Preferential activation of beta-catenin nuclear signaling in atherosclerosis susceptible vasculature and contributions to atherogenic gene expression

Shear stress represents a major contributor to vascular endothelial cell phenotype. The development of atherosclerosis tends to occur in vascular beds associated with low and reversing shear stress (atheroprone). In contrast, vascular beds exposed to relatively high and unidirectional shear stress tend to be resistant to atherosclerosis (atheroprotective). The identification of signaling pathways associated with atherogenic phenotypes presents an opportunity for the therapeutic intervention of a global health problem.;To study the effect of regional hemodynamics on endothelial cell biology, a quantitative description of the forces present in the human body is required. Phase-contrast magnetic resonance imaging was used in order to measure shear stress in the carotid bifurcation. A new parameter (the Harmonic Index) describing the relative contributions of time-varying and time-independent components of a shear stress signal was developed and found to be substantially higher in atheroprone regions compared to atheroprotected.;These quantitative shear stress profiles derived from the human vasculature were then employed to study their effects on endothelial cell biology and underlying mechanisms of atherosclerosis development. Human endothelial cells were assessed for activation of the beta-catenin/TCF signaling pathway. Application of atheroprone hemodynamic shear stress resulted in increased nuclear beta-catenin and TCF transcriptional activation compared to atheroprotective shear stress. Further, vascular endothelium in atherosclerosis susceptible regions of the mouse aorta exhibits increased nuclear beta-catenin prior to and during lesion development. Additionally, TCF-reporter mice exhibited higher TCF transcriptional activation in atheroprone regions compared to atheroprotected regions both prior to and during atherosclerosis development.;In order to assess the implications of TCF transcriptional activation in atherosclerosis development, a set of TCF-responsive genes was assessed for their regulation by atheroprone shear stress. Application of atheroprone shear stress induced the upregulation of several genes associated with atherosclerosis. Shear stress-induced activation of these genes was abolished by inhibition of endogenous beta-catenin/TCF activities. Together, the data indicate that activation of beta-catenin nuclear signaling is preferentially activated in the atheroprone vasculature by regional hemodynamics and contributes to atherogenic gene expression. This pathway may provide a novel therapeutic target for the treatment or prevention of atherosclerosis.