Endothelial monolayers (EML) line the tissues that are in direct contact with the blood or lymph, e.g. the vessels of the cardiovascular or lymphatic systems. They are continually exposed to mechanical loads, and their response to the latter within the physiological range or beyond, respectively, may play a critical role for homeostasis and pathology. The latter is particularly related to injury of the EML, which has been associated with the initiation of cardiovascular diseases [1] but also plays a role in oncology, as circulating tumor cells have to overcome the EML to exit the blood stream during metastasis [2]. Together with the epithelium, endothelial cells (EC) are special in that they form confluent layers, in which the components of the cells’ cytoskeletons are directly connected through junctions at the cell boundaries, thus forming large supracellular fibre networks. Towards a better understanding of the mechanical properties governing the deformation and fracture of the EML, large fibre network models were developed to represent the cytoskeleton, and parametrised in comparison with recent experiments on the deformation of elastomeric substrates caused by contracting ECs [3], solving the corresponding boundary value problems by a combination of finite element and molecular dynamics software [4]. Thereafter, models of the EML were used to study the different fracture patterns resulting from acute overstretch in EMLs of ‘young’ and ‘aged’ cells [5]. The results point at a pivotal role of the focal adhesion density that governs the strain transfer between substrate and cells, and strongly affects the degree of non-affinity in the deformation of the fibre network. References [1] S.-H. Lee, Stroke Revisited: Pathophysiology of Stroke: From Bench to Bedside. 1st Ed, Springer Singapore, 2000. [2] S.E. Amos and Y.S Choi, The cancer microenvironment: Mechanical challenges of the metastatic cascade. Front. Bioeng. Biotech., Vol. 9, p. 625859, 2021. [3] M.A. Reyes Lúa, Factors influencing the analysis of cell-substrate interaction. ETH Diss. No. 26609, 2020. [4] R. Jakob et al. Discrete network models of endothelial cells and their interactions with the substrate. under revision, 2023. [5] Y. Choi et al. Stretch-induced damage in endothelial monolayers. submitted, 2023.