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Transcriptional profiling of VEGF-A and VEGF-C target genes in lymphatic endothelium reveals endothelial-specific molecule-1 as a novel mediator of lymphangiogenesis.

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.

SUBMITTER: Shin JW

PROVIDER: S-EPMC2532805 | biostudies-literature | 2008 Sep

REPOSITORIES: biostudies-literature

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Transcriptional profiling of VEGF-A and VEGF-C target genes in lymphatic endothelium reveals endothelial-specific molecule-1 as a novel mediator of lymphangiogenesis.

Shin Jay W JW Huggenberger Reto R Detmar Michael M

Blood 20080709 6

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 lymphangiogenesi ...[more]

PMID: 18614759

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Project description:Ethnopharmacological relevanceLymphatic system plays an important role in maintaining the fluid homeostasis and normal immune responses, anatomic or functional obstruction of which leads to lymphedema, and treatments for therapeutic lymphangiogenesis are efficiency for secondary lymphedema. Total saponins of panaxnotoginseng (PNS) are a mixture isolated from Panaxnotoginseng (Burkill) F.H.Chen, which has been used as traditional Chinese medicine in China for treatment of cardio- and cerebro-vascular diseases. The aim of this study was to determine the effect and mechanism of PNS on lymphangiogenesis.MethodsThe Tg (fli1: egfp; gata1: dsred) transgenic zebrafish embryos were treated with different concentrations of PNS (10, 50, 100μM) for 48h with or without the 6h pretreatment of the 30μM Vascular endothelial growth factors receptor (VEGFR)-3 kinase inhibitor, followed with morphological observation and lympangiogenesis of thoracic duct assessment. The effect of PNS on cell viability, migration, tube formation and Vascular endothelial growth factors (VEGF)-C mRNA and protein expression of lymphatic endothelial cells (LECs) were determined. The role of phosphatidylinositol-3 (PI-3)-kinase (PI3K), extracellular signal-regulated kinase (ERK)1/2 pathways, c-Jun N-terminal kinase (JNK) and P38 mitogen activated protein kinases (MAPK) signaling in PNS-induced VEGF-C expression of LECs by using pharmacological agents to block each signal.ResultsPNS promotes lymphangiogenesis of thoracic duct in zebrafish with or without VEGFR3 Kinase inhibitor pre-impairment. PNS promotes proliferation, migration and tube formation of LECs. The tube formation induced by PNS could be blocked by VEGFR3 Kinase inhibitor. PNS induce VEGF-C expression of LEC, which could be blocked by ERK1/2, PI3K and P38MAPK signaling inhibitors.ConclusionPNS activates lymphangiogenesis both in vivo and in vitro by up-regulating VEGF-C expression and activation of ERK1/2, PI3K and P38MAPK signaling. These findings provide a novel insight into the role of PNS in lymphangiogenesis and suggest that it might be an attractive and suitable therapeutic agent for treating secondary lymphedema or other lymphatic system impairment related disease.

Dataset Information

Transcriptional profiling of VEGF-A and VEGF-C target genes in lymphatic endothelium reveals endothelial-specific molecule-1 as a novel mediator of lymphangiogenesis.

Publications

Transcriptional profiling of VEGF-A and VEGF-C target genes in lymphatic endothelium reveals endothelial-specific molecule-1 as a novel mediator of lymphangiogenesis.

Similar Datasets

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