Endothelial Paradigm

T he evolution of organisms has been both constrained and facilitated by many internal and external mechanical limitations. Mechanical sensing systems used by primitive cells to ensure survival have been retained, often in modified form, in multicellular animals and in the tissues and organ systems of mammals to form specialized sensors that monitor both the internal state of the organism as well as its interactions with the external environment. Mechanical stresses alter the structural and functional properties of cells (mechanotransduction) at the cellular, molecular, and genetic levels, leading to both rapid responses in the adjacent tissue and slower adaptive changes to a sustained mechanical environment. The latter often results in an alteration of intracellular tension to counterbalance the external stress. Cellular responses to direct mechanical stresses appear to involve an interplay between structural elements and biochemical second messengers. Cell surface proteins and extracellular matrix, linked by transmembrane proteins to the cytoskeleton, activate ion channels and enzymes by mechanical deformation. The signal transduction mechanisms by which mechanical stresses can be converted to electrophysiological and biochemical responses in the sensing cells and the adaptation of such cells to the external forces by altered gene expression is receiving increased attention. A change in the extracellular concentration of bioactive ligands at the cell surface as a result of fluid movement has also been identified as an indirect mechanism of mechanotransduction. Using the paradigm of endothelial cell responses to flow forces, this review attempts to 1) define the nature of direct biomechanical stresses, 2) identify key examples of bioresponses, and 3) discuss signal transduction mechanisms of mechanical stress.