The Role of Tricellular Junctions in the Transport of Macromolecules Across Endothelium
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Cardiovascular Engineering and Technology ( 2020) https://doi.org/10.1007/s13239-020-00483-x
John Tarbell
The Role of Tricellular Junctions in the Transport of Macromolecules Across Endothelium MEAN GHIM,1,3 YUMNAH MOHAMIED,1,2,4 and PETER D. WEINBERG1 1
Department of Bioengineering, Imperial College London, London SW7 2AZ, UK; 2Department of Aeronautics, Imperial College London, London SW7 2AZ, UK; 3School of Informatics, University of Edinburgh, Edinburgh, UK; and 4Section of Cardiovascular Medicine, Yale Cardiovascular Research Centre, Yale University School of Medicine, New Haven, CT, USA (Received 24 June 2020; accepted 11 August 2020) Associate Editor Hanjoong Jo oversaw the review of this article.
Abstract Purpose—Transport of water and solutes across vascular endothelium is important in normal physiology and critical in the development of various diseases, including atherosclerosis. However, there is debate about the routes for such transport. We recently showed that an albumin-sized tracer crossed endothelium at bicellular and tricellular junctions, a tracer having the size of high density lipoprotein crossed only through tricellular junctions, and a tracer with the size of low density lipoprotein was unable to cross by either route and instead traversed the cells themselves. Here we review previous work on the structure and function of tricellular junctions. We then describe a study in which we assessed the role of such junctions in the transport of an albumin-sized tracer. Methods—We examined normal endothelial monolayers, the effect of agonists that modify their permeability, and the influence of different patterns of shear stress. Results—Under normal conditions, approximately 85% of transendothelial transport occurred through tricellular junctions. This fraction was unchanged when permeability was reduced by sphingosine-1-phosphate or increased by thrombin, and also did not differ between endothelium exposed to multidirectional as opposed to uniaxial shear stress despite a > 50% difference in permeability. Conclusion—These data show that tricellular junctions dominate normal transport of this tracer and largely determine influences of agonists and shear. The effects were attributable to changes in both the number and conductivity of the junctions. Further investigation of these structures will lead to increased understanding of endothelial barrier function and may suggest new therapeutic strategies in disease.
INTRODUCTION The vascular endothelium functions as a selective barrier between blood and surrounding tissue. It regulates the exchange of water, solutes and cells, maintaining normal homeostasis. Endothelial injury may lead to hyperpermeability, where components of the blood normally confined to the vascular lumen pass through the endothelium, or the rate of such passage is increased. Currently, there are no therapeutics that address this dysfunction, which is a key issue in atherosclerosis, lung injury, vascular leak in cancer, and sepsis, among other diseases. Understanding the mechanisms b
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