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Visualization of three pathways for macromolecule transport across cultured endothelium and their modification by flow.

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Title: Visualization of three pathways for macromolecule transport across cultured endothelium and their modification by flow.
Authors: Ghim, M
Alpresa, P
Yang, S
Braakman, ST
Gray, SG
Sherwin, SJ
Van Reeuwijk, M
Weinberg, PD
Item Type: Journal Article
Abstract: Transport of macromolecules across vascular endothelium and its modification by fluid mechanical forces are important for normal tissue function and in the development of atherosclerosis. However, the routes by which macromolecules cross endothelium, the hemodynamic stresses that maintain endothelial physiology or trigger arterial disease, and the dependence of transendothelial transport on hemodynamic stresses are controversial. Here we visualised pathways for macromolecule transport and determined the effect on these pathways of different types of flow. Endothelial monolayers were cultured under static conditions or on an orbital shaker producing different flow profiles in different parts of the wells. Fluorescent tracers that bound to the substrate after crossing the endothelium were used to identify transport pathways. Maps of tracer distribution were compared with numerical simulations of flow to determine effects of different shear stress metrics on permeability. Albumin-sized tracers dominantly crossed the cultured endothelium via junctions between neighbouring cells, high-density-lipoprotein-sized tracers crossed at tricelluar junctions whilst low-density-lipoprotein-sized tracers crossed through cells. Cells aligned close to the angle that minimised shear stresses across their long axis. The rate of paracellular transport under flow correlated with the magnitude of these minimised transverse stresses, whereas transport across cells was uniformly reduced by all types of flow. These results contradict the long-standing two-pore theory of solute transport across microvessel walls and the consensus view that endothelial cells align with the mean shear vector. They suggest that endothelial cells minimise transverse shear, supporting its postulated pro-atherogenic role. Preliminary data show that similar tracer techniques are practicable in vivo.
Issue Date: 28-Jul-2017
Date of Acceptance: 19-Jul-2017
URI: http://hdl.handle.net/10044/1/50165
DOI: https://dx.doi.org/10.1152/ajpheart.00218.2017
ISSN: 1522-1539
Publisher: American Physiological Society
Start Page: H959
End Page: H973
Journal / Book Title: AJP - Heart and Circulatory Physiology
Volume: 313
Issue: 5
Copyright Statement: Copyright © 2017, American Journal of Physiology-Heart and Circulatory Physiology. This article is freely available.
Sponsor/Funder: British Heart Foundation
Funder's Grant Number: RE/08/002/23906
Keywords: endothelial permeability
transverse wall shear stress
tricellular junction
vesicles
wall shear stress
avidin-biotin
0606 Physiology
1116 Medical Physiology
Cardiovascular System & Hematology
Publication Status: Published
Conference Place: United States
Appears in Collections:Faculty of Engineering
Civil and Environmental Engineering
Bioengineering
Aeronautics



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