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

背景：在人体中，有一些系统可以扩张和收缩小动脉，以便在需要的时候迅速向组织输送精确数量的血液。然而，将血液输送到组织的微血管网络在布局和几何形状上差异很大（例如，有些小动脉很长，有些很短）。尽管在布局/几何形状上存在差异，但在健康组织中，血流受到调节以精确满足细胞的需要。有趣的是，目前尚不清楚微血管布局/几何形状如何与小动脉收缩和扩张相互作用。因此，我们研究的长期目标是了解微血管网络的几何形状和布局如何决定调节系统如何运作，从而为所有细胞提供平等的血液供应机会。交感神经系统（SNS）是血管功能和健康的重要控制者。这种控制系统通过释放神经递质来发挥作用，这些神经递质称为去甲肾上腺素（NE）、神经肽Y （NPY）和三磷酸腺苷（ATP）。交感神经递质引起血管收缩，减少小动脉的血流量。在这些微血管收缩的同时，内皮细胞（血管内部的细胞）竞争使其扩张。这种血管扩张和收缩之间的竞争被精细地调整以满足组织的需要。假设：我们假设扩张和收缩的机制与微血管的布局和几何形状密切协调。1)开发并验证血管制图软件，用于从微动脉网络显微图像中提取微血管布局和几何数据；2)确定小动脉网络布局/几何形状如何影响引起交感神经收缩的机制；3)确定小动脉网络布局/几何、交感神经收缩和血管舒张之间的关系。方法：我们开发了一种直接观察活体大鼠骨骼肌小动脉的方法（使用显微镜）。我们将在静息状态下，用药物和实验方法对微血管网络的各个层次的小动脉和红细胞进行录像，以收缩和放松血管。收集的数据将在网络布局和几何结构的背景下分析血管反应。影响：本提案中实验的综合性质将为未来的科学家提供严格、高质量的培训。我们将首先调查和描述小动脉的交感调节是如何“调谐”到网络布局和几何形状的，以及2)这种整合如何使所有细胞在不同几何形状和布局的网络中有平等的血流机会。为此，我们将开发图像处理工具并生成全面的网络几何数据，这将为研究血流和新陈代谢的科学家提供宝贵的全球贡献。

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.