Regulation of peripheral vascular function: the role of the capillaries in microvascular control

周围血管功能的调节：毛细血管在微血管控制中的作用

• 批准号: RGPIN-2019-05146
• 负责人: Murrant, Coral
• 金额: $ 2.91万
• 依托单位: University of Guelph
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=715390
• 关键词: Regulation; peripheral; vascular; function; role

Any tissue inadequately perfused with blood will fail. Matching blood flow to changing metabolic demand is critical for proper cellular and tissue function, and critical to prevent damage. This process requires a system of communication whereby tissues can signal the vasculature that an increase in metabolic rate is occurring, and the vasculature can respond by increasing blood flow accordingly. The brain and skeletal muscle require particularly sophisticated communication with the vasculature because it is possible for one part of these tissues to be active while others are not; blood flow must therefore be directed specifically to active regions and no the tissue as a whole. This careful targeting of blood flow within the tissue requires (i) an active cell communicate its need for increased oxygen to the microvasculature, and (ii) intercommunication within the microvasculature network to direct blood flow to the active cell. Our basic understanding of how these important processes happen is surprisingly incomplete. Over the next 5 years my research program will address these critical knowledge gaps, using skeletal muscle as a model and advanced methods in intravital microscopy and immunohistochemistry. First, we will explore how capillary endothelial cells respond to different types of molecular signals relevant to muscle contraction and whether all capillary endothelial cells respond in the same way. Second, we will determine how capillaries communicate with upstream arterioles. Our lab has recently discovered a pannexin-dependent communication pathway that facilitates capillary communication with upstream arterioles; we now need to characterize this this pathway within the microvascular network to fully understand its functionality. Finally, we will determine how upstream arterioles communicate with each other to cause vasodilation of very specific arterioles to promote blood flow to active skeletal muscle fibres only. We will do this by determining how the pannexin pathway integrates with the existing connexin-dependent communication pathway already characterized. This research will be the first to explore novel characteristics of capillaries and their role in coordinating blood flow during muscle contraction to match metabolic requirements. Research in this area has traditionally focused on the arterioles; our work will refocus the field onto capillaries as the locus of control of blood flow, opening the door to research directions never before considered. Moreover, this work is highly translatable to other tissues, as matching of oxygen delivery to demand is a universal problem in all tissues and essential to normal functioning. Given that impaired oxygen delivery is a significant feature of many acute and chronic diseases, our research also offers new potential to understand the dysregulation of blood flow control.

任何血液灌注不足的组织都会衰竭。将血流与不断变化的代谢需求相匹配对于细胞和组织的正常功能至关重要，对于防止损伤也至关重要。 这个过程需要一个通讯系统，组织可以通过该系统向脉管系统发出代谢率正在增加的信号，脉管系统可以通过相应地增加血流量来做出反应。 大脑和骨骼肌需要与脉管系统进行特别复杂的通信，因为这些组织的一部分可能活跃，而其他组织则不活跃；因此，血流必须专门定向到活性区域，而不是整个组织。 这种对组织内血流的仔细靶向需要（i）活性细胞将其对增加氧气的需求传达给微脉管系统，以及（ii）微脉管系统网络内的相互通信以将血流引导至活性细胞。 我们对这些重要过程如何发生的基本理解令人惊讶地不完整。 在接下来的 5 年里，我的研究计划将使用骨骼肌作为模型以及活体显微镜和免疫组织化学的先进方法来解决这些关键的知识差距。首先，我们将探讨毛细血管内皮细胞如何响应与肌肉收缩相关的不同类型的分子信号，以及是否所有毛细血管内皮细胞都以相同的方式响应。 其次，我们将确定毛细血管如何与上游小动脉沟通。 我们的实验室最近发现了一种依赖于pannexin的通讯途径，可以促进毛细血管与上游小动脉的通讯；我们现在需要表征微血管网络中的这条通路，以充分了解其功能。 最后，我们将确定上游小动脉如何相互通信以引起非常特定的小动脉的血管舒张，从而仅促进血液流向活跃的骨骼肌纤维。 我们将通过确定pannexin途径如何与已经表征的现有连接蛋白依赖性通讯途径整合来做到这一点。 这项研究将首次探索毛细血管的新特征及其在肌肉收缩过程中协调血流以满足代谢需求的作用。该领域的研究传统上集中在小动脉上。我们的工作将把这个领域重新聚焦在毛细血管上，作为血流控制的场所，为以前从未考虑过的研究方向打开大门。 此外，这项工作高度可移植到其他组织，因为氧气输送与需求的匹配是所有组织中的普遍问题，并且对于正常功能至关重要。 鉴于氧输送受损是许多急性和慢性疾病的一个重要特征，我们的研究也为了解血流控制失调提供了新的潜力。