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。

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 data from the literature and from our own video-microscopy experiments on intact skeletal muscle. The current proposal will develop a novel experiment-based computational model that incorporates realistic geometric and hemodynamic complexity, describes steady-state and dynamic regulation of arteriolar diameters and blood flow based on O2-dependent release of ATP from RBCs and other physiological mechanisms, and uses multi-scale modeling to include details of capillary-scale effects in tissue-level models (MV networks). The new capillary-tissue model will include spatially distributed capillary transport and direct diffusive interactions with larger vessels, convective transport that captures the directionality of capillary flows, and conducted signaling from capillaries and small arterioles/venules to larger-scale MV networks, all of which will enable testing of hypotheses about how different control mechanisms combine to produce observed regulation effects in skeletal muscle. Our dynamic, multi-scale model represents a new and unique approach to MV transport and regulation, and will serve as a fundamental basis for future work in physiology, bioengineering (tissue engineering, drug delivery), and medicine (sepsis, diabetes). In addition, this project will contribute greatly to highly qualified personnel gaining valuable new skills by training several graduate and undergraduate students in microcirculatory physiology, computational modeling, and in vivo experimentation.