As described in Chapter 4, local, VE-cadherin-mediated adaptive stiffening corresponded with increased recruitment of vinculin and F-actin to VE-cadherin coated beads. The mechanical response required PI3K and ROCK, organized actin, and myosin II. The role of these components in long-range remodeling of EC monolayers was not further explored because inhibitors of these components destabilized interendothelial junctions, independent of force application. Both treatment with cytochalasin D and blebbistatin induced formation of interendothelial gaps (Fig. A.2A,B). Cytochalasin D abolished F-actin fibers and organization. Nocodazole treatment, which increases actomyosin contractility, induced the formation of F- actin stress fibers throughout the cell, diminished cortical F-actin, and disrupted peripheral adherens junctions (Fig. A.2C). These effects are similar to those induced by pro-inflammatory stimuli such as thrombin (204). In comparison, untreated cells were characterized by cobblestone cell morphology, intact cell-cell junctions delineated by VE-cadherin and cortical F-actin organized around the cell periphery (Fig. A.2D).
Inhibition of PI3K with LY294002 similarly disrupted cell-cell junctions, but the overall effects were not as obvious as the other inhibitors (Fig. A.3). Cells treated with LY294002 displayed cell-cell junctions with a ruffled morphology, but the organization of F-actin was not affected. Application of VE-cadherin bond shear did not significantly alter the appearance of the EC monolayer.
A.3 Figures
Figure A.1. VE-cadherin-Fc protein production. Western blot of CHO cell clones expressing VE-cadherin-Fc.
Figure A.2. Impact of cytoskeletal inhibitors on EC monolayer integrity. (A) EC monolayers were treated with 4 µM cytochalasin D for 20 min, (B) 100 µM blebbistatin for 20 min, or (C) 20 µM nocodazole for 30 min. (D) Untreated cells. Cells were bound with beads coated with VE-cadherin-Fc, and no shear stress was applied to beads. Images represent > three independent experiments, scale bars represent 20 µm.
Figure A.3. Inhibition of PI3K disrupts cell-cell junctions. EC monolayers were treated with 30 µM LY294002, an inhibitor of PI3K, for 20 min. Shear stress (2.4 Pa) was applied for 2 min. Images represent > three independent experiments, scale bars represent 20 µm.
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