The Influence of Hypoxia on Neurovascular Regulation and Plasticity

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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.