Generation and Analysis of Smooth Muscle-Specific C/EBP-δ Transgenic Rats

血小板衍生生长因子(PDGF)被认为在多种血管重塑模型中发挥重要作用，特别是在血管疾病的早期过程中。其作用是由其特异性受体PDGF受体(PDGFR)介导的。血小板衍生生长因子α受体(PDGFaR)在血管平滑肌细胞的生长增殖中起重要作用，其基因表达受多种潜在转录核因子的调控。然而，PDGFαR基因在血管平滑肌细胞中的组织特异性反式激活的详细机制仍有待阐明。我们已经证明了大鼠PDGFαR基因在其启动子区域含有CCAAT/增强子结合蛋白(C/EBPS)的增强子核心序列，并认为C/eBP-δ是在血管平滑肌细胞中诱导PDGFαR基因组织特异性转录活性的主要因素。为了探讨C/eBP-δ蛋白在血管内皮细胞PDGFR基因转录中的作用，我们利用小鼠血管平滑肌肌动蛋白启动子与大鼠C/eBP-α基因的完整编码区的融合基因构建了C/eBP-δ转基因大鼠。本报告首次成功地靶向过表达C/eBP-δ，能够诱导PDGFR基因转录并改变细胞对PBGFs的增殖活性。靶向过表达δ可诱导高水平的αR基因表达、血管平滑肌细胞对PDGFs的易感性以及对PDGFs的增殖。这些结果表明，C/eBP-δ通过αR在血管重塑和动脉粥样硬化过程中对血管平滑肌细胞的生长具有新的作用和新的功能意义。

Platelet-derived growth factor (PDGF) is thought to play a significant role in various models of vascular remodeling, particularly in the early process of vascular diseases. Its action is mediated by its specific receptor, PDGF receptor (PDGFR). PDGF α-receptor (PDGFaR) plays an important role in the growth and proliferation of vascular smooth muscle, cells (VSMCs), and its gene expression is thought to be regulated by several potential transcriptional nuclear factors. However, the detailed mechanisms of tissue-specific transactivation of the PDGFαR gene in VSMCs remain to be clarified. We have previously demonstrated that the rat PDGFαR gene contains an enhancer core sequence for CCAAT/enhancer-binding proteins (C/EBPs) in its promoter region, and have also suggested that C/EBP-δ is the principal factor involved in the induction of tissue-specific transcriptional activity of the PDGFαR gene in VSMCs. To explore the definitive roles of C/EBP-δ protein on PDGFαR gene transcription in VSMCs, we here developed C/EBP-δ transgenic rats using a chimeric fusion gene of the mouse smooth muscle α-actin promoter and an entire coding region of rat C/EBP-δ cDNA. This report describes the first successful targeted overexpression of C/EBP-δ capable of inducing PDGFαR gene transcription and modifying cell proliferative activity to PBGFs. Targeted overexpression ofC/EBP-δ evokes high levels of PDGFαR gene expression, susceptibility to VSMC growth, and proliferation of VSMCs to PDGFs. The results obtained herein show evidence of a new role and new functional significance of C/EBP-δ on VSMC growth via PDGFαR during the process of vascular remodeling and atherosclerosis.