in the skin0 aAdenoviral expression of vascular endothelial growth factorC ind  c2001/Mar/  a623 - 90 v883 aThe growth of blood and lymphatic vasculature is mediated in part by secreted polypeptides of the vascular endothelial growth factor (VEGF) family. The prototype VEGF binds VEGF receptor (VEGFR)-1 and VEGFR-2 and is angiogenic, whereas VEGF-C, which binds to VEGFR-2 and VEGFR-3, is either angiogenic or lymphangiogenic in different assays. We used an adenoviral gene transfer approach to compare the effects of these growth factors in adult mice. Recombinant adenoviruses encoding human VEGF-C or VEGF were injected subcutaneously into C57Bl6 mice or into the ears of nude mice. Immunohistochemical analysis showed that VEGF-C upregulated VEGFR-2 and VEGFR-3 expression and VEGF upregulated VEGFR-2 expression at 4 days after injection. After 2 weeks, histochemical and immunohistochemical analysis, including staining for the lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1), the vascular endothelial marker platelet-endothelial cell adhesion molecule-1 (PECAM-1), and the proliferating cell nuclear antigen (PCNA) revealed that VEGF-C induced mainly lymphangiogenesis in contrast to VEGF, which induced only angiogenesis. These results have significant implications in the planning of gene therapy using these growth factors.1 aEnholm, B1 aKarpanen, T1 aJeltsch, M1 aKubo, H1 aStenback, F1 aPrevo, R1 aJackson, D G1 aYla-Herttuala, S1 aAlitalo, K  uhttp://view.ncbi.nlm.nih.gov/pubmed/1128289701998nas a2200265   4500008004100000245012000041210006900161260001400230300001400244490000700258520123100265100001601496700001501512700001501527700001601542700001501558700001701573700001201590700001601602700001801618700001501636700001701651700001501668856004901683       2001                        eng d00aSignalling via vascular endothelial growth factor receptor-3 is sufficient for lymphangiogenesis in transgenic mice0 aSignalling via vascular endothelial growth factor receptor3 is s  c2001/Mar/  a1223 - 310 v203 aVascular endothelial growth factor receptor-3 (VEGFR-3) has an essential role in the development of embryonic blood vessels; however, after midgestation its expression becomes restricted mainly to the developing lymphatic vessels. The VEGFR-3 ligand VEGF-C stimulates lymphangiogenesis in transgenic mice and in chick chorioallantoic membrane. As VEGF-C also binds VEGFR-2, which is expressed in lymphatic endothelia, it is not clear which receptors are responsible for the lymphangiogenic effects of VEGF-C. VEGF-D, which binds to the same receptors, has been reported to induce angiogenesis, but its lymphangiogenic potential is not known. In order to define the lymphangiogenic signalling pathway we have created transgenic mice overexpressing a VEGFR-3-specific mutant of VEGF-C (VEGF-C156S) or VEGF-D in epidermal keratinocytes under the keratin 14 promoter. Both transgenes induced the growth of lymphatic vessels in the skin, whereas the blood vessel architecture was not affected. Evidence was also obtained that these growth factors act in a paracrine manner in vivo. These results demonstrate that stimulation of the VEGFR-3 signal transduction pathway is sufficient to induce specifically lymphangiogenesis in vivo.1 aVeikkola, T1 aJussila, L1 aMakinen, T1 aKarpanen, T1 aJeltsch, M1 aPetrova, T V1 aKubo, H1 aThurston, G1 aMcDonald, D M1 aAchen, M G1 aStacker, S A1 aAlitalo, K  uhttp://view.ncbi.nlm.nih.gov/pubmed/11250889