Abstract
Cholesterol has been identified as a causative factor in numerous pathologies including atherosclerosis and cancer. One of the frequent effects of elevated cholesterol levels in humans is the compromise of endothelial function due to activation of pro-inflammatory signalling pathways. While the mechanisms involved in endothelial activation by cholesterol during an inflammatory response are well established, less is known about the mechanisms by which cholesterol may affect endothelial barrier function, which were the subject of the present study. Here we show that low density lipoprotein (LDL) increases the permeability of endothelial monolayers to high molecular weight dextrans in an LDL receptor and cholesterol-dependent manner. The increased permeability seen upon LDL treatment was not caused by disruption of cell-to-cell junctions as determined by a normal localization of VE-Cadherin and ZO-1 proteins, and no major alterations in transendothelial electrical resistance or permeability to fluorescein. We show instead that LDL increases the level of high molecular weight transcytosis and that this occurs in an LDL receptor, cholesterol and caveolae-dependent way. Our findings contribute to our understanding of the systemic pathological effects of elevated cholesterol and the transport of cargo through endothelial monolayers.
Highlights
The endothelium forms a barrier to the free passage of molecules and cells from the blood to tissues and vice-versa [1]
In this way we were able to observe that pre-treatment of endothelial cells with low density lipoprotein (LDL) for 24 hours leads to a significant increase in endothelial permeability to 70 kDa dextrans (Fig 1A)
To test whether this effect was dependent on the action of the LDL receptor (LDLR) we tried to revert the phenotype by blocking the binding of LDL to the LDLR
Summary
The endothelium forms a barrier to the free passage of molecules and cells from the blood to tissues and vice-versa [1]. Crossing the endothelium is a tightly controlled process that may have pathological consequences if compromised. Endothelial dysfunction is an early finding in the course of atherosclerosis and cancer, and has increasingly been recognized in neurodegenerative diseases, such as Alzheimer’s disease [2,3,4]. Reduced or limited endothelial barrier permeability, such as that present in the blood-brain barrier, can reduce drug delivery and limit therapeutic interventions [5]. Endothelial barrier function is achieved by the presence of specialized cell-to-cell junctional complexes, including adherens and tight junctions, which tightly regulate the passage of molecules and cells across endothelia.
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