NO synthesis but not apoptosis, mitosis or inflammation can explain correlations between flow directionality and paracellular permeability of cultured endothelium
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
Haemodynamic wall shear stress varies from site to site within the arterial system and is thought to cause local variation in endothelial permeability to macromolecules. Our aim was to investigate mechanisms underlying the changes in paracellular permeability caused by different patterns of shear stress in long-term culture. We used the swirling well system and a substrate-binding tracer that permits visualisation of transport at the cellular level. Permeability increased in the centre of swirled wells, where flow is highly multidirectional, and decreased towards the edge, where flow is more uniaxial, compared to static controls. Overall, there was a reduction in permeability. There were also decreases in early- and late-stage apoptosis, proliferation and mitosis, and there were significant correlations between the first three and permeability when considering variation from the centre to the edge under flow. However, data from static controls did not fit the same relation and a cell-by-cell analysis showed that <5% of uptake under shear was associated with each of these events. Nuclear translocation of NF-κB p65 increased and then decreased with the duration of applied shear, as did permeability, but the spatial correlation between them was not significant. Application of an NO synthase inhibitor abolished the overall decrease in permeability caused by chronic shear and the difference in permeability between the centre and edge of the well. Hence shear and paracellular permeability appear to be linked by NO synthesis and not by apoptosis, mitosis or inflammation. The effect was mediated by an increase in transport through tricellular junctions.
Date Issued
2022-07-22
Date Acceptance
2022-07-13
Citation
International Journal of Molecular Sciences, 2022, 23 (15)
ISSN
1422-0067
Publisher
MDPI AG
Journal / Book Title
International Journal of Molecular Sciences
Volume
23
Issue
15
Copyright Statement
© 2022 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
License URL
Sponsor
British Heart Foundation
Grant Number
PG/15/102/31890
Subjects
FITC-avidin
atherosclerosis
cell death
cell division
hotspots
leaky junction
orbital shaker
transport
tricellular junction
Endothelium, Vascular
Humans
Inflammation
Mitosis
Permeability
Stress, Mechanical
Endothelium, Vascular
Humans
Inflammation
Mitosis
Permeability
Stress, Mechanical
0399 Other Chemical Sciences
0604 Genetics
0699 Other Biological Sciences
Chemical Physics
Publication Status
Published
Article Number
ARTN 8076