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Lysophosphatidic acid up-regulates vascular endothelial growth factor-C and lymphatic marker expressions in human endothelial cells

Lin, C.-I., Chen, C.-N., Huang, M.-T., Lee, S.-J., Lin, C.-H., Chang, C.-C., Lee, H.
Cellular and molecular life sciences 2008 v.65 no.17 pp. 2740-2751
G-protein coupled receptors, angiogenesis, gene expression regulation, human umbilical vein endothelial cells, humans, messenger RNA, metastasis, neoplasm cells, small interfering RNA, therapeutics, vascular endothelial growth factor A, vascular endothelial growth factor C, vascular endothelial growth factor receptor-3
Lysophosphatidic acid (LPA) is a low-molecular-weight lipid growth factor, which binds to G-protein-coupled receptors. Previous studies have shown that LPA enhances vascular endothelial growth factor-A (VEGF-A) expression in cancer cells and promotes angiogenesis process. However, the roles of LPA in lymphatic vessel formation and lymphangiogenesis have not been investigated. Here, we demonstrated that LPA up-regulated VEGF-C mRNA and protein expressions in human umbilical vein endothelial cells (HUVECs). Furthermore, the expression levels of lymphatic markers, including Prox-1, LYVE-1 and podoplanin, were enhanced in LPA-stimulated tube forming endothelial cells in vitro and in vivo. Moreover, we showed that pretreatment with MAZ51, a VEGFR-3 kinase inhibitor, and introduction of VEGFR-3 siRNA suppressed LPA-induced HUVEC tube formation and lymphatic marker expressions. These results demonstrated that LPA enhances expression of lymphatic markers through activating VEGF-C receptors in endothelial cells. This study provides basic information that LPA might be a target for therapeutics against lymphangiogenesis and tumor metastasis.