αvβ3 Integrin Activation and Matrix Binding Mediate Cellular Responses to Mechanical Stretch.

Mechanical tension is a critical determinant of vascular cell growth, differentiation, apoptosis, migration and development. Integrins have been implicated in sensing force but little is known about how forces are transduced to biochemical signals. We now show that mechanical strain stimulates conformational activation of integrin αvβ3 in NIH3T3 cells by using conformation specific antibody WOW-1. LM609, an antibody against αvβ3 integrin that is insensitive to integrin conformation, showed no change in binding after stretch, excluding changes in surface expression. Stretch also induced an increase of LIBS-6 binding, evidence that conformational activation leads to new binding of integrins to ECM. PI3K and Akt are both rapidly activated by strain, and PI3K inhibition decreases integrin activation. These data strongly suggest that PI3K mediates αvβ3 integrin activation. The blocking anti-fibronectin antibody 16G3 strongly inhibited the stretch-induced activation of JNK under conditions where existing adhesions did not appear to be disrupted, indicating that new integrin-ECM binding is required for JNK activation. These data define a pathway by which early activation of PI3K, through induction of integrin activation and ECM binding, stimulates a cytoplasmic signaling pathway implicated in cellular responses.