ENDOTHELIAL DEPENDENCE OF MICROCIRCULATORY REGULATION

微循环调节的内皮依赖性

• 批准号: 6931014
• 负责人: Gabor Kaley
• 金额: $ 29.18万
• 依托单位: NEW YORK MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6931014
• 关键词: age difference; animal old age; calcium flux; cardiovascular pharmacology; dogs; gender difference; heart failure; hemodynamics; human tissue; laboratory mouse; microcirculation; nitric oxide; nitric oxide synthase; oxidative stress; oxidizing agents; oxygen consumption; prostaglandins; vascular endothelium; vasomotion

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.

描述：（申请人提供） 拟开展的工作是否基于主要研究者？以前的研究， 与本计划项目的关系以及最近获得的初步数据 与小鼠血管功能的研究有关。显著差异 骨骼肌和冠状动脉内皮介质的调节 血管内皮型一氧化氮合酶与青年和老年小鼠血管的关系 敲除（eNOS-KO）小鼠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的特点是 通过内皮衍生的合成或生物利用度的逐渐降低， NO导致内皮细胞氧化应激增加或由其引起 细胞这种与年龄相关的血管功能障碍可能导致增强的 心肌病或血管和心肌细胞坏死和凋亡的发生率， 以及缺乏以下能力的小鼠的最大寿命缩短 在具体目标1中，我们计划研究 冠状动脉和骨骼肌功能的性别差异 来自eNOS-KO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Ehrandins或EDHF） 在缺乏内皮源性NO的情况下， 年轻和年老的动物。在具体目标2中，我们将描述 血管（内皮）表型，并使用各种策略来纠正 内皮细胞产生的氧化剂和NO之间的平衡， 影响不？的生物活性，以改善与年龄相关的 小鼠的血管功能障碍。这些战略包括： cAMP增强剂，他汀类药物或ACE抑制剂的长期治疗， 运动训练和eNOS基因的病毒转染。起搏诱导 犬失代偿性心力衰竭和人扩张型心肌病 患者的特征是内皮NO合成减少， 是导致心功能不全的初始原因。相应地 具体目标3我们计划评估NO恢复的效果 在恢复冠状动脉血管功能的过程中， 心衰为此，我们将评估内皮细胞对 停止起搏后和治疗后犬的冠状小动脉 用他汀类药物治疗的狗以及心脏的冠状动脉， 左心室辅助装置（LVAD）患者。我们认为 拟议的研究将导致更好地了解与年龄有关的原因， 血管功能障碍和心脏代偿失调的过程， 具有通过NO维持内皮控制的潜力， 阻止甚至逆转这些发展的自然历史， 条件