Flow regulation and Oxygen transpot in microcirculation

描述（由申请人提供）：血流如何被调节，即灌注如何匹配组织需求并在动脉压变化的情况下维持，是心血管生物学的核心问题。提出的研究的总体目标是建立骨骼肌和其他组织微血管网络的血流调节和氧运输的定量理论模型。这些模型将阐明协调血管阻力变化的机制的作用，将为解释实验数据提供合理的结构，并可能导致改善控制组织灌注的治疗方法。具体目标是：(1)建立理论模型来模拟微血管网络对动脉压力变化的自我调节反应，并将预测结果与实验数据进行比较。网络范围从代表性的流动途径，以实际结构观察到的活体显微镜将被考虑。肌源性，代谢，剪切依赖性和传导反应的影响将包括在内。预测结果将与骨骼肌和其他组织的血流自动调节的全器官数据进行比较。(2)建立理论模型，模拟微血管网络对代谢需求变化的血流调节，并将预测结果与实验数据进行比较。我们将分析红细胞释放ATP在血流调节中的作用。一个在单个片段中描述这种机制的初步模型将扩展到更现实的网络结构。沿着血管壁传导反应的相对作用以及小静脉和相关小动脉之间的弥漫性耦合将通过模拟来评估。血流和耗氧量之间的预测关系将与骨骼肌的实验数据进行比较。(3)建立预测骨骼肌微血管网络血管张力分布的理论模型，并与实验数据进行比较。综合上述效应和三维网络几何信息的血流调节综合模型将用于预测骨骼肌微血管网络中组织和血管氧水平的分布以及血管张力的分布。预测结果将与同一血管网络中实验测量的分布进行比较。

DESCRIPTION (provided by applicant): How blood flow is regulated, i.e., how perfusion is matched to tissue demands and maintained despite changes in arterial pressure, is a central question in cardiovascular biology. The overall objective of the proposed studies is to develop quantitative theoretical models for blood flow regulation and oxygen transport in microvascular networks of skeletal muscle and other tissues. The models will clarify the roles of mechanisms that coordinate changes in vascular resistance, will provide a rational structure for interpreting experimental data, and may lead to improved therapeutic approaches for controlling tissue perfusion. The specific aims are: (1) To develop theoretical models to simulate the autoregulatory response of microvascular networks to changes in arterial pressure, and to compare predictions with experimental data. Networks ranging from a representative flow pathway to realistic structures observed by intravital microscopy will be considered. Effects of myogenic, metabolic, shear-dependent and conducted responses will be included. Predictions will be compared with whole-organ data on flow autoregulation in skeletal muscle and other tissues. (2) To develop theoretical models to simulate the regulation of blood flow by microvascular networks in responses to changes in metabolic demand, and to compare predictions with experimental data. The role of ATP release by red blood cells in flow regulation will be analyzed. A preliminary model describing this mechanism in a single segment will be extended to more realistic network structures. The relative roles of conducted responses along vessel walls and diffusive coupling between venules and associated arterioles will be assessed using simulations. Predicted relationships between blood flow and oxygen consumption will be compared with experimental data obtained in skeletal muscle. (3) To develop theoretical models to predict distributions of vascular tone in microvascular networks of skeletal muscle, and to compare these with experimental data. An integrated model for flow regulation, incorporating all the above effects and realistic information on three-dimensional network geometry, will be used to predict distributions of tissue and vessel oxygen levels and distributions of vascular tone in microvascular networks in skeletal muscle. Predictions will be compared with experimentally measured distributions in the same vascular networks.