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¹ Molecular/Cancer Biology Laboratory and Ludwig Institute for Cancer Research, Haartman Institute and Helsinki University Hospital, Biomedicum Helsinki, University of Helsinki, 00014 Helsinki, Finland
² Laboratory of Molecular and Cell Biology, Istituto Dermopatico dell'Immacolata, Istituto di Ricovero e Cura a Caraterre Scientifico, 00167 Rome, Italy
³ Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215
⁴ A.I. Virtanen Institute, University of Kuopio, 70211 Kuopio, Finland
⁵ Division of Genetics, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan

CORRESPONDENCE Kari Alitalo: Kari.Alitalo{at}Helsinki.fi

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.

Abbreviations used: E, embryonic day; P, postnatal day; PAE, porcine aortic endothelial; PECAM, platelet endothelial cell adhesion molecule; PlGF, placenta growth factor; SMA, smooth muscle -actin; SMC, smooth muscle cell; VEGF, vascular endothelial growth factor; VEGFR, VEGF receptor.

T. Tammela and M. Uutela contributed equally to this paper.

Y. He's present address is Model Animal Research Institute, Nanjing University, Nanjing 210061, China.

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