PIEZO proteins are multi-pass membrane proteins forming calcium permeable nonselective cation channels. They are remarkable for their mechanical force sensing properties and structural attributes that optimise them for force sensing. We found the PIEZO1 channel is pivotal for vascular endothelium to feel fluid shear stress and enables flow dependent vascular maturation in embryonic development. At the adult stage, we found endothelial PIEZO1 regulates blood pressure and skeletal muscle microvascular density for physical performance, muscle growth for strength and hepatobiliary gene expression for whole body lipid homeostasis. We found endothelial PIEZO1 delivers downstream effects through calpain protease activation, altered phosphorylation and abundance of NOS3 nitric oxide synthase, ADAM10-dependent NOTCH1 cleavage and intercellular communication to pericytes. As integrated ion channels with unusual blade structures deep in the membrane, PIEZOs are increasingly recognised to depend on lipid interactions. We found, for example, the ceramide lipid disables intrinsic inactivation in endothelial PIEZO1 channels to promote their activity. To generate new ideas about how the channels work as lipid-integrated machines in endothelial membrane, we established computational molecular dynamics simulations of PIEZO1 channels in membranes of endothelial composition and applied forces to observe responses, testing the models by electrophysiology and intracellular calcium measurement in cells. We found anionic lipids such as phosphatidylinositol phosphates have critical roles, controlling PIEZO1 force sensitivity via inter-blade handshaking. Lipid dysregulation is common in disease and obesity, so we are working to understand and predict how lipids interact with PIEZO force sensing and influence health.