Mitochondrial Modulation of Endothelial Phenotype

内皮是正常血管稳态的重要组成部分。据了解，正常 内皮功能在动脉粥样硬化及其危险因素如 高胆固醇血症、糖尿病和高血压。很可能是多种机制导致受损 然而，内皮功能，氧化应激的形式，活性氧（ROS）的生产出现 尤其重要。现在还广泛认识到，ROS充当信号分子，其有助于 血管损伤反应，但在动脉粥样硬化ROS信号变得失调，并有助于 内皮功能障碍尽管有这些知识，但内皮细胞中ROS信号传导的机制仍然存在。 晦涩难懂。这一建议是基于一个中心假设，即线粒体是一个重要的 氧化还原敏感信号的组成部分，因此，是内皮细胞增殖的关键决定因素。 细胞表型因此，本申请的目的是确定微扰子在以下方面的作用： 调节内皮细胞表型并阐明任何操作机制。为了实现这一目标，我们 首先将详细研究内皮细胞表型如何调节线粒体功能 例如质子动力（delta-muH+）、线粒体ROS和解偶联蛋白表达。使用此 知识和试剂，我们已经开发，我们将操纵特定的线粒体功能（δ-μ H+， UCPs）在培养的内皮细胞中的作用，并确定已知涉及 ROS，如一氧化氮生物活性、细胞增殖和迁移以及粘附分子表达。 由于细胞在体内不能完美地模拟事件，我们还将使用 UCP-2缺失小鼠和我们将开发的具有UCP-2的可诱导内皮细胞特异性过表达的小鼠。 然后我们将继续确定UCP-2操纵内皮细胞表型在体内的意义， 静息状态和对动脉损伤形式的压力的反应。成功完成这些研究 将提供关于氧化还原介导的内皮细胞表型控制的机制信息，并为我们提供 必要的洞察力，以设计新的治疗策略，重点是改善血管稳态， 动脉粥样硬化及其危险因素。

The endothelium is an important component of normal vascular homeostasis. It is known that normal endothelial function is disturbed in the setting of atherosclerosis and its risk factors such as hypercholesterolemia, diabetes, and hypertension. It is likely that multiple mechanisms contribute to impaired endothelial function, however, oxidant stress in the form of reactive oxygen species (ROS) production appear particularly important. It is also now widely appreciated that ROS act as signaling molecules that contribute to the vascular injury response, but in atherosclerosis ROS signaling becomes dysregulated and contributes to endothelial dysfunction. Despite this knowledge, the mechanisms of ROS signaling in the endothelium remain obscure. This proposal is based upon the central hypothesis that mitochondria are an important component of redox-sensitive signaling and, as a consequence, are a key determinant of endothelial cell phenotype. The objective of this application, therefore, is to determine the role of the mitochondrion in modulating endothelial cell phenotype and elucidate any operative mechanisms. To accomplish this goal, we first will undertake a detailed examination of how endothelial cell phenotype modulates mitochondrial functions such as protonmotive force (delta-muH+), mitochondrial ROS, and uncoupling protein expression. Using this knowledge and reagents we have developed, we will then manipulate specific mitochondrial functions (delta-muH+, UCPs) in cultured endothelial cells and determine the implications for endothelial functions known to involve ROS, such as nitric oxide bioactivity, cell proliferation and migration, and adhesion molecule expression. Because cells imperfectly model events in vivo, we will also manipulate mitochondrial function in vivo using UCP-2 null mice and mice we will develop with inducible endothelial cell-specific over-expression of UCP-2. We will then go on to determine the implications of UCP-2 manipulation endothelial phenotype in vivo both in the resting state and in response to stress in the form of arterial injury. Successful completion of these studies will provide mechanistic information on redox-mediated control of endothelial cell phenotype and afford us the necessary insight to design new therapeutic strategies that focus on improving vascular homeostasis in the setting of atherosclerosis and its risk factors.