Regulation of endothelial junctional permeability.
The endothelium is a semi-permeable barrier that regulates the flux of liquid and solutes, including plasma proteins, between the blood and surrounding tissue. The permeability of the vascular barrier can be modified in response to specific stimuli acting on endothelial cells. Transport across the endothelium can occur via two different pathways: through the endothelial cell (transcellular) or between adjacent cells, through interendothelial junctions (paracellular). This review focuses on the regulation of the paracellular pathway. The paracellular pathway is composed of adhesive junctions between endothelial cells, both tight junctions and adherens junctions. The actin cytoskeleton is bound to each junction and controls the integrity of each through actin remodeling. These interendothelial junctions can be disassembled or assembled to either increase or decrease paracellular permeability. Mediators, such as thrombin, TNF-alpha, and LPS, stimulate their respective receptor on endothelial cells to initiate signaling that increases cytosolic Ca2+ and activates myosin light chain kinase (MLCK), as well as monomeric GTPases RhoA, Rac1, and Cdc42. Ca2+ activation of MLCK and RhoA disrupts junctions, whereas Rac1 and Cdc42 promote junctional assembly. Increased endothelial permeability can be reversed with "barrier stabilizing agents," such as sphingosine-1-phosphate and cyclic adenosine monophosphate (cAMP). This review provides an overview of the mechanisms that regulate paracellular permeability.
Vandenbroucke
Emily
E
Department of Pharmacology and Center for Lung and Vascular Biology, The University of Illonois College of Medicine, Chicago, IL 60612, USA.
Mehta
Dolly
D
Minshall
Richard
R
Malik
Asrar B
AB
D000199:Actins / Q000502:physiology; D000818:Animals; D001692:Biological Transport; D002118:Calcium / Q000502:physiology; D002448:Cell Adhesion / Q000502:physiology; D002463:Cell Membrane Permeability / Q000502:physiology*; D004730:Endothelium, Vascular / Q000502:physiology*; D022001:Focal Adhesions / Q000502:physiology*; D007365:Intercellular Junctions / Q000502:physiology*; D008954:Models, Biological; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism; D009218:Myosins / Q000502:physiology; D020033:Protein Isoforms / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D019108:Tight Junctions / Q000502:physiology
D000199:Actins; D020033:Protein Isoforms; D011493:Protein Kinase C; D009218:Myosins; D020559:Monomeric GTP-Binding Proteins; D002118:Calcium