Intermittent Hypoxia and Cardiopulmonary Adaptation

心血管、呼吸和自主神经系统相互作用，在生理应激(如运动、高温、低氧)期间保持相对的稳态。人体在暴露于低氧环境(称为缺氧)时的适应能力突出了生理反应的重要多系统协调。对这些系统的综合研究有助于深入了解它们对低氧的适应，有助于我们全面了解人类的基本生理学。我的研究计划的长期目标是了解呼吸系统、心血管系统和自主神经系统如何相互作用、反应和适应缺氧。**心肺系统对不同强度、持续时间和重复的低氧反应的重要差异已被确定[即间歇性低氧(IH)]，但我们对控制这些差异的机制了解甚少。鉴于运动员(如曲棍球、奥运会、登山运动员)越来越多地使用高血压训练，对高血压的心肺适应特别令人感兴趣。随着加拿大在竞技体育方面继续保持强势，充分探索健康人类暴露在低氧环境中的适应背后的基本生理机制是谨慎的。**研究计划分为两个研究主题，有具体的研究目标。在主题I中，一系列研究将旨在了解交感神经活动、血管直径和暴露在低氧期间和之后的血流量之间的关系。在动物和人类中暴露于IH会导致化学感受器敏感性、交感神经活性、动脉血压和氧化应激增加。这些适应高血压的具体机制尚不清楚；然而，我们的初步研究表明，可能涉及通过肾素-血管紧张素系统的信号传递。已确定了两个研究目标：(1)确定持续与高血压对周围和脑循环中神经血管偶联的不同影响；(2)确定肾素-血管紧张素系统在增强高血压后交感神经兴奋中的作用。在主题II中，将进行一系列研究，以确定低氧如何导致肺内动静脉吻合术(IPAVA)开放。IPAVA是绕过肺的气体交换面从而减少氧气输送的肺血管。这项研究主题将确定IPAVA在保护肺毛细血管免受低氧期间高灌流压力影响方面的潜在作用。此外，它还将开发一种新的图像分析工具，用于量化通过IPAVA的血流量，并确定在缺氧过程中负责打开和关闭IPAVA的体液和机械刺激。对于主题II，已经确定了两个研究目标：(1)开发和验证一种定量分析工具，用于从搅动的生理盐水超声心动图测量通过IPAVA的血流量；(2)确定动脉缺氧与肺动脉压升高在调节急性缺氧期间IPAVA开放方面的相对重要性。**拟议的研究计划是一个合乎逻辑的扩展，纳入了我在NSERC博士后研究期间取得的新技术和发现。所有HQP将接受领导力和项目管理培训，发展独立的智力研究能力，与相关实验室合作，并将推动新方法的开发和创新。此外，HQP将参与撰写和发布他们的结果，并在高影响力的生理学期刊和会议演示中发表。

The cardiovascular, respiratory and autonomic nervous systems interact to maintain a relative homeostasis during physiological stressors (e.g., exercise, heat, hypoxia). The human body's ability to adapt when exposed to low levels of oxygen (called hypoxia) highlights an important multi-system coordination of physiological responses. The integrated study of these systems provides insight into their adaptation to hypoxia and contributes to our comprehensive understanding of basic human physiology. The long-term objective of my research program is to understand how the respiratory, cardiovascular, and autonomic nervous systems interact, respond, and adapt to hypoxia. **Important differences in the cardiopulmonary systems response to hypoxia of varying intensity, duration, and repetition [i.e. intermittent hypoxia (IH)] have been identified yet our understanding of the mechanisms controlling these differences is poorly understood. Cardiopulmonary adaptation to IH is of particular interest in light of the growing use of IH training with athletes (e.g., hockey, Olympics, mountain climbers). As Canada continues to remain strong at competitive sports, it is prudent to fully explore the basic physiological mechanisms behind the adaptations that take place when healthy humans are exposed to hypoxia. **The research program is divided into two research themes with specific research objectives. In theme I, a series of studies will be aimed at understanding the relationship between sympathetic nerve activity, vascular diameter, and blood flow during and following exposure to hypoxia. Exposure to IH in animals and humans leads to increases in chemoreceptor sensitivity, sympathetic activity, arterial blood pressure, and oxidative stress. The specific mechanisms responsible for these adaptations to IH are unknown; however, our preliminary investigations suggest signaling through the renin-angiotensin system might be involved. Two research objectives have been identified: (1) to determine the differential effect of sustained versus IH on neurovascular coupling in the peripheral and cerebral circulations; and (2) to determine the involvement of the renin-angiotensin system in potentiating sympathoexcitation following IH. In theme II, a series of studies will be aimed at identifying how hypoxia leads to the opening of intrapulmonary arteriovenous anastomoses (IPAVA). IPAVA are pulmonary vessels that bypass the gas exchange surface of the lung and thereby decrease oxygen delivery. This research theme will identify a potential role for IPAVA in protecting pulmonary capillaries from high perfusion pressures that occur during hypoxia. In addition, it will develop a new image analysis tool for quantifying blood flow through IPAVA and determine the humoral and mechanical stimuli responsible for opening and closing IPAVA during hypoxia. For theme II, two research objectives have been identified: (1) to develop and validate a quantitative analysis tool for measuring blood flow through IPAVA from agitated saline contrast echocardiograms; and (2) to determine the relative importance of arterial hypoxia versus increased pulmonary artery pressure in mediating the opening of IPAVA during acute hypoxia. **The proposed research program is a logical extension and incorporates new technologies and discoveries made during my NSERC postdoctoral fellowship. All HQP will receive leadership and project management training, develop independent intellectual research capacity, collaborate with associated laboratories, and will drive the development of new methodologies and innovation. Also, HQP will be involved in writing and publishing their results in high impact physiology journals and conference presentations.