Abstract
Endothelial dysfunction has been attributed as one of the major complications in COVID-19 patients, a global pandemic that has already caused over 4 million deaths worldwide. The dysfunction of endothelial barrier is characterized by an increase in endothelial permeability and inflammatory responses, and has even broader implications in the pathogenesis of acute respiratory syndromes such as ARDS, sepsis and chronic illnesses represented by pulmonary arterial hypertension and interstitial lung disease. The structural integrity of endothelial barrier is maintained by cytoskeleton elements, cell-substrate focal adhesion and adhesive cell junctions. Agonist-mediated changes in endothelial permeability are directly associated with reorganization of actomyosin cytoskeleton leading to cell contraction and opening of intercellular gaps or enhancement of cortical actin cytoskeleton associated with strengthening of endothelial barrier. The role of actin cytoskeleton remodeling in endothelial barrier regulation has taken the central stage, but the impact of microtubules in this process remains less explored and under-appreciated. This review will summarize the current knowledge on the crosstalk between microtubules dynamics and actin cytoskeleton remodeling, describe the signaling mechanisms mediating this crosstalk, discuss epigenetic regulation of microtubules stability and its nexus with endothelial barrier maintenance, and overview a role of microtubules in targeted delivery of signaling molecules regulating endothelial permeability and inflammation.
Highlights
Endothelial barrier formed by a lining of heterogenous mixture of endothelial cells (EC) is a highly selective semi-permeable barrier between the blood and interstitial space that is critical for maintaining tissue and organ homeostasis (Bazzoni and Dejana, 2004; Chistiakov et al, 2015)
An active and intimate cross-talk between MT and actin cytoskeleton is essential for maintaining endothelial barrier integrity
The altered MT dynamics, depolymerization of MT, is a crucial trigger for endothelial dysfunction and studies have established that MT destabilization contributes to various barrier disrupting agonists-induced acute lung injury (ALI)
Summary
Endothelial barrier formed by a lining of heterogenous mixture of endothelial cells (EC) is a highly selective semi-permeable barrier between the blood and interstitial space that is critical for maintaining tissue and organ homeostasis (Bazzoni and Dejana, 2004; Chistiakov et al, 2015). A rapid and reversible partial dissolution of peripheral MT has been reported in pulmonary EC stimulated with thrombin and is associated with rapid permeability increase (Birukova et al, 2004a) In support of this MT-dependent mechanism, cell pretreatment with MT stabilizing agent taxol rescued thrombininduced increase in endothelial permeability by attenuating Rho activation, suggesting an essential role of MT dynamics in controlling endothelial barrier function during agonists challenges. The decrease in a stable pool of MT and a partial dissolution of peripheral MT network during EC permeability caused by tumor necrosis factor-α (TNF-α) was linked to the activation of p38 mitogen-activated kinase and subsequent destabilization of MT (Petrache et al, 2003) In agreement with these results, inhibition of p38 MAPK directly suppressed nocodazole-induced MT depolymerization and endothelial barrier disruption (Birukova et al, 2005b). P38MAPK-mediated serine phosphorylation of MAP4in response to LPS and TNFα stimulation causes MT disruption leading to endothelial permeability (Li et al, 2015)
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