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

点击翻译按钮获取中文摘要

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.