Exercise training: Endothelial phenotype, CAD

运动训练（EX）通过增加内皮型一氧化氮合酶（ecNOS）诱导冠状小动脉内皮介导的血管舒张增强。内皮介导的血管舒张是一种复杂的现象。看来，增加ecNOS表达只是改善内皮功能的机制之一。项目3将实现4个特定目标，并检查整个冠状动脉树的内皮，因为EX诱导的适应似乎不均匀地发生。目的1将测试改善内皮介导的扩张的3种假设机制：a）通过环氧合酶（考克斯-1）增加PGI/2的产生; B）增加细胞色素P450 WC 11的表达;和c）由于抗氧化系统增加NO的有效性。将测量内皮功能，药理学、生物化学和分子方法将确定酶/受体的表达。目的2将检验剪切应力和扩张是孤立小动脉内皮细胞表型改变的信号这一假设。目的3是检测特定大小动脉的内皮细胞表型。我们认为冠状动脉树的内皮表型（和EX诱导的内皮表型变化）部分取决于切应力和血管壁扩张。目的4将测试机制假设负责EX的能力，以恢复高脂血症（HF）期间冠状动脉内皮功能。血管反应和内皮细胞表型的生物化学/分子表征将用于检验EX通过增加ecNOS、考克斯-1、P450 2C 11同工酶和/或抗氧化系统的表达来逆转HF诱导的冠状动脉内皮功能障碍的假设。拟议的研究将确定EX诱导的冠状动脉内皮功能增强的机制以及以下因素的重要性：1）动脉直径，2）剪切应力和3）周向壁应力（扩张）。我们还将确定EX对HF期间内皮功能障碍的影响机制。结果将允许整合这些重要的现象，在冠状动脉循环血管适应的基本过程的理解。EX诱导的内皮功能的改善可能是运动训练在预防和治疗CHD中的有益作用的核心。

Exercise training (EX) induces enhanced endothelium-mediated vasodilation in coronary arterioles in part by increasing endothelial nitric oxide synthase (ecNOS). Endothelium-mediated vasodilation is a complex phenomenon. It appears that increased ecNOS expression is only one mechanism for improved endothelial function. Project 3 will accomplish 4 specific aims and examine endothelium throughout the coronary arterial tree because EX-induced adaptations appear to occur non-uniformly. Aim 1 will test 3 hypothesized mechanisms for improved endothelium-mediated dilation: a) Increased production of PGI/2 via the cyclooxygenase (COX-1); b) Increased expression of cytochrome P450WC11; and c) increased effectiveness of NO due to antioxidant systems. Endothelium function will be measured and pharmacologic, biochemical, and molecular approaches will define expression for enzymes/receptors. Aim 2 will test the hypothesis that shear stress and distention are signals for altered endothelial phenotype in isolated arterioles. Aim 3 is designed to examined endothelial phenotype in arteries of specified size. We propose that endothelial phenotype (and EX-induced changes in endothelial phenotype) in the coronary arterial tree is partially determined by shear stress and wall distention. Aim 4 will test mechanisms hypothesized to be responsible for the ability of EX to restore endothelial function of coronary arteries during hyperlipidemia (HF). Vasomotor responses and biochemical/molecular characterization of endothelial cell phenotype will be used to test the hypothesis that EX reverses HF-induced endothelial dysfunction in coronary arteries through increased expression of ecNOS, COX-1, P450 2C11 isozyme, and/or antioxidant systems. The proposed research will ascertain mechanisms of EX-induced enhancement of endothelial function in coronary arteries and the importance of: 1) arterial diameter, 2) shear stress, and 3) circumferential wall stress (distention). We will also determine mechanisms for effects of EX on endothelial dysfunction during HF. Results will allow integration of these important phenomena in understanding of fundamental processes in vascular adaptation in the coronary circulation. EX-induced improvements in endothelial function may be of central importance to the beneficial effects of exercise training in prevention and treatment of CHD.