Regulation of blood flow is a central topic in cardiovascular biology. Many disorders involve dysfunctional flow regulation, and vasoactive drugs are frequently used in treating these disorders. Delivery of an adequate oxygen supply is the most critical function of the circulatory system. The overall objective of this project is to develop quantitative theoretical models for blood flow regulation and oxygen transport in microvascular networks. In prior studies supported by this grant, we developed a model for steady-state flow regulation in a network with a homogeneous structure. That model, which will form the basis for the proposed studies, has provided insights into the roles of myogenic, metabolic, shear-dependent and conducted responses and oxygen-dependent release of ATP by red blood cells in the regulation of flow. In the proposed work, we will examine the effects of heterogeneity, time-dependent behavior and capillary recruitment on flow regulation.
Specific Aim 1 is to develop theoretical models for flow regulation in microvascular networks with inhomogeneous structures and spatially varying metabolic demand. The models will be used to investigate the mechanisms by which perfusion is locally matched to metabolic demand in normal tissue and how this fails in abnormal states.
Specific Aim 2 is to develop theoretical models for time- dependent flow regulation in response to changes in metabolic demand and arterial pressure, and to apply this model to analyze spontaneous oscillations in arteriolar diameter and blood flow (arteriolar vasomotion) that occur in some conditions.
Specific Aim 3 is to develop theoretical models including effects of capillary recruitment, and to test their ability to describe the more than 25-fold observed dynamic range of skeletal muscle perfusion. In all these studies, emphasis will be placed on comparing model predictions with available experimental data and using these data to further develop, test and refine the models. This process will be facilitated by well established collaborations with two consultants, Dr. Axel Pries and Dr. Tuhin Roy, who have extensive experience in relevant experimental basic science and clinical areas respectively.

Public Health Relevance

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. The models will clarify the roles of mechanisms that coordinate blood flow with local tissue requirements, will provide a rational structure for interpreting experimental data, and may lead to improved therapeutic approaches for controlling tissue perfusion.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Modeling and Analysis of Biological Systems Study Section (MABS)
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Charette, Marc F
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University of Arizona
Schools of Medicine
United States
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Rasmussen, Peter M; Smith, Amy F; Sakadži?, Sava et al. (2017) Model-based inference from microvascular measurements: Combining experimental measurements and model predictions using a Bayesian probabilistic approach. Microcirculation 24:
Lücker, Adrien; Secomb, Timothy W; Weber, Bruno et al. (2017) The relative influence of hematocrit and red blood cell velocity on oxygen transport from capillaries to tissue. Microcirculation 24:
Gagnon, Louis; Smith, Amy F; Boas, David A et al. (2016) Modeling of Cerebral Oxygen Transport Based on In vivo Microscopic Imaging of Microvascular Network Structure, Blood Flow, and Oxygenation. Front Comput Neurosci 10:82
Secomb, Timothy W (2016) A Green's function method for simulation of time-dependent solute transport and reaction in realistic microvascular geometries. Math Med Biol 33:475-494
Secomb, Timothy W (2015) Krogh-cylinder and infinite-domain models for washout of an inert diffusible solute from tissue. Microcirculation 22:91-8
Smith, Amy F; Secomb, Timothy W; Pries, Axel R et al. (2015) Structure-based algorithms for microvessel classification. Microcirculation 22:99-108
Roy, Tuhin K; Secomb, Timothy W (2014) Theoretical analysis of the determinants of lung oxygen diffusing capacity. J Theor Biol 351:1-8
Roy, Tuhin K; Secomb, Timothy W (2014) Functional sympatholysis and sympathetic escape in a theoretical model for blood flow regulation. Front Physiol 5:192
Buerk, Donald G; Hirai, Daniel M; Roseguini, Bruno T et al. (2014) Commentaries on viewpoint: A paradigm shift for local blood flow regulation. J Appl Physiol (1985) 116:706-7
Fry, Brendan C; Roy, Tuhin K; Secomb, Timothy W (2013) Capillary recruitment in a theoretical model for blood flow regulation in heterogeneous microvessel networks. Physiol Rep 1:e00050

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