Laplace wall tension (WT), a tensile force, and fluid shear stress (FSS) are the principal mechanical forces experienced by vascular cells. Whereas endothelial cells (EC) are directly exposed to both forces, smooth muscle cells (SMC) experience higher levels of WT, but are only indirectly influenced by FSS. The amount of both forces a given cell experiences, however, is a major determinant of SMC and EC phenotype and, thus, vascular function. Although in the last decades multiple mechanically induced signalling pathways inducing the production and release of mediators such as nitric oxide (NO) and prostacyclin on the side of FSS or Endothelin-1 and oxidative stress induced by WT, have been characterized, neither signalling pathways exclusive or specific for mechanical forces nor the direct interaction of these pathways are satisfactorily explored. Accepting the fundamental impact of mechanical forces on vascular function, we aim at exploring this question. In the last years, with the cytoskeletal protein zyxin, we could identify a WT-specific mechanotransducer in EC as well as SMC and characterize its action as a transcription factor mediating dysfunctional gene expression in affected cells. Moreover, we explore the interplay between WT- and FSS-induced signalling at the molecular level. As an example, we characterize the impact of FSS on the WT-induced activation of zyxin. Indeed, NO is able to overcome WT-induced phenotype changes in EC by preventing zyxin activation. Another focus of our work are mechanisms as to how endothelial cells are able to prevent dysfunction for long periods also in the face of low NO bio-availability. Using a genetically determined model of endothelial dysfunction caused by insufficient NO synthesis in human EC, we could show that at several levels these cells compensate for this deficiency by increasing the synthesis of beneficial mediators or, vice versa, increasing the degradation of stress-related mediators. Together, our work aims at understanding how mechanical forces influence vascular function and how the antagonistic forces wall tension and fluid shear stress interact with each other at the molecular level.