ENDOTHELIAL DEPENDENCE OF MICROCIRCULATORY REGULATION

描述：(申请人提供) 本文的工作是在主要调查者S的基础上进行的。 与本计划项目的联系和最近获得的初步数据 与小鼠血管功能的研究有关。有显著差异的 骨骼肌和冠脉内皮细胞介质的调节 幼年和老年小鼠之间的血管与内皮型一氧化氮合酶 基因敲除(eNOS-KO)和对照小鼠被发现允许我们制定 假设随着年龄的增长观察到的血管功能障碍具有特征 通过逐渐减少内皮源性药物的合成或生物利用度 一氧化氮导致或由内皮细胞氧化应激增加引起的 细胞。这种与年龄相关的血管功能障碍可能会导致 心肌病或血管和心肌细胞坏死和细胞凋亡的发生率， 以及缺乏能力的小鼠的最长寿命减少 合成NO.在具体目标1中，我们计划调查 冠状动脉和骨骼肌功能的性别差异 ENOS-KO小鼠和对照、野生型(WT)小鼠的动脉和小动脉 研究改变的机制(通过前列腺素或EDHF) 血管内皮细胞源性一氧化氮缺乏对血管反应的调节 幼年和年老的动物。在具体目标2中，我们将描述老龄化的特征 血管(内皮)表型，并使用各种策略来纠正 内皮细胞产生氧化剂和一氧化氮之间的平衡有利于 影响NO？S生物活性以提高年龄相关性 小鼠的血管功能障碍。在这些战略中，包括政府 CAMP增强剂，他汀类药物或ACE抑制剂的慢性治疗， 运动训练和eNOS基因的病毒转染法。起搏诱导 犬失代偿性心力衰竭与人类扩张型心肌病 患者的特点是内皮细胞NO合成减少，并可能 是导致心脏功能不全的始动原因。相应地 具体目标3我们计划评估NO恢复的效果 生产在冠状动脉血管功能恢复过程中的作用 心力衰竭。为此，我们将评估内皮细胞的调节 犬心脏起搏停止后及起搏治疗后的冠状小动脉 带有他汀类药物的狗以及来自心脏的冠状小动脉 使用左心辅助装置(LVAD)的患者。我们相信， 拟议的研究将有助于更好地理解与年龄有关的原因 血管功能障碍与心脏失代偿和 有可能通过NO和NO来维持内皮控制 阻止甚至逆转这些发展的自然历史 条件。

DESCRIPTION: (provided by applicant) The work proposed is based on the principal investigator?s previous studies in connection with this Program Project and recent preliminary data obtained related to the study of vascular function in mice. Significant differences in the regulation by endothelial mediators of skeletal muscle and coronary vessels between young and aged mice and endothelial nitric oxide synthase knockout (eNOS-KO) and control mice were found to allow us to formulate the hypothesis that the vascular dysfunction observed with aging is characterized by a progressive reduction in the synthesis or bioavailability of endothelium-derived NO resulting in or caused by a increased oxidant stress in endothelial cells. This age related vascular dysfunction may result in an enhanced incidence of cardiac myopathy or vascular and myocyte mecrosis and apoptosis, and a decrease in the maximal lifespan in mice lacking the ability to synthesize NO. In Specific Aim 1 we plan to investigate the nature of the gender dependent differences in the function of coronary and skeletal muscle arteries and arterioles from eNOS-KO and control, wild type (WT) mice and to investigate the mechanisms (via prostaglandins or EDHF) of the altered mediation of vascular responses in the absence of endothelium-derived NO in young and aging animals. In Specific Aim 2 we will characterize the aging vascular (endothelial) phenotype and use a variety of strategies to redress the balance between endothelial production of oxidants and NO to favorably affect NO?s biological activity in order to improve the age-associated vascular dysfunction in mice. Among these strategies are the administration of cAMP-enhancing agents, chronic treatment with statins or ACE inhibitors, exercise training and viral transfection of the eNOS gene. Pacing-induced decompensated heart failure in dogs and dilated cardiomyopathy in human patients is characterized by a reduction in endothelial NO synthesis and may be the initiating cause leading to cardiac dysfunction. Accordingly in Specific Aim 3 we plan to evaluate the effects of the restoration of NO production in the process of recovery of coronary vascular function after heart failure. For this purpose we will assess endothelial regulation of coronary arterioles of dogs after cessation of pacing and after treatment of the dogs with statins as well as coronary arterioles from the hearts of patients with left ventricular assist devices (LVAD). We believe that the proposed studies will lead to a better understanding of the causes of age-related vascular dysfunction and the process of cardiac decompensation and have the potential of achieving maintenance of endothelial control by NO and to arrest or even reverse the natural history of the development of these conditions.