Hemodynamic forces generated by the flow of blood are crucial in maintaining homeostasis within the blood vessel wall. These forces, namely cyclic strain and shear stress are intricately involved in vascular remodeling, a process which underlies the pathogenesis of cardiovascular diseases such as atherosclerosis and restenosis. Since degradation of the extracellular matrix scaffold enables reshaping of tissue, the role matrix metalloproteinases (MMPs) has become the object of intense recent interest in relation to physiological and pathological vascular remodeling. The culminating data indicates that hemodynamic forces are important regulators of MMP expression and activity. A more complete understanding of the hemodynamic regulation of MMPs may advance the understanding of pathological vascular remodeling. We have investigated the effect of cyclic strain on the endothelial cell migration and angiogenic activity and the role of gelatinases in mediating these responses We have shown that exposure of bovine aortic endothelial cells (BAEC) to cyclic strain promoted migration and tubule formation with concurrent increases in MMP-2 and MMP-9 activity. Additionally, we have revealed that cyclic strain-induced increases in migration and tube formation are dependent on Gi-protein and integrin signaling However, cyclic strain stimulated increases in MMP-2 expression involve different signaling mechanisms, which in part, stimulate both p38- and ERK-dependent pathways through activation of Gpy and tyrosine kinase in BAEC. The participation of gelatinases in strain-induced increases in BAEC migration and tube formation was determined by inhibition of MMP activity using either a broad spectrum MMP inhibitor (GM6001) or siRNA targeted specifically to MMP-2 or MMP-9 We have shown that cyclic straininduced increases in BAEC migration are independent of MMP activity. In addition, we have demonstrated that MMP-9 but not MMP-2 is the key angiogenic switch involved in evoking cyclic straininduced angiogenesis. In conclusion, we examined the role of BAEC derived factors in regulating bovine aortic smooth muscle cell (BASMC) migration. Our data has shown that exposure of BASMC to conditioned media from cyclically strained BAEC inhibits SMC migration compared to controls and that MMP-2 is an important factor in mediating this inhibition. These findings clearly demonstrate that increases in MMP expression and activity associated with cyclic strain are important in modulating both BAEC and BASMC phenotype.