Signalling via vascular endothelial growth factor receptor-3 is sufficient for lymphangiogenesis in transgenic mice

被引:504
作者
Veikkola, T
Jussila, L
Makinen, T
Karpanen, T
Jeltsch, M
Petrova, TV
Kubo, H
Thurston, G
McDonald, DM
Achen, MG
Stacker, SA
Alitalo, K
机构
[1] Univ Helsinki, Haartman Inst, Mol Canc Biol Lab, FIN-00014 Helsinki, Finland
[2] Univ Helsinki, Haartman Inst, Ludwig Inst Canc Res, FIN-00014 Helsinki, Finland
[3] Univ Calif San Francisco, Dept Anat, San Francisco, CA 94143 USA
[4] Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94143 USA
[5] Royal Melbourne Hosp, Ludwig Inst Canc Res, Parkville, Vic 3050, Australia
关键词
angiogenesis; lymphangiogenesis; vascular endothelial growth factors (VEGFs); VEGF receptors;
D O I
10.1093/emboj/20.6.1223
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Vascular 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 irt vivo. These results demonstrate that stimulation of the VEGFR-3 signal transduction pathway is sufficient to induce specifically lymphangiogenesis in vivo.
引用
收藏
页码:1223 / 1231
页数:9
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