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| The EMBO Journal
(2001) 20, 1223–1231, doi:10.1093/emboj/20.6.1223 |
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| Signalling via vascular endothelial growth factor receptor-3 is sufficient for lymphangiogenesis in transgenic mice |
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| Tanja Veikkola1, 4, Lotta Jussila1, 4, Taija Makinen1, Terhi Karpanen1, Michael Jeltsch1, Tatiana V. Petrova1, Hajime Kubo1, Gavin Thurston2, Donald M. McDonald2, Marc G. Achen3, Steven A. Stacker3 and Kari Alitalo1 |
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1 Molecular/Cancer Biology Laboratory and Ludwig Institute for Cancer Research, Haartman Institute, University of Helsinki, PO Box 21 (Haartmaninkatu 3), 00014 Helsinki, Finland 2 Department of Anatomy and Cardiovascular Research Institute, University of California, San Francisco, CA 94143, USA 3 Ludwig Institute for Cancer Research, PO Box 2008, Royal Melbourne Hospital, Parkville, Victoria 3050, Australia 4 T.Veikkola and L.Jussila contributed equally to this work To whom correspondence should be addressed Kari Alitalo, Kari.Alitalo@helsinki.fi Received 13 October 2000; Revised 20 December 2000; Accepted 29 January 2001. |
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| Abstract |
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| 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 in vivo. These results demonstrate that stimulation of the VEGFR-3 signal transduction pathway is sufficient to induce specifically lymphangiogenesis in vivo. |
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| Keywords: angiogenesis, lymphangiogenesis, vascular endothelial growth factors (VEGFs), VEGF receptors |
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