Integrative modeling of the microcirculation: multi-scale dynamics of oxygen-dependent blood flow regulation

所有组织都需要足够的血流量来输送氧气（通过毛细血管的扩散）和支持新陈代谢。这是通过调节影响整个身体对流氧供应的参数（心输出量、呼吸、基线血管张力）以及从器官到毛细血管网络的局部调节来实现的。局部调制由微循环控制，决定了器官和组织的总流量，以及这些结构内的流量和氧气分布。微血管的一个特点是结构的复杂性，这导致了血流在空间上的不均匀。当氧气需求相对较高（运动），血流相对较低（缺血），或微血管结构（毛细血管密度）或功能（小动脉反应性）受损时，这种异质性尤为重要。此外，由于调节过程不断地使局部氧气供应与需求相匹配，微循环血流在时间上是异质性的，并且随着空间异质性的增加而增加。基于微循环在输送氧气中的关键作用，以及微血管（MV）功能异质性的重要性，我的研究使用包含现实空间和/或时间复杂性的计算模型来研究微血管生理学。微循环的许多方面已经基于对潜在的物理、化学和生物过程的数学描述，并利用文献和我们自己的实验数据进行了建模。这项工作的多尺度方面涉及细胞（和亚细胞）对血流和氧运输的影响的近似，基于这些尺度的建模，并在更大尺度（MV网络）的模型中使用这些近似。最近，基于体外实验数据，我开发了红细胞内控制o2依赖性ATP释放的信号通路的第一个模型，ATP是控制局部血流分布的关键分子。随着红细胞中血红蛋白的氧饱和度降低，红细胞释放越来越多的ATP，导致扩张信号沿内皮细胞上游传导至供血的小动脉。这种扩张增加了血流量，从而增加了红细胞饱和度降低的微血管的局部氧供应。这种将局部氧气供应与细胞需求相匹配的机制被认为在基线条件下和当氧气消耗增加时（例如在运动中）是至关重要的。该研究将通过将细胞内ATP释放途径与整个小动脉树的血流和O2运输耦合起来，构建第一个动态（~0.1-10s）的多尺度模型，通过红细胞的O2依赖性释放ATP来调节血流。在新的体内实验的支持下，有待开发的模型包括小动脉网络中的时间依赖性血流，由于ATP与内皮P2Y受体结合而引起的局部和传导直径变化的开始，以及考虑红细胞穿越MV网络的ATP运输的新欧拉/拉格朗日描述。我们基于o2调控的动态模型将使我们对微血管血流控制的理解达到前所未有的水平，因此对微循环生理学有重大影响。我们的欧拉/拉格朗日方法将特别适用于药物递送方法的开发，而我们的整体调节模型将有助于研究工程或治疗性治疗（促进或抗血管生成）的MV网络。此外，该项目将培养数名微循环生理学、计算建模和体内实验方面的研究生和本科生，为培养高素质人才做出巨大贡献。

Sufficient blood flow to all tissues is required to deliver oxygen (via diffusion from capillaries) and support metabolism. This is accomplished through modulation of parameters affecting convective O2 supply to the entire body (cardiac output, breathing, baseline vascular tone), and via local modulation from organs down to capillary networks. Local modulation is controlled by the microcirculation and determines total flow to organs and tissues, and also flow and O2 distribution within these structures. A hallmark of the microvasculature is structural complexity, which results in spatially heterogeneous blood flow. This heterogeneity is particularly important when O2 demand is relatively high (exercise), flow is relatively low (ischemia), or microvascular structure (capillary density) or function (arteriolar reactivity) is compromised. In addition, due to regulatory processes continuously matching local O2 supply to demand, microcirculatory blood flow is heterogeneous in time, and this increases when spatial heterogeneity increases. Based on the key role of the microcirculation in delivering O2, and on the importance of heterogeneity in microvascular (MV) function, my research studies MV physiology using computational models that incorporate realistic spatial and/or temporal complexity. A number of aspects of the microcirculation have been modeled based on mathematical descriptions of the underlying physical, chemical and biological processes, and utilizing experimental data from the literature and our own experiments. The multiscale aspect of this work involves approximation of cellular (and subcellular) effects on blood flow and O2 transport, based on modeling at these scales, and using these approximations in models at much larger scales (MV networks). Recently, based on in vitro experimental data, I developed the first model of the signaling pathway inside RBCs that controls O2-dependent release of ATP, a molecule believed key in controlling local distribution of blood flow. As the O2 saturation of hemoglobin in RBCs decreases, RBCs release increasing amounts of ATP, causing a dilation signal that is conducted upstream along the endothelium to feeding arterioles. This dilation increases blood flow and hence local O2 supply to the microvessel(s) whose RBCs experienced decreased saturation. This mechanism for matching local O2 supply to cellular demand is believed to be crucial under baseline conditions and when O2 consumption increases (e.g., in exercise). The proposed research will construct the first dynamic (~0.1-10s) multiscale model of blood flow regulation via O2-dependent release of ATP from RBCs, by coupling the intracellular ATP release pathway to flow and O2 transport over the entire arteriolar tree. Models to be developed, supported by novel in vivo experiments, include time-dependent blood flow in arteriolar networks, initiation of local and conducted diameter changes due to ATP binding to endothelial P2Y receptors, and a novel Eulerian/Lagrangian description of ATP transport that considers RBCs traversing MV networks. Our dynamic model of O2-based regulation will permit an unprecedented level of understanding of blood flow control in the microvasculature, and therefore have a major impact on microcirculatory physiology. Our Eulerian/Lagrangian approach will be particularly applicable to development of drug delivery methods, while our overall regulation model will be useful in studying engineered or therapeutically-treated (pro- or anti-angiogenic) MV networks. In addition, this project will contribute greatly to the training of highly qualified personnel by training several graduate and undergraduate students in microcirculatory physiology, computational modeling, and in vivo experimentation.