Cytoskeletal Dynamics and Lung Fluid Balance

Abstract

This article examines the role of the endothelial cytoskeleton in the lung's ability to restrict fluid and protein to vascular space at normal vascular pressures and thereby to protect lung alveoli from lethal flooding. The barrier properties of microvascular endothelium are dependent on endothelial cell contact with other vessel-wall lining cells and with the underlying extracellular matrix (ECM). Focal adhesion complexes are essential for attachment of endothelium to ECM. In quiescent endothelial cells, the thick cortical actin rim helps determine cell shape and stabilize endothelial adherens junctions and focal adhesions through protein bridges to actin cytoskeleton. Permeability-increasing agonists signal activation of "small GTPases" of the Rho family to reorganize the actin cytoskeleton, leading to endothelial cell shape change, disassembly of cortical actin rim, and redistribution of actin into cytoplasmic stress fibers. In association with calcium- and Src-regulated myosin light chain kinase (MLCK), stress fibers become actinomyosin-mediated contractile units. Permeability-increasing agonists stimulate calcium entry and induce tyrosine phosphorylation of VE-cadherin (vascular endothelial cadherin) and β-catenins to weaken or pull apart endothelial adherens junctions. Some permeability agonists cause latent activation of the small GTPases, Cdc42 and Rac1, which facilitate endothelial barrier recovery and eliminate interendothelial gaps. Under the influence of Cdc42 and Rac1, filopodia and lamellipodia are generated by rearrangements of actin cytoskeleton. These motile evaginations extend endothelial cell borders across interendothelial gaps, and may initiate reannealing of endothelial junctions. Endogenous barrier protective substances, such as sphingosine-1-phosphate, play an important role in maintaining a restrictive endothelial barrier and counteracting the effects of permeability-increasing agonists.

Lung Circulation

“…As a consequence, agonism of several endothelial barrier disrupting pathways have produced differential effects on lung EC permeability in vivo compared to in vitro (641). Recent excellent reviews have discussed some of the controversies, and the signaling cascades underlying maintenance and loss of endothelial barrier function and various mechanisms by which fluid flux occurs in detail (146,327,413,646,651,727). Thus, in this section, we will highlight major pathways that have been implicated, focusing on some of the more recent findings.…”

“…Complete reviews of the role of the cytoskeleton in regulating permeability have been published (146,651). Adherens junctions, in particular, are directly linked to cytoskeletal elements, like actin, such that actin/myosin contraction "tugs" on the adherens junction and VE-cadherin pairs from adjacent cells to dissociate them from each other.…”

Mechanisms Regulating Endothelial Permeability

“…If the σ ¼ 0, vessel is completely permeable to fluid and solutes, whereas if the σ ¼ 1, capillary is impermeable. 2,3,37,38 IEJ PROTEINS IEJs are composed of adherens junctions (AJs), TJs, and connexins ( Fig. 1).…”

“…2,3,9,10 Interestingly, the sieving property of endothelium linearly correlated with molecular radii from 0.1 nm to 3.6 nm but became independent of the molecular radius above 3.6 nm. 2,3 On the basis of these findings, two endothelial transport mechanisms were defined for solute/ ion influx. 2,3,7,11,12 The transport of macromolecules larger than 3 nm, such as albumin, IgG, and other macromolecules, occurs through the transcellular pathway, which is also called transcytosis or vesicular transport.…”

“…2,3 On the basis of these findings, two endothelial transport mechanisms were defined for solute/ ion influx. 2,3,7,11,12 The transport of macromolecules larger than 3 nm, such as albumin, IgG, and other macromolecules, occurs through the transcellular pathway, which is also called transcytosis or vesicular transport. 3,[12][13][14] Molecules smaller than 3 nm, such as glucose, water, and ions, can pass through interendothelial junctions (IEJs) through the paracellular pathway.…”