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

背景：在人体内，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将准确数量的血液输送到组织中。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有很大的不同(例如，有些微动脉很长，有些很短)。尽管布局/几何结构不同，但在健康的组织中，血流被调节以精确地满足细胞的需求。有趣的是，目前尚不清楚微血管布局/几何结构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，以便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。这种控制系统通过从神经释放神经递质去甲肾上腺素(NE)、神经肽Y(NPY)和三磷酸腺苷(ATP)来发挥作用。交感神经递质引起血管收缩，减少小动脉的血流量。在这些收缩微血管的同时，内皮(血管内部的细胞)竞相扩张它们。血管扩张和收缩之间的竞争是微调的，以满足组织的需要。假设：我们假设血管扩张和收缩的机制与微血管的布局和几何形状密切相关。目的：1)开发和验证血管标测软件，用于从微动脉网络的显微图像中提取微血管布局和几何数据；2)确定微动脉网络布局/几何形状如何影响引起交感收缩的机制；3)确定微动脉网络布局/几何、交感收缩和血管扩张之间的关系。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)。我们将在静息条件下，使用收缩和松弛血管的药物和实验方法，拍摄这些微血管网络各级的小动脉和红细胞的视频。收集的数据将在网络布局和几何形状的背景下进行血管响应分析。影响：该提案中的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。我们将首先研究和描述1)小动脉的交感神经调节如何与网络布局和几何形状“调谐”，以及2)这种整合如何使所有细胞在几何和布局不同的网络中有平等的血液流动机会。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，这将是世界范围内研究血流和新陈代谢的科学家的宝贵贡献。

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.