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

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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.