Vascular Integration: How do resistance arterioles merge multiple vasomotor inputs for a coordinated response?

血管整合：阻力小动脉如何合并多个血管舒缩输入以做出协调反应？

• 批准号: RGPIN-2018-05450
• 负责人: Frisbee, Jefferson
• 金额: $ 2.4万
• 依托单位: University of Western Ontario
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=651209
• 关键词: Vascular; Integration; How; do; resistance

Background: Resistance arterioles in the body play a critical role in regulating bulk blood flow to, and perfusion distribution within, tissues and organs. In order to do this effectively, they must integrate a myriad of vasomotor stimuli in a manner that allows them to regulate their tone effectively and produce an appropriate outcome. While there has been extensive investigation on the major individual regulators of vascular tone (e.g., myogenic activation, adenosine-induced dilation), there has been comparatively little investigation into how these stimuli are integrated by the arteriole to produce the outcome. ******Approach: To address this, we will use well-established and validated techniques for studying vascular function, our innovative multi-scale approach to the study of parameter interaction for vascular tone regulation, and the novel approaches developed by our collaborative team to study how resistance arterioles integrate physiologically critical vasoactive stimuli to determine their diameter and reactivity. In order to keep the experimental number manageable, we will focus on the interactions of myogenic activation (intrinsic vascular control), adrenergic control (extrinsic vascular control) and adenosine-induced dilation (parenchymal cell influences). ******Microvascular networks will be studied using the in situ gluteus maximus muscle preparation, developed and perfected by our collaborator (Jackson), while ex vivo microvessels will be assessed using our well established double-cannulation procedures. If needed, we will also use our established in vivo hindlimb preparation to gain insight into microvascular network and resistance arteriolar behavior via tracer washout kinetics. Integrating all of these results, we will utilize the novel computational approaches developed by our collaborator (Goldman) to identify novel targets for study and vascular relationships that will be targeted in our evolving program.******Contribution to HQP Training: In order to maximize the training potential from this projects and the resulting HQP, we will utilize our long-standing approach of immersing our trainees into studies interrogating these relationships at multiple levels of resolution, spanning in situ microvascular networks, ex vivo isolated microvessels, high resolution biomarker and metabolite profiling (for mechanistic insight), with additional training in basic computational approaches to the study of microvascular network behavior.******Impact: As our program develops, we will not only gain truly novel insight into how resistance arterioles regulate their tone in a complex environment of fluctuating stimuli, but we will also produce HQP of exceptional quality as they will have been thoroughly trained in the study of microvascular function at multiple levels of spatial resolution spanning metabolite production to in situ and in vivo blood perfused skeletal muscles.

背景：体内的阻力小动脉在调节组织和器官的大血流量和灌注分布方面起着关键作用。为了有效地做到这一点，他们必须以一种允许他们有效地调节他们的音调并产生适当结果的方式整合无数的血管舒缩刺激。虽然对血管张力的主要个体调节因子（如肌原性激活、腺苷诱导的扩张）进行了广泛的研究，但对这些刺激如何被小动脉整合以产生结果的研究相对较少。******方法：为了解决这个问题，我们将使用成熟和有效的技术来研究血管功能，我们创新的多尺度方法来研究血管张力调节的参数相互作用，以及我们合作团队开发的新方法来研究阻力小动脉如何整合生理上关键的血管活性刺激，以确定其直径和反应性。为了使实验数量可控，我们将重点关注肌原性激活（内在血管控制）、肾上腺素能控制（外在血管控制）和腺苷诱导的扩张（实质细胞影响）之间的相互作用。******微血管网络将使用由我们的合作者（Jackson）开发和完善的臀大肌原位准备进行研究，而离体微血管将使用我们完善的双插管程序进行评估。如果需要，我们还将使用我们建立的体内后肢准备，通过示踪剂冲刷动力学来深入了解微血管网络和抵抗小动脉行为。综合所有这些结果，我们将利用我们的合作者（Goldman）开发的新型计算方法来确定研究和血管关系的新目标，这些目标将在我们不断发展的项目中成为目标。******对HQP培训的贡献：为了最大限度地提高这个项目的培训潜力和由此产生的HQP，我们将利用我们长期以来的方法，让我们的学员沉浸在研究中，在多个分辨率水平上探究这些关系，包括原位微血管网络、离体分离微血管、高分辨率生物标志物和代谢物分析（用于机制洞察），并在微血管网络行为研究的基本计算方法方面进行额外的培训。******影响：随着我们项目的发展，我们不仅将获得真正新颖的见解，了解阻力小动脉如何在波动刺激的复杂环境中调节其张力，而且我们还将生产出质量卓越的HQP，因为他们将在多个空间分辨率的微血管功能研究中进行彻底的训练，包括代谢物产生到原位和体内血液灌注骨骼肌。