LDL-Cholesterol Increases the Transcytosis of Molecules through Endothelial Monolayers

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.

Myocardial oedema: pathophysiological basis and implications for the failing heart

“…Regarding adherens junctions, reduced VEcadherin/β-catenin expression in dilated cardiomyopathy was associated with endothelial cell degeneration, 60 whereas in post-ischaemic MO, Src inhibition prevented VEGF-mediated disruption of Flk/VE-cadherin/β-catenin complex and attenuated post-ischaemic MO, fibrosis and mortality. 61 In addition, key risk factors for HF development and progression have been shown experimentally to promote endothelial hyperpermeability by disrupting EIJ, namely, renin-angiotensin-aldosterone system activation, 62 inflammation, 63,64 hypoxia, 65 cardioplegic arrest, 66 hyperglycaemia, 67 oxidative stress, 68 increased circulating LDL 69,70 and free fatty acid 71 levels.…”

Berberine Exerts a Protective Effect on Gut-Vascular Barrier via the Modulation of the Wnt/Beta-Catenin Signaling Pathway During Sepsis

“…At indicated time points (0, 2, 4, 6, 8 hr), the TEER was measured by using Millicell-ERS (Millipore, Germany) as previously described [31][32][33]. The TEER were detected and compared as the percent change from corresponding baseline values.…”

Ethanolic Extract of Garcinia kola Stem Bark Inhibits LDL-Uptake and LPS-Induced Anxa-1 and ICAM-1 Expression in Human Umbilical Vein Endothelial Cells (HUVECS)

“…The evaluation of G. kola ethanolic extract activity on LDL-uptake revealed a significant decrease in LDL uptake by endothelial cells stimulated with LPS and treated with the ethanolic extract at the concentrations of 50 and 100 µg/ml. Some studies using an in vitro permeability system and blocking LDL binding to LDL-receptors using an anti-LDL receptor antibody, revealed that LDL was responsible for an increase of the permeability of endothelial cells in an LDL-receptor-dependent manner (Magalhaes et al, 2016) 27 . The ethanolic extract of G. kola would therefore act by inhibiting specific LDL-receptors.…”