title: ROCK2 primes the endothelium for vascular hyperpermeability responses by raising baseline junctional tension.
abstract: Rho kinase mediates the effects of inflammatory permeability factors by increasing actomyosin-generated traction forces on endothelial adherens junctions, resulting in disassembly of intercellular junctions and increased vascular leakage. In vitro, this is accompanied by the Rho kinase-driven formation of prominent radial F-actin fibers, but the in vivo relevance of those F-actin fibers has been debated, suggesting other Rho kinase-mediated events to occur in vascular leak. Here, we delineated the contributions of the highly homologous isoforms of Rho kinase (ROCK1 and ROCK2) to vascular hyperpermeability responses. We show that ROCK2, rather than ROCK1 is the critical Rho kinase for regulation of thrombin receptor-mediated vascular permeability. Novel traction force mapping in endothelial monolayers, however, shows that ROCK2 is not required for the thrombin-induced force enhancements. Rather, ROCK2 is pivotal to baseline junctional tension as a novel mechanism by which Rho kinase primes the endothelium for hyperpermeability responses, independent from subsequent ROCK1-mediated contractile stress-fiber formation during the late phase of the permeability response.
authors: Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, van der Boechorststraat 7, 1081BT Amsterdam, The Netherlands.
authors: Cora M L
authors: CM
authors: Beckers
authors: Department of Pharmacology, Center for Lung and Vascular Biology, University of Illinois, College of Medicine, Chicago, IL 60612, USA.
authors: Nebojsa
authors: N
authors: Knezevic
authors: Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, van der Boechorststraat 7, 1081BT Amsterdam, The Netherlands.
authors: Erik T
authors: ET
authors: Valent
authors: Department of Pharmacology, Center for Lung and Vascular Biology, University of Illinois, College of Medicine, Chicago, IL 60612, USA.
authors: Mohammad
authors: M
authors: Tauseef
authors: Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Boston, MA, USA.
authors: Ramaswamy
authors: R
authors: Krishnan
authors: Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Boston, MA, USA.
authors: Kavitha
authors: K
authors: Rajendran
authors: Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
authors: C Corey
authors: CC
authors: Hardin
authors: Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, van der Boechorststraat 7, 1081BT Amsterdam, The Netherlands.
authors: Jurjan
authors: J
authors: Aman
authors: Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, van der Boechorststraat 7, 1081BT Amsterdam, The Netherlands.
authors: Jan
authors: J
authors: van Bezu
authors: Surface Logix-737, Concord Ave., Cambridge, MA 02138, USA.
authors: Paul
authors: P
authors: Sweetnam
authors: Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, van der Boechorststraat 7, 1081BT Amsterdam, The Netherlands.
authors: Victor W M
authors: VW
authors: van Hinsbergh
authors: Department of Pharmacology, Center for Lung and Vascular Biology, University of Illinois, College of Medicine, Chicago, IL 60612, USA.
authors: Dolly
authors: D
authors: Mehta
authors: Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, van der Boechorststraat 7, 1081BT Amsterdam, The Netherlands; Department of Pharmacology, Center for Lung and Vascular Biology, University of Illinois, College of Medicine, Chicago, IL 60612, USA. Electronic address: nieuwamerongen@vumc.nl.
authors: Geerten P
authors: GP
authors: van Nieuw Amerongen
mesh_terms: D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects; D002478:Cells, Cultured; D017097:Electric Impedance; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D007365:Intercellular Junctions / Q000187:drug effects / Q000201:enzymology*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D015398:Signal Transduction; D022502:Stress Fibers / Q000201:enzymology; D013917:Thrombin / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D047428:Protein Kinase Inhibitors; C515851:ROCK1 protein, human; C515852:ROCK2 protein, human; C515854:Rock1 protein, mouse; C515855:Rock2 protein, mouse; D054460:rho-Associated Kinases; D013917:Thrombin
keywords: Contraction; Endothelial; HUVEC; Permeability; Rho kinase