Investigation of physiological and pathological vascular functions using engineered systems
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The vasculature is a highly complex, hierarchical system that performs a variety of functions in both physiological and pathological contexts. To maintain tissue homeostasis for example, the endothelium which lines all vascular structures generates a semi-permeable barrier that controls the exchange of fluids, ions, and solutes between the blood and tissue. During phases of tissue growth and wound repair, the vasculature undergoes angiogenesis, the development of new blood vessels, to provide adequate oxygen and nutrients to the new and healing tissues. In pathological situations such as cancer, blood vessels have been demonstrated to support tumor growth and provide access to the circulatory system for metastatic progression. This dissertation focuses on elucidating new mechanisms that are involved in regulating these three dynamic functions of the vasculature. In Chapter 2, we discuss preliminary work connecting the Notch signaling pathway with the ability for endothelial cells to mechanically couple to their substrate, a property that is known to regulate endothelial barrier function. Using traditional methods in two-dimensional traction force microscopy, we observed reductions in traction stresses generated by endothelial monolayers treated with a Notch inhibitor. This was accompanied by a decrease in cell- matrix tethering through focal adhesions. In Chapter 3, we utilized an engineered model of angiogenesis to probe the role of endothelial cell contractility in the formation of new vascular sprouts. Through these studies, we established an essential role of non-muscle myosin II in maintaining multicellularity during sprout morphogenesis. And in Chapter 4, we described the adaptation of a cranial window model for studying melanoma brain metastases and demonstrated the utility of this system to monitor dynamic interactions between cancer cells and the brain vasculature. Together, the work in this dissertation provides new insights into and techniques for probing outstanding questions regarding various key functions of the vasculature.