Transcriptional and posttranscriptional regulation of angiopoietin-2 expression mediated by IGF and PDGF in vascular smooth muscle cells
Transcriptional and posttranscriptional regulation of angiopoietin-2 expression mediated by IGF and PDGF in vascular smooth muscle cells
复制标题
DOI：
10.1152/ajpcell.00050.2005
复制
发表时间：
2006-02-01
影响因子：
5.5
通讯作者：
Howard, EW
中科院分区：
文献类型：
--
作者：
Phelps, ED;Updike, DL;Howard, EW
血管生成素在血管发育和血管生成中起重要作用。血管生成素-1（Ang 1）和血管生成素-2（Ang 2）均与受体酪氨酸激酶Tie 2结合。然而，虽然Ang 1信号导致血管结构的稳定，但Ang 2与血管不稳定有关。因此，这两种Tie 2配体的比例对于血管稳定性和重塑至关重要。本研究确定了生长因子介导的血管平滑肌细胞（VSMCs）Ang 2表达减少的机制。血管平滑肌细胞对PDGF的反应是在4小时内下调Ang 2 mRNA水平75%，随后Ang 2蛋白水平下降。内源性转录率的定量显示，PDGF刺激并没有改变Ang 2的转录率，而是诱导了快速Ang 2 mRNA不稳定的转录后机制。PDGF处理后Ang 2 mRNA半衰期减少至少50%。PDGF诱导的mRNA更新机制依赖于多种MAPK途径，包括ERK和JNK。与此相反，IGF-I，这并没有显着激活ERK或JNK，刺激增加Ang 2的表达，通过转录激活。这些发现表明，血管平滑肌细胞通过多种机制调节Ang 2的表达，包括转录的变化以及转录后mRNA的不稳定。
Angiopoietins play a significant role in vascular development and angiogenesis. Both angiopoietin-1 (Ang1) and angiopoietin-2 (Ang2) bind the receptor tyrosine kinase Tie2. However, while Ang1 signaling results in the stabilization of vessel structure, Ang2 has been linked to vascular instability. The ratio of these two Tie2 ligands is thus critical for vascular stability and remodeling. This study identifies a mechanism of growth factor-mediated reduction in Ang2 expression in vascular smooth muscle cells (VSMCs). In response to PDGF, VSMCs downregulated Ang2 mRNA levels by 75% within 4 h, with a subsequent decrease in Ang2 protein levels. Quantitation of endogenous transcription rates revealed that PDGF stimulation did not alter Ang2 transcription rates, but instead induced a posttranscriptional mechanism of rapid Ang2 mRNA destabilization. The Ang2 mRNA half-life was reduced by at least 50% after PDGF treatment. The PDGF-induced mRNA turnover mechanism was dependent on several MAPK pathways, including ERK and JNK. In contrast, IGF-I, which did not significantly activate ERK or JNK, stimulated increased Ang2 expression through transcriptional activation. These findings demonstrate that VSMCs adjust Ang2 expression through multiple mechanisms, including changes in transcription as well as posttranscriptional mRNA destabilization.