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

一个健康的血管系统的中心是组成所有血管(内皮)内层的单层内皮细胞。事实上，内皮功能障碍会导致炎症状态的加剧，从而对血流控制造成不利影响。尽管最近在了解内皮功能障碍的广泛危险因素(如不活动、吸烟、肥胖、糖尿病等)方面取得了进展，但仍有几个基本问题。这些问题源于对基本的内皮生物学缺乏充分的了解。因此，这项研究计划的首要目标是描述人类内皮功能的新机制。具体地说，这项研究计划将探索内皮源性细胞外小泡(微囊泡)、跨膜受体Notch1和内皮祖细胞(EPC)之间的相互作用。揭示这些新的血管内皮细胞功能机制在健康成年人中的作用将显著提高基础内皮生物学的知识，从而代表着一条令人兴奋的研究途径。在短期(五年)的研究计划中，微囊、Notch1和EPC对血管内皮功能的影响将在改变的管壁剪应力(即血液在管壁上产生的摩擦力)的统一透镜下确定。血管壁剪切力的改变是公认的内皮细胞应激源，它可以改善或恶化其功能。在这方面，微囊、Notch1和内皮祖细胞将在三种不同的模式下进行研究：A)局部(ARM)血流紊乱，增加振荡切变；B)热应激和热习服，增加顺行切变；以及C)高原(低氧)习服，表面上抑制内皮对切变的反应。在这些模式下，将解决几个悬而未决的问题。这些问题包括：A)振荡切变增加是否通过与微泡、Notch1和内皮祖细胞相关的机制导致内皮功能障碍？B)热应激是否通过与继发于顺行切变率增加的微泡、Notch1和内皮祖细胞改变相关的机制来改善内皮功能？以及，c)高海拔地区血管内皮功能受损是否与低氧条件下剪切模式的改变如何影响微泡、Notch1和内皮祖细胞有关？这些问题的答案将为首席研究员(贝恩博士)和他的团队更好地描述人类血管内皮生物学的核心原则铺平道路。贝恩博士的长期研究计划将为人类与微泡、Notch1和内皮祖细胞相关的生物适应提供证据，进而为未来的靶向血管治疗提供所需的基本基础知识。

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.