A novel integrative approach to understanding skeletal muscle hemodynamics: The interplay between static network geometry and acute arteriolar control

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BACKGROUND: In the body, there are systems that act to dilate and constrict arterioles in an effort to quickly deliver precise amounts of blood to tissues when they need it. However, the microvascular networks that carry blood to tissues differ greatly in layout and geometry (e.g., some arterioles are very long and some are very short). Despite differences in layout/geometry, in healthy tissues, blood flow is regulated to precisely meet the needs of cells. Interestingly, it is currently unknown how microvascular layout/geometry interacts with arteriolar constriction and dilation. Thus, the long-term goal of our research is to understand how the geometry and layout of microvascular networks dictate how regulatory systems operate to give all cells equal opportunity for blood supply. The sympathetic nervous system (SNS) is an important controller of vascular function and health. This control system exerts its effects by releasing neurotransmitters from nerves called norepinephrine (NE), neuropeptide Y (NPY), and adenosine triphosphate (ATP). Sympathetic neurotransmitters cause vasoconstriction and decrease blood flow in arterioles. At the same time as these constrict microvessels, the endothelium (cells on the inside of vessels) competes to dilate them. This competition between vasodilation and constriction is finely tuned to meet the needs of the tissue. HYPOTHESIS: We hypothesize that that mechanisms of dilation and constriction are intimately coordinated with the microvascular layout and geometry. OBJECTIVES: 1) Develop and validate vascular mapping software for extraction of microvascular layout and geometric data from microscopic images of arteriolar networks; 2) Determine how arteriolar network layout/geometry affects the mechanisms that cause sympathetic constriction; and 3) Determine the relationship between arteriolar network layout/geometry, sympathetic constriction, and vasodilation. APPROACH: We have developed a means to directly observe skeletal muscle arterioles in live rats (using a microscope). We will take videos of these arterioles and red blood cells at all levels of microvascular networks under resting conditions and with drugs and experimental methods that constrict and relax vessels. The data collected will be analyzed for vascular responses in the context of network layout and geometry. IMPACT: The integrated nature of experiments in this proposal will provide rigorous, high-quality training for future scientists. We will be first to 1) investigate and describe how sympathetic regulation of arterioles is “tuned” to network layout and geometry, and 2) how this integration gives all cells equal opportunity to blood flow in networks that vary in geometry and layout. To this end, we will develop image-processing tools and generate comprehensive network geometry data, which will be invaluable worldwide contributions to scientists who study blood flow and metabolism.