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: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=685130
• 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量血流和灌注分布方面发挥着关键作用。 为了有效地做到这一点，他们必须整合无数的血管舒缩刺激，使他们能够有效地调节自己的语气并产生适当的结果。 虽然对血管张力的主要个体调节因子（例如肌源性激活、腺苷诱导的扩张）进行了广泛的研究，但对这些刺激如何通过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，我们将使用成熟且经过验证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，以及我们开发的新方法合作团队研究阻力小动脉如何整合生理关键血管活性刺激以确定其直径和反应性。 为了保持实验数量的可控性，我们将重点关注肌源性激活（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。 ******将使用我们的合作者（杰克逊）开发和完善的原位臀大肌制剂来研究微血管网络，同时将使用我们完善的双插管程序来评估离体微血管。 如果需要，我们还将使用我们已建立的体内后肢准备，通过示踪剂冲洗动力学深入了解微血管网络和阻力小动脉行为。 整合所有这些结果，我们将利用我们的合作者（高盛）开发的新颖计算方法来确定新的研究目标和血管关系，这些目标将成为我们不断发展的计划的目标。******对 HQP 培训的贡献：为了最大限度地发挥这些项目和由此产生的 HQP 的培训潜力，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，以多个分辨率级别探究这些关系，涵盖原位微血管网络、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），以及研究微血管网络行为的基本计算方法的额外培训。******影响：随着我们计划的发展，我们不仅会获得真正新颖的见解研究阻力小动脉如何在复杂的波动刺激环境中调节其音调，但我们也将生产出卓越质量的 HQP，因为它们将在多个空间分辨率水平的微血管功能研究中接受过全面的培训涵盖代谢产物的原位和体内血液灌注骨骼肌。