The integrin expression profile modulates orientation and dynamics of force transmission at cell-matrix adhesions

Integrin adhesion receptors connect the extracellular matrix (ECM) to the cytoskeleton and serve as bidirectional mechanotransducers. During development, angiogenesis, wound healing and cancer progression, the relative abundance of fibronectin receptors, including integrins alpha 5 beta 1 and alpha v beta 3, changes, thus altering the integrin composition of cell-matrix adhesions. Here, we show that enhanced alpha v beta 3 expression can fully compensate for loss of alpha 5 beta 1 and other beta 1 integrins to support outside-in and inside-out force transmission. alpha 5 beta 1 and alpha v beta 3 each mediate actin cytoskeletal remodeling in response to stiffening or cyclic stretching of the ECM. Likewise, alpha 5 beta 1 and alpha v beta 3 support cellular traction forces of comparable magnitudes and similarly increase these forces in response to ECM stiffening. However, cells using alpha v beta 3 respond to lower stiffness ranges, reorganize their actin cytoskeleton more substantially in response to stretch, and show more randomly oriented traction forces. Centripetal traction force orientation requires long stress fibers that are formed through the action of Rho kinase (ROCK) and myosin II, and that are supported by alpha 5 beta 1. Thus, altering the relative abundance of fibronectin-binding integrins in cell-matrix adhesions affects the spatiotemporal organization of force transmission.