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: 8620712
• 负责人: David D. Gutterman
• 金额: $ 40.19万
• 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/8620712
• 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（由适用提供）：血管内稳态高度取决于内皮释放的因素，其中最突出的是一氧化氮（NO），前列环蛋白和内皮衍生的过度溶因（EDHF）。每个都在剪切（或流）介导的扩散（FMD）中起作用，这是最重要的生理内皮依赖性扩张器反应。衰老或冠状动脉疾病（CAD）及其危险因素的存在可能会改变这些词典的介体。我们的初步数据在人类心中首次证明，前列腺素介导了儿童的FMD，而在没有CAD的成年人中，没有扮演主要的角色。但是，在具有CAD受试者的血管中，EDHF（过氧化氢； H2O2氢）是冠状动脉微循环中FMD的唯一​​介体。虽然从内皮中释放的调解人中的这种多样性可能对维持词典有益，但每个介体对细胞增殖，凋亡以及对的生物学作用都不同。 动脉粥样硬化。理解哪个介体在生活的不同阶段及其在疾病存在下的变化对于更好地理解包括动脉粥样硬化在内的血管病理学至关重要。该应用的总体目的是确定信号传导可塑性确保持续扩张器对剪切的反应的途径，并了解从健康变为疾病的变化所涉及的机制。我们将探讨以下假设：没有介导的没有CAD的成年人中的FMD并行起作用以抑制线粒体ROS。我们将测试新的假设，即刺激线粒体生物发生并抑制活性氧的产生的PGC-1的无激活是造成这种抑制作用的。我们将通过测试与衰老过程密切相关的端粒酶活性进一步追求该机制，还可以调节剪切激活的信号通路。有人提出，端粒酶是一个关键的中间体，被NO激活，而NO激活的端粒酶又刺激了PGC-1。降低端粒酶活性有望引起过渡到内皮衍生的H2O2作为疾病中FMD的关键介体。我们还将探索挑衅性的初步数据，表明中性鞘磷脂酶刺激的神经酰胺的产生可以通过升高细胞ROS并减少端粒酶活性来策划从NO到H2O2的过渡。拟议的工作为人心脏中衰老和疾病对内皮病理生理学的影响提供了新的转化和机械洞察力，对导致冠状动脉疾病的海角血管变化的发展和预防直接影响。