Signalling via vascular endothelial growth factor receptor-3 is sufficient for lymphangiogenesis in transgenic mice.
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.
Veikkola
T
T
Molecular/Cancer Biology Laboratory and Ludwig Institute for Cancer Research, Haartman Institute, University of Helsinki, PO Box 21 (Haartmaninkatu 3), 00014 Helsinki, Finland.
Jussila
L
L
Makinen
T
T
Karpanen
T
T
Jeltsch
M
M
Petrova
T V
TV
Kubo
H
H
Thurston
G
G
McDonald
D M
DM
Achen
M G
MG
Stacker
S A
SA
Alitalo
K
K
D000818:Animals; D016228:Endothelial Growth Factors / Q000378:metabolism*; D006207:Half-Life; D006965:Hyperplasia; D008208:Lymphatic System / Q000254:growth & development / Q000378:metabolism* / Q000473:pathology; D008222:Lymphokines / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D019899:Paracrine Communication; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D017978:Receptors, Growth Factor / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D012867:Skin / Q000098:blood supply / Q000254:growth & development / Q000378:metabolism* / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A; D042582:Vascular Endothelial Growth Factor C; D042643:Vascular Endothelial Growth Factor D; D040321:Vascular Endothelial Growth Factor Receptor-3; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D008222:Lymphokines; D017978:Receptors, Growth Factor; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; D042582:Vascular Endothelial Growth Factor C; D042643:Vascular Endothelial Growth Factor D; D042442:Vascular Endothelial Growth Factors; D020794:Receptor Protein-Tyrosine Kinases; D040321:Vascular Endothelial Growth Factor Receptor-3