Substrate stiffening promotes endothelial monolayer disruption through enhanced physical forces

A hallmark of many, sometimes life-threatening, inflammatory diseases and disorders is vascular leakage. The extent and severity of vascular leakage is broadly mediated by the integrity of the endothelial cell (EC) monolayer, which is in turn governed by three major interactions: cell-cell and cell-...

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Bibliographic Details
Published in:American Journal of Physiology: Cell Physiology 2011-01, Vol.300 (1), p.C146-C154
Main Authors: Krishnan, Ramaswamy, Klumpers, Darinka D, Park, Chan Y, Rajendran, Kavitha, Trepat, Xavier, van Bezu, Jan, van Hinsbergh, Victor W M, Carman, Christopher V, Brain, Joseph D, Fredberg, Jeffrey J, Butler, James P, van Nieuw Amerongen, Geerten P
Format: Article
Language:English
Subjects:
Acrylic Resins
Antigens, CD - metabolism
Biochemistry
Biomechanical Phenomena
Biomechanics
Cadherins - metabolism
Cell Adhesion - drug effects
Cell Adhesion - physiology
Cells
Cells, Cultured
Cellular biology
Culture Media - chemistry
Endothelial Cells - cytology
Endothelial Cells - drug effects
Endothelial Cells - physiology
Humans
Kinases
Membranes, Artificial
Microscopy
rho-Associated Kinases - metabolism
Thrombin - pharmacology
Vascular Biology
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Summary:A hallmark of many, sometimes life-threatening, inflammatory diseases and disorders is vascular leakage. The extent and severity of vascular leakage is broadly mediated by the integrity of the endothelial cell (EC) monolayer, which is in turn governed by three major interactions: cell-cell and cell-substrate contacts, soluble mediators, and biomechanical forces. A potentially critical but essentially uninvestigated component mediating these interactions is the stiffness of the substrate to which the endothelial monolayer is adherent. Accordingly, we investigated the extent to which substrate stiffening influences endothelial monolayer disruption and the role of cell-cell and cell-substrate contacts, soluble mediators, and physical forces in that process. Traction force microscopy showed that forces between cell and cell and between cell and substrate were greater on stiffer substrates. On stiffer substrates, these forces were substantially enhanced by a hyperpermeability stimulus (thrombin, 1 U/ml), and gaps formed between cells. On softer substrates, by contrast, these forces were increased far less by thrombin, and gaps did not form between cells. This stiffness-dependent force enhancement was associated with increased Rho kinase activity, whereas inhibition of Rho kinase attenuated baseline forces and lessened thrombin-induced inter-EC gap formation. Our findings demonstrate a central role of physical forces in EC gap formation and highlight a novel physiological mechanism. Integrity of the endothelial monolayer is governed by its physical microenvironment, which in normal circumstances is compliant but during pathology becomes stiffer.
ISSN:0363-6143
1522-1563
DOI:10.1152/ajpcell.00195.2010