Endothelium and Vascular Function

(申请人摘要) 本计划项目拨款续期申请描述了我们计划进行的研究 作为我们关于血管内皮细胞作用的项目的延续 细胞在心血管功能调节中的多种作用 生理和病理生理状态。项目负责人代表 相关研究学科，每一门学科都将对 调查人员的合作努力。项目的共同主题 是多方面的作用，在当地发布的， 内皮衍生的介质，主要是一氧化氮(NO)和氧自由 自由基物种--在调节血管平滑肌功能中，以及 小鼠、狗、牛心脏和骨骼肌实质细胞代谢 和人类。参与调查的人员一直走在前列 在这一领域的研究，预计由于 协调计划提出，血管内皮细胞介质在血液中的作用 血管生物学及其在衰老引起的变化中的可能作用 疾病状态，如心力衰竭，将变得更加清晰。整体而言 该计划的目标是检验这样一个假设，即内皮细胞的减少 NO合成和/或生物利用度是主要的致病因素 血管和心肌细胞功能的改变，以及细胞死亡 心力衰竭和衰老。我们计划获得进一步的机械洞察力 了解NO在这些过程中的作用，并评估其有益影响 旨在纠正NO缺乏症的干预措施 逆转与衰老和心力衰竭相关的各种方法 细胞功能的恶化。项目2将研究两国之间的相互作用 活性O2和NO衍生物种在信号系统控制中的作用 影响冠状动脉收缩功能。项目5将研究 一氧化氮生成减少和恢复的病理生理学意义 关于心力衰竭的发展。项目6将调查是否 氧化应激进行性增加，心肌细胞和细胞死亡 以心脏失代偿和衰老为特征。项目4将具有AS 其目标是试图通过各种方法逆转小鼠的血管衰老 目的：重建NO对微血管功能的控制作用。行政部门 CORE将支持这些研究项目。分子生物学的核心将 协调所有与转基因小鼠群体有关的工作，包括 老化血管表型的特征。尽管这些 多学科的方法，我们将更好地了解原因 失代偿性心力衰竭和衰老的血管后果 与内皮细胞源性一氧化氮的合成和活性有关，而血管内皮生长因子 通过加强这些疾病的后遗症的减弱或逆转 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.