Contractile Forces

Tethering Forces

Figure 1 Actomyosin contractile elements compete with cellular tethering forces to regulate EC permeability. The left-hand cell illustrates cytoskeletal changes associated with agonist-induced EC barrier disruption. Thrombin binding to its PAR-1 receptor leads to Rho and MLCK activation along actin stress fibers, actomyosin interaction, contraction, and increased permeability. Conversely, the right-hand cell shows the barrier-enhancing cytoskeletal changes produced by sphingosine 1-phosphate (S1P), which strengthens the cortical actin ring through Edg receptor binding and subsequent downstream Rac activation, cortical actin formation, and adherens junction and focal adhesion rearrangement to decrease permeability. Vascular barrier integrity is dependent upon a balance of these two competing forces.

thrombin-induced EC barrier dysfunction. Recent studies suggest that Rho and MLCK may differentially regulate MLC phosphorylation according to spatial localization within ECs.

Barrier Enhancement

Cytoskeletal rearrangements are also essential for production of EC barrier enhancement by various agonists, such as the platelet-derived phospholipid sphingosine 1-phosphate (S1P), which dramatically reduces pulmonary vascular permeability. S1P binds to G-protein coupled Edg receptors on EC to initiate a series of cytoskeletal protein rearrangements that decreases EC permeability (Figure 1). Activation of the small GTPase Rac results in formation of a prominent cortical actin ring that accompanies S1P-induced EC barrier enhancement. In addition to inducing this cortical actin cytoskeletal rearrangement, S1P alters cell-cell and cell-matrix contacts to reduce EC permeability. S1P dramatically increases localization and interaction of VE-cadherin and catenin proteins at EC cell-cell junctions (adherens junctions). Moreover, while the barrier disrupting agent thrombin rearranges cell-matrix contacts so that focal adhesion proteins assemble at the ends of massive actin stress fibers to anchor cell contraction that pulls ECs apart, S1P induces differential focal adhesion protein rearrangement that associates with cortical actin ring formation that enhances EC barrier function.

Ongoing studies of these contrasting models of EC barrier disruption and enhancement continue to provide insights into potential targets for therapeutic modulation of vascular permeability. This recent work has described additional agonists with impressive EC barrier-enhancing properties. For example, hepatocyte growth factor (HGF) significantly increases pulmonary EC barrier function through enhanced cortical cytoskeleton linkage to cell-cell tethering junctions. Although HGF-induced barrier enhancement requires actin rearrangement and rapidly activates Rac in a manner similar to S1P, the mechanistic pathways are not identical since HGF requires PI-3'-kinase activity whereas S1P does not. Thus, multiple signaling pathways exist for promotion of EC barrier function. The 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reduc-tase inhibitor and cholesterol lowering agent, simvastatin, induces actin cytoskeletal cortical rearrangement and gene expression alterations over time that protect pulmonary EC barrier integrity from thrombin disruption without affecting basal permeability. In addition, the importance of mechanical forces in regulation of EC permeability is being increasingly recognized. The application of physiologic levels of shear stress to cultured pulmonary EC results in enhanced cortical actin and other cytoskeletal rearrangements that promote barrier function. Conversely, stretch forces similar to those produced during mechanical ventilation make pulmonary EC more sensitive to the barrier disrupting effects of thrombin.

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