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Abstract
Atherogenesis is associated with elevated plasma levels of oxidized low-density lipoproteins (oxLDL). In vivo, oxLDL causes liver endothelial swelling, and disrupts liver sinusoidal endothelial cell (LSECs) fenestrations. We mapped the nanoscale kinetics of these changes in vitro in isolated rat LSECs challenged with oxLDL and monitored viability with endocytosis and cytotoxicity assays. OxLDL disrupted LSEC ultrastructure – increasing oxLDL concentrations and oxidation levels caused sieve plate loss, fenestration fusion, and gap formation. Importantly, these effects were not uniform across all LSECs. LSECs retained the ability to endocytose ligands irrespective of the presence of oxLDL. However, increasing oxidation levels and concentrations of oxLDL inhibited LSEC mediated degradation of endocytosed ligands. Viability was unaffected by any oxLDL challenge. In conclusion, oxLDL disrupts LSEC ultrastructural morphology in vitro but LSECs remain viable and mostly maintain the scavenging function during oxLDL challenge.
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1 University of Tromsø -The Arctic University of Norway, Vascular Biology Research Group, Department of Medical Biology, Faculty of Health Sciences, Tromsø, Norway (GRID:grid.10919.30) (ISNI:0000 0001 2259 5234); University of Tromsø -The Arctic University of Norway, Optical Nanoscopy Research Group, Department of Physics and Technology, Faculty of Science and Technology, Tromsø, Norway (GRID:grid.10919.30) (ISNI:0000 0001 2259 5234)
2 University of Tromsø -The Arctic University of Norway, Vascular Biology Research Group, Department of Medical Biology, Faculty of Health Sciences, Tromsø, Norway (GRID:grid.10919.30) (ISNI:0000 0001 2259 5234)
3 University of Tromsø -The Arctic University of Norway, Nuclear Medicine and Radiation Biology Research Group, Department of Clinical Medicine, Tromsø, Norway (GRID:grid.10919.30) (ISNI:0000 0001 2259 5234); University Hospital of North Norway, The PET Imaging Center, Tromsø, Norway (GRID:grid.412244.5) (ISNI:0000 0004 4689 5540)
4 University of Tromsø -The Arctic University of Norway, Translational Vascular Research Group, Department of Clinical Medicine, Faculty of Health Sciences, Tromsø, Norway (GRID:grid.10919.30) (ISNI:0000 0001 2259 5234)
5 Bielefeld University, Biomolecular Photonics, Faculty of Physics, Bielefeld, Germany (GRID:grid.7491.b) (ISNI:0000 0001 0944 9128)
6 Nutritional Ecology and Physiology Lab, ANZAC Research Institute, Concord Repatriation General Hospital, Concord, NSW, Australia; and The University of Sydney, Charles Perkins Centre, Sydney, Australia (GRID:grid.456991.6) (ISNI:0000 0004 0428 8494)
7 University of Tromsø -The Arctic University of Norway, Optical Nanoscopy Research Group, Department of Physics and Technology, Faculty of Science and Technology, Tromsø, Norway (GRID:grid.10919.30) (ISNI:0000 0001 2259 5234)
8 University of Tromsø -The Arctic University of Norway, Vascular Biology Research Group, Department of Medical Biology, Faculty of Health Sciences, Tromsø, Norway (GRID:grid.10919.30) (ISNI:0000 0001 2259 5234); Nutritional Ecology and Physiology Lab, ANZAC Research Institute, Concord Repatriation General Hospital, Concord, NSW, Australia; and The University of Sydney, Charles Perkins Centre, Sydney, Australia (GRID:grid.456991.6) (ISNI:0000 0004 0428 8494)