Show simple item record

dc.contributor.authorKe, Y.
dc.contributor.authorKarki, P.
dc.contributor.authorZhang, C.
dc.date.accessioned2019-09-13T16:41:58Z
dc.date.available2019-09-13T16:41:58Z
dc.date.issued2019
dc.identifier.urihttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85063995846&doi=10.1091%2fmbc.E18-07-0422&partnerID=40&md5=19fccc86e54223eb14f6c7d5751466f7
dc.identifier.urihttp://hdl.handle.net/10713/10686
dc.description.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.en_US
dc.description.sponsorshipThis 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.en_US
dc.description.urihttps://doi.org/10.1091/mbc.E18-07-0422en_US
dc.language.isoen-USen_US
dc.publisherAmerican Society for Cell Biologyen_US
dc.relation.ispartofMolecular Biology of the Cell
dc.subject.meshRespiration, Artificial--adverse effectsen_US
dc.titleMechanosensitive Rap1 activation promotes barrier function of lung vascular endothelium under cyclic stretchen_US
dc.typeArticleen_US
dc.identifier.doi10.1091/mbc.E18-07-0422
dc.identifier.pmid30759056


This item appears in the following Collection(s)

Show simple item record