Multicellular Regulation of Tensional Homeostasis

Vascular endothelial cells are exposed to routine and directed mechanical forces due to the pulsatile nature of blood flow. As a result, these cells undergo cytoskeletal remodeling and elicit adaptive changes in cell signaling that protect them against atherosclerosis. A main purpose of this remodeling is to minimize alterations in intracellular mechanical tension caused by external forces and to maintain it at a preferred (homeostatic) level. It has been purported that normal physiological functions of the endothelium requires tensional homeostasis across a broad range of length scales, from the subcellular level to the tissue level. Our recent study challenged this view, however. We measured reorientation of cellular traction forces in isolated endothelial cells in response to periodic uniaxial stretch. We found that within ∼40-50 min from the onset of stretch the traction field reorients in the direction perpendicular to the stretch axis, but exhibits a highly dynamic and erratic behavior long after reorientation is completed. Moreover, even in the absence of external stretch the traction field remains dynamic and erratic while the cell spreading area changes very little and cells do not migrate. Here, we hypothesized that tensional homeostasis of the endothelium requires intercellular cooperation. We measured cellular traction forces in two-dimensional endothelial cell clusters of different sizes and at different length scales over an extended time period and analyzed traction dynamics. Our analysis revealed that dynamic fluctuation of traction forces diminished with increasing cluster size and with increasing strength of the traction field, suggesting that cell-cell cooperation might promote tensional homeostasis in the endothelium. Using a mathematical model, we showed that the cell clusters might regulate the homeostatic state of stress through mechanical interdependence between adjacent cells.