PIEZO1 and PIEZO2 proteins form trimeric calcium-permeable non-selective cation channels that are activated by mechanical forces. We found significance of PIEZO1 in cardiovascular biology, showing its sensing of physiological fluid shear stress and role in embryonic vascular maturation [1]. By generating conditional genetic deletion in the adult mouse we found that in endothelium it is required for elevated blood pressure during physical activity, capillary density in skeletal muscle, physical exercise performance and lipid homeostasis via signalling to parenchymal regulatory genes in liver and small intestine [2-4]. We found evidence for it as a master mediator of force sensing, conferring force sensitivity on many other mechanisms: calcium-regulated proteases (CAPN2, ADAM10), nitric oxide production via NOS3, cell interaction via NOTCH1, cell apoptosis via thrombospondin-2 and (in cardiac fibroblasts) inflammation and fibrosis via p38, interleukin-6 and tenascin c. We found that it locates to endothelial cell-cell junctions where it interacts with cell adhesion molecules, PECAM1 and CDH5, to regulate junctional remodelling. With a clinical genetics team we identified natural variants that associate with lymphedema and disrupt the channel’s ability to sense force [5]. To understand how it operates at the molecular level, we worked with a computation molecular dynamics team in develop models of the channel in endothelial membrane, predicting and testing structural rearrangements and lipid interactions. To explore potential therapeutic implications, we worked with medicinal chemists to develop pharmacology that activates or inhibits the channels. Overall, we suggest that PIEZO1 forms an exceptional mechanical detector of the cardiovascular system with importance spanning lymphatic drainage, skeletal muscle function and lipid homeostasis.