AT THE

Coronary heart disease (CHD) is a major health concern for Americans and people worldwide. Arteriogenesis, an adaptive remodeling process in which pre-existing collateral arterioles remodel to form large diameter conductance arteries, has received recent attention for its therapeutic potential in treating CHD, but the mechanisms regulating the process remain incompletely understood. In particular, little is known about how collateral flow, and the resulting effect of shear stress acting along the collateral vessel wall, regulates coronary collateralization. This Thesis combines a series of experimental systems to define the responses evoked in endothelial cells exposed to hemodynamic waveforms characteristic of coronary collateral vessels and the subsequent paracrine effects on smooth muscle cells. Initially, a lumped parameter model of the human coronary collateral circulation was used to simulate normal (NCC) and adaptive remodeling (ACC) coronary collateral shear stress waveforms. These waveforms were then applied to cultured human endothelial cells (EC) and the resulting differences in EC gene expression were assessed by genome-wide transcriptional profiling, identifying genes distinctly regulated by collateral flow, including genes important fo