CD154-CD13 Pathway in Inflammation-driven Angiogenesis

描述（由申请人提供）： 心肌灌注受损触发炎症和血管生成反应; 增强血管生成是一个新兴的主题， 缺血心肌这些过程的相互依赖性由以下几点说明： 观察到炎症是诱导所必需的， 维持病理性血管生成，其中血管生成生长因子募集 炎性细胞转移到心肌血管生成部位。两者的诱导 VEGF和CD 13/APN血管生成调节因子通过炎症介质CD 154 在内皮细胞中建立了炎症和 血管生成CD 13/APN在血管生成性梗死周围组织中的表达 心肌梗死后与CD 154共定位的区域，因此 表明心肌血管生成依赖于这两个过程。VEGF和 PlGF（胎盘生长因子）形成协同活性异二聚体， 还诱导CD 13/APN表达。这些数据引发了分子机制 将炎症与早期（PlGF，VEGF）和晚期（PlGF，VEGF）的表达联系起来， (CD13/APN）血管生成调节剂。我们假设炎症反应 CD 154介导的CD 13/APN表达是通过VEGF和PlGF依赖的 机制，从而刺激心肌缺血区域的血管生成。 这些研究的目的是阐明连接 炎症细胞信号的诱导，进展和维持， 心肌缺血中的血管生成。我们将确定信号， CD 154诱导CD 13/APN的转录机制 体外培养内皮细胞。CD 154-CD 154的组分的贡献 CD 13/APN通路对心肌梗死后血管生成和伤口愈合的影响 和局部缺血/再灌注损伤将在以下小鼠模型中进行评价： 转基因动物体内的心肌疾病。阐明 负责炎症调节的分子机制 血管生成将提供新的机制，了解心肌 血管生成和更合理的治疗缺血性疾病的方法的基础 心血管疾病

DESCRIPTION (provided by applicant): Impaired myocardial perfusion triggers inflammatory and angiogenic responses; enhancing angiogenesis is an emerging theme for the revascularization of ischemic myocardium. The interdependence of these processes is illustrated by the observation that inflammation is essential for the induction and maintenance of pathologic angiogenesis where angiogenic growth factors recruit inflammatory cells to myocardial sites of angiogenesis. Induction of both VEGF and the CD13/APN angiogenic regulator by the inflammatory mediator CD154 in endothelial cells establishes an essential link between inflammation and angiogenesis. CD13/APN expression is induced in the angiogenic peri-infarct zone after myocardial infarction where it co-localizes with CD154, thus indicating that myocardial angiogenesis relies on both processes. VEGF and PlGF (placental growth factor) form synergistically active heterodimers that also induce CD13/APN expression. These data invoke a molecular mechanism linking inflammation to expression of both early (PlGF, VEGF) and late (CD13/APN) angiogenic regulators. We hypothesize that the inflammatory mediator CD154 induces CD13/APN expression via a VEGF and PlGF-dependent mechanism, thereby stimulating angiogenesis in regions of myocardial ischemia. The goal of these studies is to elucidate the molecular mechanisms linking inflammatory cell signals to the induction, progression, and maintenance of angiogenesis in myocardial ischemia. We will determine the signaling and transcriptional mechanisms of CD13/APN induction by CD154 in primary endothelial cells in vitro. The contribution of components of the CD154- CD13/APN pathway to angiogenesis and wound healing after myocardial infarction and ischemia/reperfusion injury will be evaluated in murine models of myocardial disease in genetically modified animals in vivo. Elucidation of the molecular mechanisms responsible for the inflammatory regulation of angiogenesis will provide new mechanistic insights into myocardial angiogenesis and a basis for more rational approaches to treating ischemic cardiovascular disease.