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1 Department of Mechanical Engineering and Biological Engineering Division, Massachusetts Institute of Technology, Cambridge, MA, USA
2 Department of Medicine, Brigham & Women's Hospital, Boston, MA, USA
* To whom correspondence should be addressed. E-mail: rdkamm{at}mit.edu.
Vascular endothelial cells rapidly transduce local mechanical forces into biological signals through numerous processes including the activation of focal adhesion sites. In order to examine the mechanosensing capabilities of these adhesion sites, focal adhesion translocation was monitored with GFP-paxillin while applying nN-level magnetic trap shear forces to the cell apex via integrin-linked magnetic beads. A nongraded, time dependent (~ minutes) steady load threshold for mechanotransduction was established between 0.90 and 1.45 nN. Activation was greatest near the point of forcing (< 7.5 µm), indicating that shear forces imposed on the apical cell membrane transmit non-uniformly to the basal cell surface and that focal adhesion sites may function as individual mechanosensors responding to local levels of force. Results from a continuum, viscoelastic finite element model of magnetocytometry that represented experimental focal adhesion attachments provided support for a non-uniform force transmission to basal surface focal adhesion sites. To further understand the role of force transmission on focal adhesion activation and dynamics, sinusoidally varying forces were applied at 0.1, 1.0, 10, and 50 Hz with a 1.45 nN offset and a 2.25 nN maximum. At 10 and 50 Hz, focal adhesion activation did not vary with spatial location, as observed for steady loading, while the response was minimized at 1.0 Hz. Furthermore, applying the tyrosine kinase inhibitors genistein and PP2, a specific Src family kinase inhibitor, showed tyrosine kinase signaling has a role in force-induced translocation. These results highlight the mutual importance of force transmission and biochemical signaling in focal adhesion mechanotransduction.
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