CD154-CD13 Pathway in Inflammation-driven Angiogenesis

描述(由申请人提供)： 心肌灌注受损会引发炎症和血管生成反应； 促进血管生成是血管重建术的一个新兴主题 缺血心肌。这些过程的相互依存性如下所示 观察到炎症是诱导和感染的关键因素 在血管生成生长因子招募的地方维持病理性血管生成 炎性细胞向心肌部位血管生成。对两者的归纳 血管内皮生长因子与炎症介质CD154介导的CD13/APN血管生成调节因子 在血管内皮细胞中建立了炎症和 血管生成。CD13/APN在血管生成梗死灶周围的表达 心肌梗死后与CD154共定位的区域，因此 这表明心肌血管生成依赖于这两个过程。血管内皮生长因子和 PlGF(胎盘生长因子)形成协同活性的异二聚体， 并诱导CD13/APN的表达。这些数据引发了一种分子机制 炎症与早期(PlGF、VEGF)和晚期表达的关系 (CD13/APN)血管生成调节因子。我们假设炎症性疾病 介质CD154通过依赖血管内皮生长因子和平台生长因子诱导CD13/APN的表达 机制，从而刺激心肌缺血区的血管生成。 这些研究的目的是阐明连接的分子机制 炎性细胞信号参与血管内皮细胞瘤的诱导、进展和维持 心肌缺血中的血管生成。我们将确定信令和 CD154诱导原代培养人CD13/APN的转录机制 体外培养内皮细胞。CD154组分的贡献- CD13/APN通路在心肌梗死后血管生成和伤口愈合中的作用 而缺血/再灌注损伤将在小鼠模型中进行评估 转基因动物体内的心肌疾病。澄清： 炎症调控的分子机制研究进展 血管生成将为研究心肌梗死提供新的机制见解 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.