Transcriptional profiling of VEGF-A and VEGF-C target genes in lymphatic endothelium reveals endothelial-specific molecule-1 as a novel mediator of lymphangiogenesis
Open Access
- 15 September 2008
- journal article
- research article
- Published by American Society of Hematology in Blood
- Vol. 112 (6), 2318-2326
- https://doi.org/10.1182/blood-2008-05-156331
Abstract
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 (LECs). 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 LECs 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 siRNA-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 pathologic lymphatic vessel activation.This publication has 69 references indexed in Scilit:
- Adrenomedullin signaling is necessary for murine lymphatic vascular developmentJCI Insight, 2008
- Endocan is a VEGF-A and PI3K regulated gene with increased expression in human renal cancerExperimental Cell Research, 2007
- VEGF-C–induced lymphangiogenesis in sentinel lymph nodes promotes tumor metastasis to distant sitesBlood, 2006
- A multivariate empirical Bayes statistic for replicated microarray time course dataThe Annals of Statistics, 2006
- Down Syndrome Candidate Region 1,a Downstream Target of VEGF, Participa tes in Endothelial Cell Migration and AngiogenesisJournal of Vascular Research, 2004
- Bioinformatic analysis of primary endothelial cell gene array data illustrated by the analysis of transcriptome changes in endothelial cells exposed to VEGF-A and PlGFAngiogenesis, 2004
- Vascular Endothelial Growth Factor–Regulated Gene Expression in Endothelial CellsArteriosclerosis, Thrombosis, and Vascular Biology, 2003
- Role of Angiopoietins and Tie receptor tyrosine kinases in angiogenesis and lymphangiogenesisCell and tissue research, 2003
- Ligand-induced Vascular Endothelial Growth Factor Receptor-3 (VEGFR-3) Heterodimerization with VEGFR-2 in Primary Lymphatic Endothelial Cells Regulates Tyrosine Phosphorylation SitesOnline Journal of Public Health Informatics, 2003
- Using Bayesian Networks to Analyze Expression DataJournal of Computational Biology, 2000