Theorectal and Experimental Investigations of Microcirculatory Signaling

描述（由申请人提供）：血压对盐摄入的敏感性出现在高血压患者和正常血压患者中，这是一个主要的健康问题，因为它与心血管风险增加有关。先前的研究表明l -精氨酸-一氧化氮（NO）系统在盐敏感性中起核心作用。尽管有重要的先前贡献，关于NO在血管张力调节中的作用的基本问题仍然没有答案，这阻碍了当前优化现有干预措施和/或开发新的治疗策略的努力。因此，本研究计划旨在填补对血管阻力调节机制理解的重要空白，并将这一知识转化为临床可检验的假设，以改善高血压的治疗实践。本研究的中心假设是血管阻力的调节来自于Ca2+和no依赖信号通路的非线性相互作用。改变的NO/Ca2+动力学有助于盐敏感性高血压微循环的不同表型。在这项研究中，我们采用了一种创新的理论建模和体外实验的协同方法来阐明微循环中的信号机制。数学模型整合了细胞水平的生物物理详细机制，以描述宏观组织水平的生理功能。总体目标是提供一个理论框架，指导盐敏感性新治疗策略的发展。体外实验研究有助于模型开发和测试模型生成的假设。在盐敏感性高血压动物模型中评估微循环表型和血管反应性。NO刺激联合抑制血管紧张素系统或Ca2+稳态效应的协同策略被评估为恢复正常血管功能的能力。

DESCRIPTION (provided by applicant): Blood pressure sensitivity to salt intake appears in both hypertensives and normotensives and represents a major health problem as it is associated with increased cardiovascular risk. Prior investigations have suggested a central role for the L-arginine-nitric oxide (NO) system in salt sensitivity. Despite significant prior contributions, fundamental questions about the role of NO in the regulation of vascular tone remain unanswered and this impedes current efforts to optimize available interventions and/or develop new therapeutic strategies. Therefore, this research proposal aims to fill an important gap in the understanding of the mechanisms that regulate vascular resistance and to translate this knowledge into clinically testable hypotheses for improved therapeutic practice in hypertension. The central hypothesis of this study is that regulation of vascular resistance emerges from the nonlinear interaction of Ca2+ and NO-dependent signaling pathways. Altered NO/Ca2+ dynamics contribute to a different phenotype in the microcirculation of salt-sensitive hypertensives. In this study we follow an innovative synergistic approach of theoretical modeling and in vitro experimentation to elucidate signaling mechanisms in the microcirculation. Mathematical models integrate biophysically detailed mechanisms at the cellular level to describe physiological function at a macroscale tissue level. The overall goal is to provide a theoretical framework that will guide the development of novel therapeutic strategies in salt sensitivity. In vitro experimental studies assist in model development and test model generated hypotheses. Microcirculatory phenotype and vascular reactivity are assessed in an animal model of salt sensitive hypertension. Synergistic strategies of NO stimulation combined with inhibition of the angiotensin system or effectors of Ca2+ homeostasis are evaluated for their ability to restore normal vascular function. Relevance: Salt intake affects blood pressure levels in a large percentage of the population. This condition, referred to as salt sensitivity, represents a major public health problem as it is associated with an increased risk for cardiovascular disease. In this study we utilize a novel approach of combining computational modeling and experimentation to investigate the mechanisms that link salt intake and blood pressure. Preliminary results suggest that combination of available pharmaceutics can have beneficial effects in restoring function in the microcirculation and will be tested in hypertensive animals.