title: Loss of cortactin causes endothelial barrier dysfunction via disturbed adrenomedullin secretion and actomyosin contractility.
abstract: Changes in vascular permeability occur during inflammation and the actin cytoskeleton plays a crucial role in regulating endothelial cell contacts and permeability. We demonstrated recently that the actin-binding protein cortactin regulates vascular permeability via Rap1. However, it is unknown if the actin cytoskeleton contributes to increased vascular permeability without cortactin. As we consistently observed more actin fibres in cortactin-depleted endothelial cells, we hypothesised that cortactin depletion results in increased stress fibre contractility and endothelial barrier destabilisation. Analysing the contractile machinery, we found increased ROCK1 protein levels in cortactin-depleted endothelium. Concomitantly, myosin light chain phosphorylation was increased while cofilin, mDia and ERM were unaffected. Secretion of the barrier-stabilising hormone adrenomedullin, which activates Rap1 and counteracts actomyosin contractility, was reduced in plasma from cortactin-deficient mice and in supernatants of cortactin-depleted endothelium. Importantly, adrenomedullin administration and ROCK1 inhibition reduced actomyosin contractility and rescued the effect on permeability provoked by cortactin deficiency in vitro and in vivo. Our data suggest a new role for cortactin in controlling actomyosin contractility with consequences for endothelial barrier integrity.
authors.affiliation: Department for Molecular Biomedicine, Center of Research and Advanced Studies (CINVESTAV-IPN), 07360 Mexico-City, Mexico.
authors.forename: Alexander
authors.initials: A
authors.lastname: García Ponce
authors.affiliation: Department for Molecular Biomedicine, Center of Research and Advanced Studies (CINVESTAV-IPN), 07360 Mexico-City, Mexico.
authors.forename: Alí F
authors.initials: AF
authors.lastname: Citalán Madrid
authors.affiliation: Department for Molecular Biomedicine, Center of Research and Advanced Studies (CINVESTAV-IPN), 07360 Mexico-City, Mexico.
authors.forename: Hilda
authors.initials: H
authors.lastname: Vargas Robles
authors.affiliation: Department for Molecular Biomedicine, Center of Research and Advanced Studies (CINVESTAV-IPN), 07360 Mexico-City, Mexico.
authors.forename: Sandra
authors.initials: S
authors.lastname: Chánez Paredes
authors.affiliation: Department for Physiology, Biophysics and Neurosciences, Center of Research and Advanced Studies (CINVESTAV-IPN), 07360 Mexico-City, Mexico.
authors.forename: Porfirio
authors.initials: P
authors.lastname: Nava
authors.affiliation: Department for Infectomics and Molecular Pathogenesis, Center of Research and Advanced Studies (CINVESTAV-IPN), 07360 Mexico-City, Mexico.
authors.forename: Abigail
authors.initials: A
authors.lastname: Betanzos
authors.affiliation: Department of Anesthesiology, Intensive Care and Pain Medicine, University Clinic of Münster, 48149 Münster, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Zarbock
authors.affiliation: Division of Molecular Cell Biology, Zoological Institute, TU Braunschweig, 38106 Braunschweig, Germany.|Department of Cell Biology, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany.
authors.forename: Klemens
authors.initials: K
authors.lastname: Rottner
authors.affiliation: Department for Vascular Cell Biology, Max-Planck-Institute for Molecular Biomedicine, 48149 Münster, Germany.
authors.forename: Dietmar
authors.initials: D
authors.lastname: Vestweber
authors.affiliation: Department for Molecular Biomedicine, Center of Research and Advanced Studies (CINVESTAV-IPN), 07360 Mexico-City, Mexico.
authors.forename: Michael
authors.initials: M
authors.lastname: Schnoor
mesh_terms: D000205:Actomyosin / Q000502:physiology; D053607:Adrenomedullin / Q000378:metabolism*; D000818:Animals; D002199:Capillary Permeability / Q000502:physiology*; D003285:Contractile Proteins / Q000096:biosynthesis / Q000235:genetics; D051356:Cortactin / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D042783:Endothelial Cells / Q000502:physiology*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008168:Lung / Q000166:cytology; D008297:Male; D051379:Mice; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D000089804:Shelterin Complex; D034501:Telomere-Binding Proteins / Q000378:metabolism; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000502:physiology
chemical_list: C507862:ADM protein, human; C495868:CTTN protein, human; D003285:Contractile Proteins; D051356:Cortactin; C495869:Cttn protein, mouse; D034741:RNA, Small Interfering; D000089804:Shelterin Complex; C440809:TERF2IP protein, human; D034501:Telomere-Binding Proteins; D053607:Adrenomedullin; D000205:Actomyosin; C515851:ROCK1 protein, human; D054460:rho-Associated Kinases; C000620839:Rap1 protein, mouse; D020827:rap1 GTP-Binding Proteins