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，其中最突出的是一氧化氮（NO）、前列环素和内皮源性超极化因子（EDHF）。它们都在剪切（或流动）介导的扩张（FMD）中发挥作用，这是最重要的生理内皮依赖性扩张反应。衰老或冠心病（CAD）及其危险因素的存在可改变这些扩张介质。我们的初步数据首次在人类心脏中证明，前列腺素介导儿童FMD，而在无CAD的成人中，NO起主导作用。然而，在冠心病患者的血管中，EDHF（过氧化氢；H2O2）是冠状动脉微循环中FMD的唯一介质。虽然内皮中介质释放的多样性可能有利于维持扩张，但每种介质对细胞增殖、凋亡和趋向性有不同的生物学作用