Angiogenic Signals in Diabetic Complications

在糖尿病患者中，异常的血管生成有助于终末器官的发育， 损害在这方面，“过度”的血管生成和血管内皮细胞活性的增加， 生长因子（VEGF）信号通路与糖尿病并发症有关， 视网膜病变相反，血管生成反应不足，促进血管生成的能力降低， 心脏和特别是外周骨骼肌中的侧支血管生长导致更多的 糖尿病血管病变的严重表现。然而，负责的机制 糖尿病中血管生成的失控以及这种失调如何调节组织 病理学尚不清楚。我们假设VEGF相关通路中的异常信号是一种 糖尿病并发症（包括外周动脉疾病（PAD））发病机制中的关键因素 和肾病。此外，我们认为，个别组织的不同性质决定了 糖尿病对局部血管生成反应的影响，从而形成所产生的病理。因此，委员会认为， 为了开发更好的糖尿病PAD和肾病模型，我们将产生小鼠品系， 靶向血液中特定细胞谱系的血管生成信号通路的可诱导改变 血管、骨骼肌和肾脏。因为VEGF活性的增强和减弱都 独立与糖尿病并发症相关，我们将生产模型， 下调血管生成信号。本研究的远期目标是：（1）了解 血管生成因子的改变如何促进糖尿病并发症的发展;（2） 为了开发糖尿病PAD和肾病的小鼠模型， 各自的人类条件。为实现这些目标，我们提出以下具体目标： 开发对与血管生成相关的关键信号通路进行遗传修饰的小鼠模型。 2.为了确定糖尿病对血管生成信号的影响，在一个成熟的模型中， 外周动脉疾病3.为了确定改变的血管生成信号对血管生成的影响， 糖尿病中蛋白尿和肾病的发展。

In humans with diabetes, abnormal angiogenesis contributes to the development of end-organ damage. In this regard, "excessive" angiogenesis and increased activity of the vascular endothelial growth factor (VEGF) signaling pathway have been associated with diabetic complications such as retinopathy. In contrast, an inadequate angiogenesis response with a reduced capacity to promote collateral blood vessel growth in cardiac and particularly peripheral skeletal muscle result in more severe manifestations of vascular disease in diabetes. However, the mechanisms responsible for the loss of control of angiogenesis in diabetes and how this dysregulation modulates tissue pathology are not clear. We hypothesize that abnormal signaling in VEGF-associated pathways is a critical factor in the pathogenesis of diabetic complications including peripheral artery disease (PAD) and nephropathy. Furthermore, we posit that distinct properties of individual tissues determine the effects of diabetes on the local angiogenesis response, shaping the resulting pathology. Accordingly, to develop better models of diabetic PAD and nephropathy, we will generate mouse lines with inducible alterations of angiogenic signaling pathways targeted to specific cell lineages in blood vessels, skeletal muscle and kidney. Because both enhanced and diminished VEGF activities have independently been associated with diabetic complications, we will produce models with up- or down-regulated angiogenic signaling. The long-term goals of our studies are: (1) To understand how alterations in angiogenic factors contribute to the development of diabetic complications and (2) To develop mouse models of diabetic PAD and nephropathy that more faithfully reproduce the respective human conditions. To achieve these goals we propose the following specific aims: 1.To develop mouse models with genetic modifications of key signaling pathways linked to angiogenesis. 2. To determine the effects of diabetes on angiogenic signaling in a well-established model of peripheral artery disease. 3. To define the consequences of altered angiogenic signaling on the development of albuminuria and nephropathy in diabetes.