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: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=717148
• 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构成所有血管内层的单层内皮细胞（内皮）。事实上，内皮功能障碍会导致炎症加剧，从而对血流的控制产生不利影响。尽管最近在了解内皮功能障碍的广泛危险因素（如缺乏运动、吸烟、肥胖、糖尿病等）方面取得了进展，但仍存在一些基本问题。这些问题源于缺乏对基本内皮生物学的充分理解。因此，本研究计划的首要目标是表征人类内皮功能的新机制。具体来说，本研究项目将探索内皮来源的细胞外囊泡（微囊泡）、跨膜受体Notch1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著提高内皮生物学的基础知识，因此代表了一个令人兴奋的研究途径。