Published online before print May 12, 2005, doi: 10.1161/01.RES.0000168918.27576.78
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Submitted on September 17, 2004
Revised on April 27, 2005
Accepted on April 28, 2005
Overexpression of VEGF-C Causes Transient Lymphatic Hyperplasia but not Increased Lymphangiogenesis in Regenerating Skin
Jeremy Goldman ;
From the Biomedical Engineering Department (J.G., T.L., M.A.S.), Northwestern University, Evanston, Ill; Derald H. Ruttenberg Cancer Center (M.S.), Mt. Sinai School of Medicine, New York; and the Institute for Biological Engineering and Biotechnology (M.A.S.), Swiss Federal Institute of Technology Lausanne (EPFL), Lausanne, Switzerland
* To whom correspondence should be addressed. E-mail: melody.swartz{at}epfl.ch.
Vascular endothelial growth factor (VEGF)-C is necessary for lymphangiogenesis and holds potential for lymphangiogenic therapy in diseases lacking adequate lymphatic drainage. However, the ability of VEGF-C to enhance sustainable, functional lymphatic growth in adult tissues remains unclear. To address this, we evaluated VEGF-C overexpression in adult lymphangiogenesis in regenerating skin. We used a model of mouse tail skin regeneration incorporating a suspension of either VEGF-C overexpressing tumor cells, which provide a continuous supplement of excess VEGF-C to the natural regenerating environment for more than 25 days, or otherwise identical control-transfected tumor cells. We found that excess VEGF-C did not enhance the rate of lymphatic endothelial cell (LEC) migration, the density of lymphatic vessels, or the rate of functionality - even though lymphatic hyperplasia was present early on. Furthermore, the hyperplasia disappeared when VEGF-C levels diminished, which occurred after 25 days, rendering the lymphatics indistinguishable from those in control groups. In vitro, we showed that whereas cell-derived VEGF-C could induce chemoattraction of LECs across a membrane (which involves amoeboid-like transmigration), it did not increase LEC chemoinvasion within a 3-dimensional fibrin matrix (which requires proteolytic migration). These results suggest that whereas excess VEGF-C may enhance early LEC proliferation and cause lymphatic vessel hyperplasia, it does not augment the physiological rate of migration or functionality, and by itself cannot sustain any lasting effects on lymphatic size, density, or organization in regenerating adult skin.
Key words: VEGFR-3 • chemotaxis • in vivo • in vitro • lymphatic endothelial cell • mouse
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