The study investigates the role of Piezo1 channels in regulating vascular structure and function. Piezo1 is shown to be a sensor of frictional force (shear stress) and a determinant of vascular development in both embryos and adults. Global or endothelial-specific disruption of *Piezo1* in mice results in embryonic lethality and abnormal vasculature. Piezo1 depletion in human umbilical vein endothelial cells (HUVECs) suppresses migration and tube formation, and exogenous Piezo1 confers sensitivity to shear stress. Piezo1-dependent shear stress-evoked Ca2+ entry is crucial for endothelial cell migration and alignment, and is linked to eNOS activity. Proteomic analysis reveals that Piezo1 is involved in the regulation of actin cytoskeleton and focal adhesion proteins, suggesting a role for calpain activation in the downstream mechanism. These findings highlight Piezo1 as a pivotal integrator in vascular biology, with implications for understanding vascular physiology and diseases such as atherosclerosis and cancer.The study investigates the role of Piezo1 channels in regulating vascular structure and function. Piezo1 is shown to be a sensor of frictional force (shear stress) and a determinant of vascular development in both embryos and adults. Global or endothelial-specific disruption of *Piezo1* in mice results in embryonic lethality and abnormal vasculature. Piezo1 depletion in human umbilical vein endothelial cells (HUVECs) suppresses migration and tube formation, and exogenous Piezo1 confers sensitivity to shear stress. Piezo1-dependent shear stress-evoked Ca2+ entry is crucial for endothelial cell migration and alignment, and is linked to eNOS activity. Proteomic analysis reveals that Piezo1 is involved in the regulation of actin cytoskeleton and focal adhesion proteins, suggesting a role for calpain activation in the downstream mechanism. These findings highlight Piezo1 as a pivotal integrator in vascular biology, with implications for understanding vascular physiology and diseases such as atherosclerosis and cancer.