Abstract
Related Transcriptional Enhancer Factor-1 (RTEF-1) has been suggested to induce angiogenesis through regulating target genes. Whether RTEF-1 has a direct role in angiogenesis and what specific genes are involved in RTEF-1 driven angiogenisis have not been elucidated. We found that over-expressing RTEF-1 in Human dermal microvascular endothelial cells-1 (HMEC-1) significantly increased endothelial cell aggregation, growth and migration while the processes were inhibited by siRNA of RTEF-1. In addition, we observed that Endothelial differentiation gene-1 (Edg-1) expression was up-regulated by RTEF-1 at the transcriptional level. RTEF-1 could bind to Edg-1 promoter and subsequently induce its activity. Edg-1 siRNA significantly blocked RTEF-1-driven increases in endothelial cell aggregation in a Matrigel assay and retarded RTEF-1-induced endothelial cell growth and migration. Pertussis Toxin (PTX), a Gi/Go protein sensitive inhibitor, was found to inhibit RTEF-1 driven endothelial cell aggregation and migration. Our data demonstrates that Edg-1 is a potential target gene of RTEF-1 and is involved in RTEF-1-induced angiogenesis in endothelial cells. Gi/Go protein coupled receptor pathway plays a role in RTEF-1 driven angiogenesis in endothelial cells.
Highlights
Related Transcriptional Enhancer Factor 1 (RTEF-1), known as TEAD4 (TEA domain family member 4), is a member of the Transcription Enhancer Factor family, and plays important roles in a variety of physiological and pathological conditions
In a DNA microarray data from human umbilical vein endothelial cells (HUVEC), we found that Endothelial differentiation gene-1 (Edg-1) was significantly down-regulated following RTEF-1 knockdown by RTEF-1 Small interfering RNA (siRNA) (p = 0.0002, vs negative control siRNA treated HUVEC) (Figure S1)
Edg-1 mRNA increased to 1.80 fold in RTEF-1o/e Human dermal microvascular endothelial cells-1 (HMEC-1) cells and decreased to 0.13 fold and 0.30 fold in RTEF-1 knockdown HMEC-1 cells compared to their corresponding controls (Figure 2A)
Summary
Related Transcriptional Enhancer Factor 1 (RTEF-1), known as TEAD4 (TEA domain family member 4), is a member of the Transcription Enhancer Factor family, and plays important roles in a variety of physiological and pathological conditions. RTEF-1 targets the promoters of many genes and shares a highly conserved domain capable of binding to the MCAT element CATN(T/C)(T/C) [1,2] in the promoter region of genes expressed in endothelial [3], cardiac [4], skeletal and smooth muscle cells [5], as well as myofibroblasts [6]. RTEF-1 is involved in the stimulation of angiogenesis under hypoxia via transcriptional regulation of its target genes [7]. RTEF-1 is shown to transcriptionally regulate Hypoxia inducible factor (HIF)-1 and accelerate recovery rates from hind limb ischemic injury [3]. RTEF-1 impacts the Fibroblast growth factor (FGF)/FGFR system through the eNOS pathway in the regulation of angiogenesis and vasodilation [8]. The direct effect of RTEF-1 on angiogenesis in endothelial cells and new target genes that might be involved in RTEF-1 driven angiogenesis has not been fully understood
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