Despite recent advances, cardiovascular diseases have remained the leading cause of mortality in the western world. Hypertension, also known as ‘the silent killer’, is the most common chronic cardiovascular stress and induces multiple pathological cardiac remodeling processes resulting in heart failure. Surprisingly, what cells within the cardiovascular system trigger cardiac remodeling in response to hypertension and what are the processes that facilitate its transduction are still unclear. Taking advantage of an Angiotensin II-dependent hypertension mouse model, we find that extracellular matrix (ECM)-related mechanical signals initiated by smooth muscle cells (SMC) induce the remodeling processes following hypertension. We demonstrate that deletion of the key ECM-modifying enzyme LYSYL OXIDASE (LOX) specifically in SMC uncouples between the two highly associated processes – hypertension and pathological cardiac remodeling. These results raise the hypothesis that the two processes could also be pharmacologically uncoupled in the clinic thus serving as a future route for the treatment of hypertension. However, towards this aim, further dissection of the mechanisms underlying sensation and transduction of hypertension are required. Here, we set two main aims: i) characterize the spatio-temporal ECM changes following hypertension in wild-type and in mice devoid of LOX specifically in their SMC; and ii) to characterize the biomechanical changes in the cells sheathing the cardiac vessels. The designed experiments presented in this proposal will grant us novel insights into these key questions and allow us to generate sufficient preliminary data for successful applications to competitive external grants.