The chapter discusses the role of mechanical forces, particularly blood flow, in regulating vascular tone, structure, and the localization of atherosclerotic lesions. Hemodynamic shear stresses on the endothelium are key regulators of these processes, and the chapter reviews the mechanisms by which these forces are transmitted and transduced into biophysical, biochemical, and gene regulatory responses. The endothelium, located between the blood and vascular wall, is exposed to significant fluid forces. These forces influence endothelial functions such as anticoagulation, lumen diameter control, and vascular permeability. Hemodynamic factors, including shear stress and stretch forces, directly affect the endothelium, while also indirectly modifying local chemical concentrations and receptor interactions. The chapter details the morphological responses of endothelial cells to shear stress, such as cell alignment and cytoskeletal reorganization. It also explores the interactions between hemodynamic forces and the endothelium, including force transmission through the cytoskeleton and signal filtering and adaptation mechanisms. The text highlights the role of plasma membrane proteins as mechanoreceptors, particularly ion channels, in transducing mechanical signals into intracellular responses. It discusses the activation of various ion channels, such as potassium and calcium channels, in response to shear stress and stretch, and their potential roles in modulating vascular tone and function. Overall, the chapter provides a comprehensive overview of the mechanisms by which mechanical forces from blood flow are detected and translated into biological responses in the endothelium, emphasizing the complexity and diversity of these processes.The chapter discusses the role of mechanical forces, particularly blood flow, in regulating vascular tone, structure, and the localization of atherosclerotic lesions. Hemodynamic shear stresses on the endothelium are key regulators of these processes, and the chapter reviews the mechanisms by which these forces are transmitted and transduced into biophysical, biochemical, and gene regulatory responses. The endothelium, located between the blood and vascular wall, is exposed to significant fluid forces. These forces influence endothelial functions such as anticoagulation, lumen diameter control, and vascular permeability. Hemodynamic factors, including shear stress and stretch forces, directly affect the endothelium, while also indirectly modifying local chemical concentrations and receptor interactions. The chapter details the morphological responses of endothelial cells to shear stress, such as cell alignment and cytoskeletal reorganization. It also explores the interactions between hemodynamic forces and the endothelium, including force transmission through the cytoskeleton and signal filtering and adaptation mechanisms. The text highlights the role of plasma membrane proteins as mechanoreceptors, particularly ion channels, in transducing mechanical signals into intracellular responses. It discusses the activation of various ion channels, such as potassium and calcium channels, in response to shear stress and stretch, and their potential roles in modulating vascular tone and function. Overall, the chapter provides a comprehensive overview of the mechanisms by which mechanical forces from blood flow are detected and translated into biological responses in the endothelium, emphasizing the complexity and diversity of these processes.