Mechanism of Flow-Induced Dilation in the Human Microcirculation

描述（由申请人提供）：血管稳态高度依赖于内皮释放的因子，其中最主要的是一氧化氮（NO）、前列环素和内皮源性超极化因子（EDHF）。每一种都在剪切（或流动）介导的扩张（FMD）中发挥作用，FMD是最重要的生理性内皮依赖性扩张反应。衰老或冠状动脉疾病（CAD）及其危险因素的存在可以改变这些扩张介质。我们的初步数据首次证明，在人类心脏中，野牡丹素介导儿童FMD，而在没有CAD的成人中，NO起主导作用。然而，在CAD受试者的血管中，EDHF（过氧化氢; H2 O2）是冠状动脉微循环中FMD的唯一介质。虽然从内皮释放的介质的这种多样性可能有益于维持扩张，但每种介质对细胞增殖、凋亡和细胞凋亡倾向具有不同的生物学作用。 动脉粥样硬化因此，了解哪种介质在生命的不同阶段参与，以及它们在疾病存在时如何变化，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。本申请的总体目标是确定信号传导可塑性确保整个生命过程中对剪切的持续扩张反应的途径，并了解从健康到疾病的变化所涉及的机制。我们将探讨这一假设，即NO介导的FMD在成年人没有CAD的行为平行，以抑制线粒体ROS。我们将测试新的假设，即NO激活PGC-1，刺激线粒体生物合成和抑制活性氧的产生，是负责这种抑制。我们将通过检测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这一机制。有人提出端粒酶是一个关键的中介，由NO激活，NO反过来刺激PGC-1？。预期端粒酶活性降低会引起向内皮源性H2 O2的转变，H2 O2是疾病中FMD的关键介质。我们还将探讨挑衅性的初步数据表明，中性鞘磷脂酶刺激的神经酰胺的生产可以通过提高细胞活性氧和降低端粒酶活性协调从NO到H2 O2的过渡。拟议的工作提供了新的翻译和机制的洞察到衰老和疾病对内皮病理生理学在人类心脏的发展和预防岬血管变化，导致冠状动脉疾病的直接影响。

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.