Final Report Summary - RHOMECHANOVASC (Regulation of Rho proteins by mechanical forces in the vascular system) Over the last 10 years numerous studies have revealed that cells respond to their physical environment. Cells can “sense” and convert mechanical forces into specific biochemical signals that ultimately regulate cellular processes. Our project aimed to identify the molecular mechanisms which regulate the cellular response to force and to evaluate the role of these mechanisms during cardiovascular diseases development (CVD). During the outgoing phase, we were able to accomplish the first objective of the project. By combining biochemical and biophysical approaches, we identified two GEFs, LARG and GEF-H1, as key molecules that regulate the cellular adaptation to force. We show that stimulation of integrins with tensional force triggers activation of these two GEFs and their recruitment to adhesion complexes. Surprisingly, activation of LARG and GEF-H1 involves distinct signalling pathways. Our results reveal that LARG is activated by the Src family tyrosine kinase Fyn, whereas GEF-H1 catalytic activity is enhanced by ERK downstream of a signalling cascade that includes FAK and Ras. This work was published in Nature Cell Biology (Guilluy et., Nat Cell Biol. 2011 Jun;13(6):722-7). During the return phase, we analyzed the pathophysiological relevance of LARG and GEF-H1 in the vascular system. In a collaborative work, we found that GEF-H1 regulates the endothelial response to shear stress, indicating that GEF-H1 may play a role during atherosclerosis development. Interestingly we observed that Ras, GEF-H1 upstream regulator, is activated in arteries isolated from old rats, suggesting that the mechanosensitive GEF, GEF-H1, could contribute to the vascular defects associated with age.