The extracellular matrix (ECM) affects many aspects of cell growth and behavior. Not only do cells respond to the composition of the ECM, but they also respond to its physical properties, adjusting to the stiffness of their physical environment by generating tension within the cytoskeleton. In the vascular system, the large arteries from the central arterial system become stiffer with age. It is now well established that arterial stiffening significantly contributes to cardiovascular disease (CVD) development. Recent studies have highlighted that ECM stiffness affects endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) differentiation, proliferation and motility, suggesting that the cellular response to ECM stiffness may play an important role during the development of aging-associated CVD. We recently found that LARG and GEF-H1 regulate the mechanical response to force on integrins. In preliminary results we found that these two proteins are activated in response to ECM stiffness, suggesting that LARG and GEF-H1 may also regulate the mechanical response to ECM stiffness. In this proposal we will test this hypothesis and we will investigate the role of LARG and GEF-H1 in ECs and VSCMs during arterial stiffening.