Submitted May 12, 2008
Accepted July 2, 2008
Transcriptional profiling of VEGF-A and VEGF-C target genes in lymphatic endothelium reveals endothelial-specific molecule-1 as a novel mediator of lymphangiogenesis
Jay W. Shin, Reto Huggenberger, and Michael Detmar*
Institute of Pharmaceutical Sciences, ETH Zurich, Zurich, Switzerland
* Corresponding author; email: michael.detmar{at}pharma.ethz.ch.
Lymphatic vessel growth and activation, mediated by vascular endothelial growth factor (VEGF)-C and/or VEGF-A, have important roles in metastasis and in chronic inflammation. We aimed to comprehensively identify downstream molecular targets induced by VEGF-A or VEGF-C in lymphatic endothelium, by analyzing the time-series transcriptional profile of treated human dermal lymphatic endothelial cells (LEC). We identified a number of genes, many not previously known to be involved in lymphangiogenesis, that were characterized either as early response genes, transiently induced genes or progressively induced genes. Endothelial-specific molecule-1 (ESM-1) was one of the genes that were most potently induced by both VEGF-A and VEGF-C. Whereas ESM-1 induction by VEGF-A was mainly dependent on activation of VEGFR-2, VEGF-C-mediated induction depended on the activity of both VEGFR-2 and VEGFR-3. Incubation of LEC with ESM-1 increased the stimulatory effects of both VEGF-A and VEGF-C on LEC proliferation and migration, whereas ESM-1 alone had no effect. Importantly, VEGF-A (or VEGF-C) induction of LEC proliferation and migration were significantly inhibited by small interfering RNAs-mediated silencing of ESM-1 in vitro and in vivo. These studies reveal ESM-1 as a novel mediator of lymphangiogenesis and as a potential target for the inhibition of pathological lymphatic vessel activation.
