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Vascular Endothelia Mechanically Sense Barrier Quality and Maintain Functional Integrity through ROS‐Dependent Actin Remodeling
Author(s) -
Carman Christopher,
Kamei Masataka,
Varghese Laya,
Sciuto Tracey,
Dvorak Ann,
Martinelli Roberta
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.85.4
Subject(s) - lamellipodium , microbiology and biotechnology , cortactin , barrier function , endothelium , mechanotransduction , ve cadherin , adherens junction , contractility , wound healing , actin , rac1 , endothelial stem cell , chemistry , biology , cytoskeleton , cadherin , immunology , cell , signal transduction , in vitro , biochemistry , endocrinology
Objective: Mechanisms for maintenance of endothelial integrity are of enormous biomedical importance. Despite its tenuous structure and constitutive exposure to disruptive strains, the endothelium normally exhibits extremely robust barrier properties. The objective of this study was to elucidate fundamental mechanisms by which the endothelium senses and responds to integrity disruptions in order to maintain its barrier function. Results: We show that in response to ~5‐50 micron‐scale disruptions in the endothelium, induced by transmigrating leukocytes or a mechanical probe, endothelial cells generate unique ‘ventral lamellipodia' that propagate via integrins toward and across these ‘micro‐wounds' to close them and promote re‐annealing of the adherens junctions. Experiments combining probe‐induced micro‐wounding, pharmacologic modulation of contractility & substrate stretching manipulations demonstrate that endothelia 'sense' breaches in its barrier as force imbalance and specifically loss of isometric tension upon rupture of adhesions. Such loss if tension was acutely/locally translated into biomechanical signals for reparative actin remodeling. Indeed, ventral lamellipodia were enriched in the Rac1 effectors cortactin, IQGAP, and p47Phox and exhibited localized production of H2O2. Together with Apr2/3, these were functionally required for effective micro‐wound healing and maintenance of endothelial barrier function. Conclusion We propose that barrier disruptions are detected as local release of isometric tension, which is directly coupled to reactive oxygen species‐dependent self‐restorative actin remodeling dynamics.