Endothelium and Vascular Function

（申请人摘要） 本计划项目补助金更新申请描述了我们计划 作为我们关于血管内皮细胞作用的项目的延续， 细胞在多种心血管功能的调节中 生理和病理生理状态。项目负责人代表 相关的研究学科，其中每一个将有助于 调查人员的合作努力。项目的共同主题 是当地释放的人之间互动的多方面作用， 内皮源性介质，主要是一氧化氮（NO），和无氧 自由基-调节血管平滑肌功能， 小鼠、犬、牛心脏和骨骼肌中的实质细胞代谢 还有人类参与调查的人员一直站在 在这方面的研究，预计，由于 协调方案提出，内皮介质在血液中的作用 血管生物学以及它们在衰老引起的变化中的可能作用 和疾病状态，如心力衰竭，将变得更加清晰。整体 该计划的目标是检验内皮细胞减少的假设， NO的合成和/或生物利用度是其主要致病因素， 血管和肌细胞功能的改变，以及细胞死亡， 心力衰竭和衰老的关系我们计划进一步深入了解 NO在这些过程中的作用，并评估有益的影响， 针对纠正NO缺乏的干预措施， 各种方法来逆转衰老和心力衰竭相关的 细胞功能恶化。项目2将研究 反应性O2和NO衍生的物种在信号系统的控制， 影响冠状血管收缩功能。项目5将审查 NO生成减少和恢复的病理生理相关性 心力衰竭的发展项目6将调查 氧化应激的进行性增加，以及心肌细胞和细胞死亡， 心脏失代偿和衰老的特征。项目4将作为 其目标是试图通过各种方法逆转小鼠的血管老化， 通过NO重建微血管功能的控制。 核心将支持研究项目。分子生物学核心将 协调所有与转基因小鼠群体有关的工作，包括 老化血管表型的表征。虽然这些 多学科的方法，我们将获得更好的了解的原因 失代偿性心力衰竭和衰老的血管后果， 与内皮源性NO的合成和活性有关， 通过增强免疫力来减轻或逆转这些疾病的后遗症 NO的生物利用度

(Applicant's abstract) This Program Project Grant renewal application describes studies we plan to perform as a continuation of our project on the role of vascular endothelial cells in the regulation of cardiovascular function in a variety of physiological and pathophysiological states. The project leaders represent related research disciplines, each of which will contribute to the collaborative efforts of the investigators. The common theme of the projects is the multifaceted role of the interaction among the locally released, endothelium-derived mediators, -primarily nitric oxide (NO), and oxygen free radical species -in the regulation of vascular smooth muscle functions, and parenchymal cell metabolism in heart and skeletal muscle of mice, dogs, bovine and humans. The participating investigators have been in the forefront of research in this area and it is anticipated that, as a result of the coordinated program proposed, the role of endothelial mediators in blood vessel biology as well as their possible role in the changes evoked by aging and disease states, such as heart failure, will become clearer. The overall goal of the program is to test the hypothesis that a reduction in endothelial NO synthesis and/or bioavalaibility is the dominant pathogenetic factor in the alterations of vascular and myocyte function, and cell death, as a consequence of the heart failure and aging. We plan to gain further mechanistic insight into the role of NO in these processes and to evaluate the beneficial effects of interventions directed towards the correction fo the NO deficiency by a variety of methods to reverse the aging - and heart failure - related deterioration of cellular function. Project 2 will study interactions between reactive O2 and NO-derived species in the control of signaling systems that affect coronary vessel contractile function. Project 5 will examine the pathophysiologic relevance of the reduction and restoration fo NO production on the development of heart failure. Project 6 will investigate whether the progressive increase in oxidative stress, and myocyte and cell death are characteristic of cardiac decompensation and aging. Project 4 will have as its goal to attempt to reverse vascular aging in mice by a variety of methods to reestablish control of microvascular function by NO. The Administrative Core will support the research projects. The Molecular Biology Core will coordinate all work related to the transgenic mouse colony, including the characterization of the aging vascular phenotype. Though these multidisciplinary approaches we will gain a better understanding of the causes of decompensated heart failure and the vascular consequences of aging as they relate to the synthesis and activity of endothelium - derived NO, and the attenuation or reversal of the sequelae of these conditions by enhancing the bioavailability of NO.