The vascular endothelium is exposed to a spectrum of fluid mechanical forces generated by blood flow. Some of these mechanical forces, such as fluid shear stress, can directly modulate the expression of many endothelial genes that play essential roles in endothelium functions. Previous studies have identified various shear stress response elements (SSREs) within the promoters of certain endothelial genes that regulate their expression by interacting with various transcription factors. Nitric oxide and its biosynthetic enzyme, the constitutive endothelial nitric oxide synthase (eNOS, also NOSifi), play critically important roles in the normal homeostasis and pathophysiology of the vessel wall. The induction of eNOS gene expression by shear stress has been observed by our group and several other laboratories. We have performed promoter analysis and found that the GATA site in the eNOS promoter is likely the SSRE.
The specific aims of this proposal are to identify the responsible transcription factor(s) and to study the mechanism of its activation by shear stress. Results from our studies will not only aid in the understanding of how endothelial cells sense and transduce shear stress signals, but also provide new insights into the link between hemodynamic forces and atherosclerosis.
