title: Cytoskeletal rearrangement mediates human microvascular endothelial tight junction modulation by cytokines.
abstract: The tight junction (TJ) is a specialized intercellular structure responsible for the regulation of ionic and macromolecular flux across cell monolayers. Because plasma leakage is believed to occur mainly across the microvasculature, we hypothesized that microvascular endothelial cells (MVEC) may form more intact, regulatable TJ than other endothelial cell (EC) types, allowing further insight into the control of EC permeability. Primary cultures of MVEC monolayers produced transmonolayer electrical resistances (TER) of 120-155 omega.cm2, approximately 10 times that of large-vessel EC. Treatment with tumor necrosis factor and interferon-gamma caused a 50% decrease in the TER and a striking fragmentation of the basal, continuous interendothelial cell zonula occludens-1 protein (ZO-1) distribution determined by immunofluorescence. Fragmentation was inhibited by cytochalasin D, and confocal microscopy demonstrated a colocalization between F actin and ZO-1. These findings suggest that the F actin cytoskeleton plays a central role in endothelial TJ barrier regulation and that dynamic cytoskeletal alterations may primarily control vascular permeability.
authors.affiliation: Molecular Cardiobiology Program, Boyer Center for Molecular Medicine, New Haven, Connecticut, USA.
authors.forename: M S
authors.initials: MS
authors.lastname: Blum
authors.forename: E
authors.initials: E
authors.lastname: Toninelli
authors.forename: J M
authors.initials: JM
authors.lastname: Anderson
authors.forename: M S
authors.initials: MS
authors.lastname: Balda
authors.forename: J
authors.initials: J
authors.lastname: Zhou
authors.forename: L
authors.initials: L
authors.lastname: O'Donnell
authors.forename: R
authors.initials: R
authors.lastname: Pardi
authors.forename: J R
authors.initials: JR
authors.lastname: Bender
mesh_terms: D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000199:Actins / Q000502:physiology*; D003994:Bucladesine / Q000494:pharmacology; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology*; D003599:Cytoskeleton / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D004594:Electrophysiology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure*; D006801:Humans; D007231:Infant, Newborn; D007371:Interferon-gamma / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials; D008565:Membrane Proteins / Q000502:physiology; D008833:Microcirculation / Q000502:physiology*; D010750:Phosphoproteins / Q000502:physiology; D012867:Skin / Q000098:blood supply; D019108:Tight Junctions / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014471:Umbilical Veins; D062826:Zonula Occludens-1 Protein
chemical_list: D000199:Actins; D016207:Cytokines; D008565:Membrane Proteins; D010750:Phosphoproteins; C569042:TJP1 protein, human; D014409:Tumor Necrosis Factor-alpha; D062826:Zonula Occludens-1 Protein; D003994:Bucladesine; D007371:Interferon-gamma; D015056:1-Methyl-3-isobutylxanthine