Myosin light chain kinase in microvascular endothelial barrier function.
Microvascular barrier dysfunction is implicated in the initiation and progression of inflammation, posttraumatic complications, sepsis, ischaemia-reperfusion injury, atherosclerosis, and diabetes. Under physiological conditions, a precise equilibrium between endothelial cell-cell adhesion and actin-myosin-based centripetal tension tightly controls the semi-permeability of microvascular barriers. Myosin light chain kinase (MLCK) plays an important role in maintaining the equilibrium by phosphorylating myosin light chain (MLC), thereby inducing actomyosin contractility and weakening endothelial cell-cell adhesion. MLCK is activated by numerous physiological factors and inflammatory or angiogenic mediators, causing vascular hyperpermeability. In this review, we discuss experimental evidence supporting the crucial role of MLCK in the hyperpermeability response to key cell signalling events during inflammation. At the cellular level, in vitro studies of cultured endothelial monolayers treated with MLCK inhibitors or transfected with specific inhibiting peptides have demonstrated that induction of endothelial MLCK activity is necessary for hyperpermeability. Ex vivo studies of live microvessels, enabled by development of the isolated, perfused venule method, support the importance of MLCK in endothelial permeability regulation in an environment that more closely resembles in vivo tissues. Finally, the role of MLCK in vascular hyperpermeability has been confirmed with in vivo studies of animal disease models and the use of transgenic MLCK210 knockout mice. These approaches provide a more complete view of the role of MLCK in vascular barrier dysfunction.
Shen
Qiang
Q
Division of Research, Department of Surgery, University of California at Davis School of Medicine, 4625 2nd Avenue, Sacramento, CA 95817, USA.
Rigor
Robert R
RR
Pivetti
Christopher D
CD
Wu
Mack H
MH
Yuan
Sarah Y
SY
D000205:Actomyosin / Q000378:metabolism; D000818:Animals; D001826:Body Fluids / Q000378:metabolism*; D002199:Capillary Permeability / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology / Q000503:physiopathology; D006801:Humans; D007249:Inflammation / Q000201:enzymology / Q000503:physiopathology; D018836:Inflammation Mediators / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D055806:Microvessels / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology / Q000503:physiopathology; D023421:Models, Animal; D018994:Myosin Light Chains / Q000378:metabolism; D009219:Myosin-Light-Chain Kinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction
D018836:Inflammation Mediators; D018994:Myosin Light Chains; D047428:Protein Kinase Inhibitors; D000205:Actomyosin; D009219:Myosin-Light-Chain Kinase