Mechanical tugging force regulates the size of cell–cell junctions

TLDR

Actomyosin contractility generates mechanical forces at cell–cell and cell–matrix contacts, and while increased loading at cell–matrix adhesions promotes focal adhesion growth, it remains unclear whether forces similarly regulate the size of cell–cell adhesions. The study aims to determine how adherens junctions respond to mechanical tugging forces. To this end, the authors employed microfabricated force sensors that quantitatively report endothelial cell–cell tugging force and adherens junction size. AJ size is directly regulated by endothelial cell–cell tugging forces, with myosin activation increasing and inhibition decreasing AJ size, and mechanical tugging alone can trigger AJ growth, indicating that coordinated myosin–Rac1 signaling and mechanical forces are essential for junctional stability and multicellular integrity.

Abstract

Actomyosin contractility affects cellular organization within tissues in part through the generation of mechanical forces at sites of cell–matrix and cell–cell contact. While increased mechanical loading at cell–matrix adhesions results in focal adhesion growth, whether forces drive changes in the size of cell–cell adhesions remains an open question. To investigate the responsiveness of adherens junctions (AJ) to force, we adapted a system of microfabricated force sensors to quantitatively report cell–cell tugging force and AJ size. We observed that AJ size was modulated by endothelial cell–cell tugging forces: AJs and tugging force grew or decayed with myosin activation or inhibition, respectively. Myosin-dependent regulation of AJs operated in concert with a Rac1, and this coordinated regulation was illustrated by showing that the effects of vascular permeability agents (S1P, thrombin) on junctional stability were reversed by changing the extent to which these agents coupled to the Rac and myosin-dependent pathways. Furthermore, direct application of mechanical tugging force, rather than myosin activity per se, was sufficient to trigger AJ growth. These findings demonstrate that the dynamic coordination of mechanical forces and cell–cell adhesive interactions likely is critical to the maintenance of multicellular integrity and highlight the need for new approaches to study tugging forces.