The Influence of Hypoxia on Neurovascular Regulation and Plasticity

缺氧对神经血管调节和可塑性的影响

• 批准号: RGPIN-2014-06637
• 负责人: Steinback, Craig
• 金额: $ 2.11万
• 依托单位: University of Alberta
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2015
• 资助国家: 加拿大
• 起止时间: 2015-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=589133
• 关键词: Influence; Hypoxia; Neurovascular; Regulation; Plasticity

The delivery of oxygen to organs and tissues is critical to life. Hypoxia is a reduction in oxygen availability caused by decreased oxygen content within the environment (ambient air) or an impairment of oxygen diffusion or convection within the organism (varied disease processes). In response to hypoxia, the body activates mechanisms designed to correct (i.e. increased ventilation) and compensate for (i.e. redistribution of blood to critical tissues) the reduction in oxygen. The purpose of this grant is to examine the compensatory mechanisms, in particular the sympathetic nervous system, engaged during acute and chronic adaptation to hypoxic stress. The sympathetic nervous system is an important regulator of vascular function and is highly sensitive to changes in homeostasis. During exposure to hypoxia, oxygen sensitive receptors (chemoreceptors) are stimulated and communicate with cardiovascular centres in the brain. In turn, the sympathetic nervous system is activated, sending signals to blood vessels to constrict causing blood flow redistribution and optimization of oxygen delivery to critical tissues. The mechanisms linking the detection of reduced oxygen by the chemoreceptors to an end-organ vascular response can be described as the “neurovascular cascade”. The aim of my research program is to examine the influence of hypoxia on the regulation and plasticity of five fundamental themes within the “neurovascular cascade”: 1) Chemoreflex activation and adaptation, 2) Central integration, 3) Neural recruitment, 4) Neurotransmitter release and receptor binding, and 5) Functional changes in vascular regulation. This includes the following research questions: 1) How does the duration of hypoxia influence sympathetic activation and adaptation? 2) How does the duration of hypoxia influence the persistence of sympathetic activity following exposure? 3) Does chemoreceptor sensitization interact with other sympathetic related reflexes (e.g. baroreflex, metaboreflex, etc) to cause sympathetic hyperactivity? 4) How chemoreceptor stimulation influence neural activation and recruitment patterns? 5) How does hypoxia alter neurotransmitter release and or receptor binding during and or following exposure? 6) What are the vascular implications of post-hypoxic sympathetic hyperactivity? To answer these questions, I propose to examine healthy human subjects. Interventions will be designed to engage chemoreceptor activity using hypoxia while directly measuring sympathetic nervous system activity utilizing microneurography. Neurotransmitter release (i.e. blood samples) and receptor sensitivity (i.e. infusion of vasoactive substances) will be used to examine aspects of neurovascular communication, and non-invasive tools will be used to assess vascular end-organ responses (e.g. ultrasound and arterial tonometry for measures of vascular resistance and mechanics). The proposed program of study will be uniquely positioned to assess the mechanistic regulation of neurovascular function during and following exposure to various forms of hypoxia.

向器官和组织输送氧气对生命至关重要。缺氧是由于环境(环境空气)中含氧量减少或机体内氧气扩散或对流障碍(各种疾病过程)而导致的氧气可获得性降低。作为对缺氧的反应，身体激活旨在纠正(即增加通风)和补偿(即将血液重新分配到关键组织)的氧气减少的机制。这项资助的目的是研究在急性和慢性适应低氧应激过程中的代偿机制，特别是交感神经系统。 交感神经系统是血管功能的重要调节器，对动态平衡的变化高度敏感。在低氧环境中，氧敏感受体(化学感受器)受到刺激，并与大脑中的心血管中心进行通信。反过来，交感神经系统被激活，向血管发送信号以收缩，导致血流重新分配，并优化向关键组织的氧气输送。将化学感受器检测到的氧还原与器官末梢血管反应联系起来的机制可以被描述为“神经血管级联反应”。 我的研究项目的目的是研究低氧对“神经血管级联反应”中五个基本主题的调节和可塑性的影响： 1)化学感受性反射的激活和适应； 2)集中整合， 3)神经招募； 4)神经递质释放和受体结合，以及 5)血管调节功能改变。 这包括以下研究问题： 1)低氧持续时间如何影响交感神经的激活和适应？ 2)低氧持续时间如何影响暴露后交感神经活动的持续性？ 3)化学感受器敏化是否与其他与交感神经有关的反射(如压力反射、代谢性反射等)相互作用而引起交感神经亢进？ 4)化学感受器刺激如何影响神经激活和募集模式？ 5)低氧如何在暴露期间和/或之后改变神经递质的释放和/或受体结合？ 6)低氧后交感神经过度活动对血管有何影响？ 为了回答这些问题，我建议对健康的人类受试者进行检查。干预措施将被设计为利用低氧进行化学感受器活动，同时利用显微神经学直接测量交感神经系统活动。神经递质释放(即血液样本)和受体敏感性(即血管活性物质的注入)将用于检查神经血管通讯的各个方面，而非侵入性工具将用于评估血管末端器官反应(例如，用于测量血管阻力和力学的超声波和动脉血压测量)。拟议的研究计划将独特地定位于评估暴露在各种形式的缺氧期间和之后的神经血管功能的机械调节。