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

血小板衍生生长因子（PDGF）被认为在各种血管重构模型中发挥重要作用，特别是在血管疾病的早期过程中。其作用由其特异性受体PDGF受体（PDGFR）介导。PDGF α-受体（PDGFaR）在血管平滑肌细胞（VSMCs）的生长和增殖中起重要作用，其基因表达被认为受几种潜在转录核因子的调控。然而，PDGFαR基因在VSMCs中组织特异性转激活的具体机制尚不清楚。我们之前已经证明，大鼠PDGFαR基因在其启动子区域含有CCAAT/增强子结合蛋白（C/EBP）的增强子核心序列，并且还表明C/EBP-δ是诱导VSMCs中PDGFαR基因组织特异性转录活性的主要因素。为了探究C/EBP-δ蛋白在VSMCs中对PDGFαR基因转录的决定性作用，我们利用小鼠平滑肌α-肌动蛋白启动子基因和大鼠C/EBP-δ cDNA的整个编码区嵌合融合基因，培育了C/EBP-δ转基因大鼠。本报告首次成功地靶向过表达了能够诱导PDGFαR基因转录并改变PBGFs细胞增殖活性的C/EBP-δ。靶向过表达c /EBP-δ引起PDGFαR基因的高水平表达，对VSMC生长的易感性，以及VSMC对PDGFs的增殖。本研究结果表明，在血管重构和动脉粥样硬化过程中，C/EBP-δ通过PDGFαR对VSMC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.