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Analysis of VEGF-responsive genes involved in the activation of endothelial cells.

ABSTRACT: BACKGROUND: Identification of the genes and pathways associated with the activation of endothelial cells (ECs) could help uncover the role of ECs in wound healing, vascular permeability, blood brain barrier function, angiogenesis, diabetic retinopathy, atherosclerosis, psoriasis, and growth of solid tumors. DESIGN: Herein, we embedded ECs in 3D type I collagen gel, left unstimulated or stimulated with VEGF165, and subjected to suppression subtractive hybridization followed by differential display (SSHDD). Gene fragments obtained from SSHDD were subjected to DNA sequence analysis. Database search with nucleotide sequence were performed using the BLAST algorithm and expression of candidate genes determined by northern blot analysis. RESULTS: A total of approximately 32 cDNA fragments, including known regulators of angiogenesis, and a set of genes that were not reported to be associated with activation of ECs and angiogenesis previously were identified. We confirmed the mRNA expression of KDR, alpha2 integrin, Stanniocalcin, including a set of 11 candidate genes. Western immunoblotting results indicated that KDR, alpha2 integrin, MMP-1, MMP-2, and VE-cadherin genes were indeed active genes. CONCLUSION: We have identified a set of 11 VEGF-responsive endothelial cell candidate genes. Their expression in endothelial cell is confirmed by northern blot analyses. This preliminary report forms as a foundation for functional studies to be performed to reveal their roles in EC activation and pathophysiological events associated with the vasculature including tumor growth.

SUBMITTER: Wary KK

PROVIDER: S-EPMC179881 | biostudies-literature | 2003 Jul

REPOSITORIES: biostudies-literature

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Analysis of VEGF-responsive genes involved in the activation of endothelial cells.

Wary Kishore K KK Thakker Geeta D GD Humtsoe Joseph O JO Yang Jun J

Molecular cancer 20030709

<h4>Background</h4>Identification of the genes and pathways associated with the activation of endothelial cells (ECs) could help uncover the role of ECs in wound healing, vascular permeability, blood brain barrier function, angiogenesis, diabetic retinopathy, atherosclerosis, psoriasis, and growth of solid tumors.<h4>Design</h4>Herein, we embedded ECs in 3D type I collagen gel, left unstimulated or stimulated with VEGF165, and subjected to suppression subtractive hybridization followed by differ ...[more]

PMID: 12904264

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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.

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Analysis of VEGF-responsive genes involved in the activation of endothelial cells.

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Analysis of VEGF-responsive genes involved in the activation of endothelial cells.

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