title: Myosin light chain kinase signaling in endothelial barrier dysfunction.
abstract: Microvascular barrier dysfunction is a serious problem that occurs in many inflammatory conditions, including sepsis, trauma, ischemia-reperfusion injury, cardiovascular disease, and diabetes. Barrier dysfunction permits extravasation of serum components into the surrounding tissue, leading to edema formation and organ failure. The basis for microvascular barrier dysfunction is hyperpermeability at endothelial cell-cell junctions. Endothelial hyperpermeability is increased by actomyosin contractile activity in response to phosphorylation of myosin light chain by myosin light chain kinase (MLCK). MLCK-dependent endothelial hyperpermeability occurs in response to inflammatory mediators (e.g., activated neutrophils, thrombin, histamine, tumor necrosis factor alpha, etc.), through multiple cell signaling pathways and signaling molecules (e.g., Ca(++) , protein kinase C, Src kinase, nitric oxide synthase, etc.). Other signaling molecules protect against MLCK-dependent hyperpermeability (e.g., sphingosine-1-phosphate or cAMP). In addition, individual MLCK isoforms play specific roles in endothelial barrier dysfunction, suggesting that isoform-specific inhibitors could be useful for treating inflammatory disorders and preventing multiple organ failure. Because endothelial barrier dysfunction depends upon signaling through MLCK in many instances, MLCK-dependent signaling comprises multiple potential therapeutic targets for preventing edema formation and multiple organ failure. The following review is a discussion of MLCK-dependent mechanisms and cell signaling events that mediate endothelial hyperpermeability.
authors.affiliation: Department of Surgery, University of California at Davis School of Medicine, Sacramento, California, USA.
authors.forename: Robert R
authors.initials: RR
authors.lastname: Rigor
authors.forename: Qiang
authors.initials: Q
authors.lastname: Shen
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Pivetti
authors.forename: Mack H
authors.initials: MH
authors.lastname: Wu
authors.forename: Sarah Y
authors.initials: SY
authors.lastname: Yuan
mesh_terms: D000818:Animals; D004727:Endothelium / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology; D006801:Humans; D058990:Molecular Targeted Therapy; D009219:Myosin-Light-Chain Kinase / Q000737:chemistry / Q000378:metabolism*; D010539:Permeability / Q000187:drug effects; D020011:Protective Agents / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D020011:Protective Agents; D009219:Myosin-Light-Chain Kinase