Vandenbroucke Emily, Mehta Dolly, Minshall Richard, Malik Asrar B
Department of Pharmacology and Center for Lung and Vascular Biology, The University of Illonois College of Medicine, Chicago, IL 60612, USA.
Ann N Y Acad Sci. 2008 Mar;1123:134-45. doi: 10.1196/annals.1420.016.
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.
内皮是一种半透性屏障，可调节血液与周围组织之间液体和溶质（包括血浆蛋白）的通量。血管屏障的通透性可因作用于内皮细胞的特定刺激而改变。物质穿过内皮可通过两种不同途径：穿过内皮细胞（跨细胞途径）或通过相邻细胞之间的内皮间连接（旁细胞途径）。本综述重点关注旁细胞途径的调节。旁细胞途径由内皮细胞之间的黏附连接组成，包括紧密连接和黏附连接。肌动蛋白细胞骨架与每个连接相连，并通过肌动蛋白重塑来控制每个连接的完整性。这些内皮间连接可被拆卸或组装，以增加或降低旁细胞通透性。凝血酶、肿瘤坏死因子-α和脂多糖等介质刺激内皮细胞上各自的受体，启动信号传导，增加胞质Ca2+并激活肌球蛋白轻链激酶（MLCK），以及单体GTP酶RhoA、Rac1和Cdc42。Ca2+激活MLCK和RhoA会破坏连接，而Rac1和Cdc42则促进连接组装。增加的内皮通透性可用“屏障稳定剂”（如鞘氨醇-1-磷酸和环磷酸腺苷（cAMP））逆转。本综述概述了调节旁细胞通透性的机制。
