Distinct vascular endothelial growth factor signals for lymphatic vessel enlargement and sprouting.
Lymphatic vessel growth, or lymphangiogenesis, is regulated by vascular endothelial growth factor-C (VEGF-C) and -D via VEGF receptor 3 (VEGFR-3). Recent studies suggest that VEGF, which does not bind to VEGFR-3, can also induce lymphangiogenesis through unknown mechanisms. To dissect the receptor pathway that triggers VEGFR-3-independent lymphangiogenesis, we used both transgenic and adenoviral overexpression of placenta growth factor (PlGF) and VEGF-E, which are specific activators of VEGFR-1 and -2, respectively. Unlike PlGF, VEGF-E induced circumferential lymphatic vessel hyperplasia, but essentially no new vessel sprouting, when transduced into mouse skin via adenoviral vectors. This effect was not inhibited by blocking VEGF-C and -D. Postnatal lymphatic hyperplasia, without increased density of lymphatic vessels, was also detected in transgenic mice expressing VEGF-E in the skin, but not in mice expressing PlGF. Surprisingly, VEGF-E induced lymphatic hyperplasia postnatally, and it did not rescue the loss of lymphatic vessels in transgenic embryos where VEGF-C and VEGF-D were blocked. Our data suggests that VEGFR-2 signals promote lymphatic vessel enlargement, but unlike in the blood vessels, are not involved in vessel sprouting to generate new lymphatic vessels in vivo.
Wirzenius
Maria
M
Molecular/Cancer Biology Laboratory and Ludwig Institute for Cancer Research, Haartman Institute and Helsinki University Hospital, Biomedicum Helsinki, University of Helsinki, 00014 Helsinki, Finland.
Tammela
Tuomas
T
Uutela
Marko
M
He
Yulong
Y
Odorisio
Teresa
T
Zambruno
Giovanna
G
Nagy
Janice A
JA
Dvorak
Harold F
HF
Ylä-Herttuala
Seppo
S
Shibuya
Masabumi
M
Alitalo
Kari
K
D000256:Adenoviridae; D000818:Animals; D015153:Blotting, Western; D001973:Bromodeoxyuridine; D017931:DNA Primers; D005822:Genetic Vectors / Q000235:genetics; D042583:Lymphangiogenesis / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
D017931:DNA Primers; C000608037:Pgf protein, mouse; D011257:Pregnancy Proteins; D042461:Vascular Endothelial Growth Factor A; D000072483:Placenta Growth Factor; D040262:Receptors, Vascular Endothelial Growth Factor; D001973:Bromodeoxyuridine