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: 2017
• 资助国家: 加拿大
• 起止时间: 2017-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=630659
• 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, and5) 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。缺氧是由环境（环境空气）中氧含量减少或机体内氧扩散或对流受损（各种疾病过程）引起的氧气可用性减少。在缺氧的情况下，身体会激活相应的机制来纠正（如增加通气）和补偿（如血液重新分配到关键组织）氧气的减少。这项资助的目的是研究代偿机制，特别是交感神经系统，参与急性和慢性适应缺氧应激。交感神经系统是血管功能的重要调节器，对体内平衡的变化高度敏感。在暴露于缺氧时，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交流。反过来，交感神经系统被激活，向血管发出收缩信号，导致血流重新分配，并优化向关键组织的氧气输送。将化学感受器检测还原氧与末端器官血管反应联系起来的机制可以被描述为“神经血管级联”。我的研究计划旨在研究缺氧对“神经血管级联”中五个基本主题的调节和可塑性的影响：1)化学反射激活和适应，2)中枢整合，3)神经募集，4)神经递质释放和受体结合，5)血管调节的功能变化。这包括以下研究问题：1)缺氧的持续时间如何影响交感神经的激活和适应？2)缺氧持续时间如何影响暴露后交感神经活动的持续性？3)化学感受器致敏是否与其他交感神经相关反射（如压力反射、代谢反射等）相互作用导致交感神经过度活跃？4)化学受体刺激如何影响神经激活和募集模式？5)缺氧如何改变暴露期间和之后的神经递质释放和受体结合？6)缺氧后交感神经过度活跃对血管的影响是什么？为了回答这些问题，我建议检查健康的人类受试者。干预措施将设计为利用缺氧参与化学受体活动，同时利用微神经摄影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（即血管活性物质的输注）将用于检查神经血管通信的各个方面，非侵入性工具将用于评估血管末端器官的反应（例如，用于测量血管阻力和力学的超声和动脉血压计）。该研究计划将独特地定位于评估暴露于各种形式的缺氧期间和之后神经血管功能的机制调节。