Mechanosensitive Rap1 activation promotes barrier function of lung vascular endothelium under cyclic stretch
JournalMolecular Biology of the Cell
PublisherAmerican Society for Cell Biology
MetadataShow full item record
AbstractMechanical ventilation remains an imperative treatment for the patients with acute respiratory distress syndrome, but can also exacerbate lung injury. We have previously described a key role of RhoA GTPase in high cyclic stretch (CS)-induced endothelial cell (EC) barrier dysfunction. However, cellular mechanotransduction complexes remain to be characterized. This study tested a hypothesis that recovery of a vascular EC barrier after pathologic mechanical stress may be accelerated by cell exposure to physiologic CS levels and involves Rap1-dependent rearrangement of endothelial cell junctions. Using biochemical, molecular, and imaging approaches we found that EC pre- or postconditioning at physiologically relevant low-magnitude CS promotes resealing of cell junctions disrupted by pathologic, high-magnitude CS. Cytoskeletal remodeling induced by low CS was dependent on small GTPase Rap1. Protective effects of EC preconditioning at low CS were abolished by pharmacological or molecular inhibition of Rap1 activity. In vivo, using mice exposed to mechanical ventilation, we found that the protective effect of low tidal volume ventilation against lung injury caused by lipopolysaccharides and ventilation at high tidal volume was suppressed in Rap1 knockout mice. Taken together, our results demonstrate a prominent role of Rap1-mediated signaling mechanisms activated by low CS in acceleration of lung vascular EC barrier restoration. Copyright 2019 Ke et al.
SponsorsThis work was supported by grants HL076259, HL087823, HL107920, and HL130431 from the National Heart, Lung, and Blood Institute; AG048231 from the National Institute on Aging; and GM122940 and GM114171 from the National Institute of General Medical Sciences.
Identifier to cite or link to this itemhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85063995846&doi=10.1091%2fmbc.E18-07-0422&partnerID=40&md5=19fccc86e54223eb14f6c7d5751466f7; http://hdl.handle.net/10713/10686
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