Impact of endothelial microvesicles, Notch1, and endothelial progenitor cells on vascular endothelial function

内皮微泡、Notch1和内皮祖细胞对血管内皮功能的影响

• 批准号: RGPIN-2020-05760
• 负责人: Bain, Anthony
• 金额: $ 2.19万
• 依托单位: University of Windsor
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2021
• 资助国家: 加拿大
• 起止时间: 2021-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=740811
• 关键词: Impact; endothelial; microvesicles; Notch1; progenitor

Central to a healthy vascular system is the single layer of endothelial cells that make up the inner lining of all blood vessels (the endothelium). Indeed, endothelial dysfunction leads to a heightened state of inflammation with consequential detriments to the control of blood flow. Despite recent advances in understanding the broad risk factors of endothelial dysfunction (such as inactivity, smoking, obesity, diabetes, etc.), several fundamental questions remain. These questions stem from the lack of fully understanding basic endothelial biology. Accordingly, the overarching objective of this research program is to characterize novel mechanisms for endothelial function in humans. Specifically, this research program will explore the interplay between endothelial-derived extracellular vesicles (microvesicles), the transmembrane receptor, Notch1, and endothelial progenitor cells (EPCs). Uncovering the role of these novel mechanisms for vascular endothelial function in healthy adults will significantly enhance the knowledge of basic endothelial biology, and thus represents an exciting avenue of research.   In the short term (five year) research program, the impact of microvesicles, Notch1, and EPCs on vascular endothelial function will be determined under the unified lens of altered vessel-wall shear stress (i.e. the frictional force generated by the blood on the vessel wall). An alteration in vessel wall shear is an acknowledged stressor on the endothelium, which can either improve or deteriorate its function. In this respect, microvesicles, Notch1, and EPCs will be investigated under three distinct models: A) localized (arm) disturbed blood flow which increases oscillatory shear; B) heat stress and heat acclimation which increase anterograde shear; and C) high altitude (hypoxia) acclimatization which ostensibly inhibits the endothelial response to shear. Under these models, several unanswered questions will be addressed. These include; A) does increased oscillatory shear cause endothelial dysfunction through mechanisms related to microvesicles, Notch1, and EPCs? B) does heat stress improve endothelial function through mechanisms relating to alterations in microvesicles, Notch1, and EPCs secondary to increased anterograde shear? and, C) are impairments in vascular endothelial function at high altitude related to alterations in how changes in shear pattern impact microvesicles, Notch1, and EPCs in hypoxia? The answer to these questions will pave the way for the Principal Investigator (Dr. Bain) and his team to better describe the core principles of vascular endothelial biology in humans. Dr. Bain's long-term research program will provide evidence for human biological adaptations relating to microvesicles, Notch1, and endothelial progenitor cells, in turn providing the basic fundamental knowledge required for future targeted vascular therapy.

健康血管系统的核心是单层内皮细胞，它们构成所有血管的内层（内皮）。事实上，内皮功能障碍导致炎症状态升高，从而影响血流控制。尽管最近在了解内皮功能障碍的广泛风险因素（如不活动、吸烟、肥胖、糖尿病等）方面取得了进展，几个基本问题仍然存在。这些问题源于缺乏对基础内皮生物学的充分理解。因此，本研究计划的总体目标是表征人类内皮功能的新机制。具体来说，这项研究计划将探讨内皮细胞衍生的细胞外囊泡（微泡），跨膜受体，Notch 1和内皮祖细胞（EPCs）之间的相互作用。揭示这些新机制在健康成人血管内皮功能中的作用将显着提高基础内皮生物学的知识，因此代表了一个令人兴奋的研究途径。 在短期（5年）研究计划中，将在改变血管壁剪切应力（即血液对血管壁产生的摩擦力）的统一透镜下确定微泡、Notch 1和EPCs对血管内皮功能的影响。血管壁剪切力的改变是内皮上公认的应激源，其可以改善或恶化其功能。在这方面，将在三种不同的模型下研究微泡、Notch 1和EPCs：A）局部（臂）扰动血流，其增加振荡剪切; B）热应激和热适应，其增加顺行剪切;和C）高海拔（缺氧）适应，其表面上抑制内皮对剪切的反应。在这些模型下，将解决几个未回答的问题。这些包括：A）增加的振荡剪切是否通过与微泡、Notch 1和EPCs相关的机制引起内皮功能障碍？B）热应激是否通过与微泡、Notch 1和EPCs继发于顺行剪切增加的改变相关的机制改善内皮功能？以及，C）高海拔地区血管内皮功能的损伤是否与剪切模式的变化如何影响缺氧中的微泡、Notch 1和EPCs的改变有关？ 这些问题的答案将为主要研究者（Bain博士）及其团队更好地描述人类血管内皮生物学的核心原理铺平道路。Bain博士的长期研究计划将为与微泡、Notch 1和内皮祖细胞相关的人类生物学适应性提供证据，从而为未来的靶向血管治疗提供所需的基础知识。