Numerous studies in man and in animals support the relation between low or turbulent shear stress and atherosclerotic plaque location. However, little is known regarding the role of shear stress on the progression and composition of pre-established plaques. A recent prospective study in patients revealed that atherosclerosis regression is a realistic goal in patients, and it can be achieved through increased shear stress. We have used a model of arteriovenous fistula (AVF) developed in the lab, connecting the right common carotid artery with the jugular vein, to increase blood flow over established plaques in the brachiocephalic artery of LDL receptor knockout mice. Animals are placed on a high-fat diet for 12 weeks (wk0-wk12), then divided in three groups : control, sham, or AVF. Sham and AVF animals are maintained on high-fat for 4 weeks post-surgery. Atherosclerotic plaque size in the brachiocephalic artery averages 100,100±13,900μm² at wk12 (control animals) and progresses to 134,200±15,100μm² in sham by wk16, whereas it actually regresses by 53% in AVF in the same timeline (63,500±15,100μm²; p<0.02). Relative smooth muscle cell, macrophage, and collagen content are equivalent between groups, but matrix metalloproteinase (MMP) activity is enhanced in the AVF mice, suggesting that these enzymes might participate in the remodeling process. Indeed, in mice treated with MMP inhibitors and TIMP plasmids, MMP expression and activity diminish, and AVF fails to reduce plaque size. Hence, a favorable local shear stress may reverse the atherosclerotic process through a process involving metalloproteinases.