Each step of vascular development needs to be carefully regulated; endothelial precursors must be specified, these cells then proliferate and coalesce to form vascular cords, and finally they lumenate, undergo angiogenic branching and remodeling, and recruit smooth muscle cells to establish a mature vessel. An aberration at any of these steps during embryonic development is incompatible with life, and vascular pathologies in the adult are associated with numerous diseases including stroke, arteriosclerosis, diabetic retinopathies and cancer progression. My work has aimed to understand how endothelial precursors are specified, and more precisely the cell-signaling pathways and transcriptional networks that guide their fate. This work leads us to conclude the following: (1) blood island precursor cells in the Xenopus embryo can give rise to either blood or endothelial cells, and it is BMP-mediated activation of the erythroid transcriptional program that regulates cell fate, (2) endothelial specification requires the Ets transcription factor Etv2. Persistence of Etv2 expression in blood/endothelial cell precursors allows these cells to develop into endothelium, and overexpression of Etv2 in any of the three germ layers causes activation of every endothelial marker examined. Along the way we have characterized a number of small-molecule inhibitors that should be useful to the Xenopus community and applicable to other model systems.

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published_or_final_version / Zoology / Master / Master of Philosophy

published_or_final_version / Zoology / Master / Master of Philosophy

No description available.

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Dysfunction of the vascular endothelium can initiate atherosclerosis. Mechanical forces, particularly wall shear stress (WSS) are believed to cause endothelial dysfunction. Present in vitro cell culture models are often simplified and thus, ignore the wall shear stress spatial gradients inherent in complex geometries. The aim of this project was to study endothelial cell response in an anatomically correct right coronary artery model (RCA) under more physiologically realistic flow conditions. / Human Abdominal Aortic Endothelial Cells (HAAECs) were seeded in the lumen of a pre-treated faithful RCA and a straight tubular model. The cells were subjected to steady or non-reversing oscillatory flow (Re=196, alpha=1.82) at a mean physiological flow rate of 20 dynes/cm2 for 8, 12 and 24 hours of flow. The results show that under all flow conditions, the cells became progressively more elongated and aligned. Moreover, differences in endothelial morphology in the inner (myocardial) and outer (pericardial) walls were seen in the inlet region. The morphologic adaptation to steady and oscillatory flow was similar. The results suggest that spatial, not temporal gradients in shear in the inlet region are responsible for the differential endothelial cell response.

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