Mechanism of Flow-Induced Dilation in the Human Microcirculation

人体微循环中血流引起的扩张机制

• 批准号: 8434415
• 负责人: David D. Gutterman
• 金额: $ 44.04万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-15 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8434415
• 关键词: Adult; Age; Aging; Aging-Related Process; Animals; Apoptosis; Atherosclerosis; Attenuated; Biogenesis; Biological; Biological Availability; Biology; Blood Vessels; Cause of Death; Cell Nucleus; Cell Proliferation; Cells; Ceramides; Child; Climacteric; Coronary; Coronary Arteriosclerosis; Coronary heart disease; Data; Development; Dilator; Disease; Endothelial Cells; Endothelium; Ensure; Enzymes; Epoprostenol; Figs - dietary; Functional disorder; Generations; Goals; Health; Heart; Homeostasis; Human; Hydrogen Peroxide; Individual; Lead; Left; Length; Letters; Life; Link; Lipids; Mediating; Mediator of activation protein; Microcirculation; Mitochondria; Nitric Oxide; Onset of illness; Oxidation-Reduction; Pathology; Pathway interactions; Patients; Physiological; Play; Prevention; Process; Production; Promontory; Prostaglandin H2; Prostaglandins; Prostaglandins I; Reactive Oxygen Species; Risk Factors; Role; Signal Pathway; Signal Transduction; Sphingomyelinase; Staging; Superoxides; Telomerase; Testing; Time; Tissues; Vasodilation; Vasodilator Agents; Woman; Work; Youth; acute stress; age effect; attenuation; base; insight; men; normal aging; novel; public health relevance; release factor; response; telomere

DESCRIPTION (provided by applicant): Vascular homeostasis is highly dependent upon factors released from the endothelium, the most prominent of which are nitric oxide (NO), prostacyclin, and endothelium-derived hyperpolarizing factor (EDHF). Each plays a role in shear- (or flow-)mediated dilation (FMD), the most important physiological endothelium-dependent dilator response. Aging or the presence of coronary disease (CAD) and its risk factors can change these mediators of dilation. Our preliminary data demonstrate for the first time in human hearts, that prostaglandins mediate FMD in children, while in adults without CAD, NO plays the predominant role. However in vessels from subjects with CAD, EDHF (hydrogen peroxide; H2O2) is the sole mediator of FMD in the coronary microcirculation. While this diversity in mediator release from the endothelium may be beneficial to maintain dilation, each mediator has a different biological effect on cellular proliferation, apoptosis, and propensity for atherosclerosis. Thus understanding which mediator is involved at different stages of life and how they change in the presence of disease is critical to a better understanding of vascular pathology including atherosclerosis. The overall goal of this application is to determine the pathways by which signaling plasticity ensures continued dilator responses to shear throughout life, and to understand the mechanism involved in the change from health to disease. We will explore the hypothesis that NO which mediates FMD in adults without CAD acts in parallel to suppress mitochondrial ROS. We will test the novel hypothesis that NO-activation of PGC-1 ¿, which stimulates mitochondrial biogenesis and inhibits generation of reactive oxygen species, is responsible for this suppression. We will pursue the mechanism further by testing whether telomerase activity, critically linked to the aging process, also modulates signaling pathways activated by shear. It is proposed that telomerase is a key intermediary, activated by NO which in turn stimulates PGC-1¿. Decreased telomerase activity is expected to provoke a transition to endothelial derived H2O2 as a key mediator of FMD in disease. We will also explore provocative preliminary data showing that neutral sphingomyelinase-stimulated production of ceramide could orchestrate the transition from NO to H2O2 by elevating cellular ROS and reducing telomerase activity. The proposed work provides new translational and mechanistic insight into the effect of aging and disease on endothelial pathophysiology in the human heart with direct implications for the development and prevention of promontory vascular changes that lead to coronary artery disease.

描述（由申请人提供）：血管稳态高度依赖于内皮释放的因子，其中最重要的是一氧化氮（NO）、前列环素和内皮源性超极化因子（EDHF），每种因子都在剪切力中发挥作用。 （或血流）介导的扩张（FMD），最重要的生理性内皮依赖性扩张剂反应或冠状动脉疾病（CAD）的存在。我们的初步数据首次证明，在人类心脏中，前列腺素介导儿童的 FMD，而在没有 CAD 的成人中，NO 起着主导作用，但在患有 CAD 的血管中，NO 起着主导作用。 EDHF（过氧化氢；H2O2）是冠状动脉微循环中 FMD 的唯一介质，虽然内皮释放介质的多样性可能有利于维持扩张，但每种介质具有不同的生物学效应。细胞增殖、凋亡和倾向 因此，了解生命不同阶段涉及哪些介质以及它们在疾病存在时如何变化对于更好地了解包括动脉粥样硬化在内的血管病理学至关重要。整个生命过程中持续的扩张器对剪切的反应，并了解从健康到疾病的变化所涉及的机制，我们将探讨在没有 CAD 的成人中介导 FMD 的同时抑制线粒体 ROS 的假设。新假设：PGC-1 的 NO 激活 ¿刺激线粒体生物发生并抑制活性氧的产生，我们将通过测试与衰老过程密切相关的端粒酶活性是否也调节剪切激活的信号通路来进一步研究该机制。端粒酶是一个关键的中间体，由 NO 激活，进而刺激 PGC-1¿端粒酶活性的降低预计会引发向内皮源性 H2O2 的转变，作为疾病中 FMD 的关键介质。我们还将探索令人兴奋的初步数据，这些数据表明中性鞘磷脂酶刺激的神经酰胺产生可以通过提高细胞 ROS 来协调从 NO 到 H2O2 的转变。这项工作为衰老和疾病的影响提供了新的转化和机制见解。人类心脏的内皮病理生理学对导致冠状动脉疾病的岬血管变化的发生和预防有直接影响。