The mechanical properties of the extracellular environment emerge as critical regulators of cellular functions. Cell mechanotransduction is mainly studied in vitro at initial stages of cell adhesion and very little is known about the mechanoresponses of cells with established tensional dynamics, resembling cells embedded in tissues. Here, we provide in vivo evidence that talin-dependent cell-matrix adhesions are global regulators of vascular mechanics and establish talin as an essential and required mechanosensor in neovessels and already developed tumours. At the molecular level, we demonstrate that talin exploits alternative mechanisms to dynamically-adjust the mechanical integrity of endothelial cells. Our mutational studies indicate a previously unknown role for the requirement of the talin-head in mechanosensing and demonstrate that the talin-head and the talin-rod alone are sufficient to maintain mechanical stability of endothelial cells. Overall, our results underpin the significance of mechanical signals in regulating vascular morphology in steady-state conditions and ultimately modulate cancer progression.Talin mechanosensing is required to maintain cell morphology and control developmental and tumour angiogenesis.