title: Endothelial cell activation promotes foam cell formation by monocytes following transendothelial migration in an in vitro model.
abstract: Foam cells are a pathological feature present at all stages of atherosclerosis. Foam cells develop from monocytes that enter the nascent atheroma and subsequently ingest modified low density lipoproteins (LDL). The regulation of this process has previously been studied in vitro using cultured macrophage fed modified LDL. We used our existing in vitro model of transendothelial migration (TEM) to study this process in a more physiologically relevant setting. In our model, monocytes undergo TEM across a primary endothelial monolayer into an underlying three-dimensional collagen matrix in the presence of 20% human serum. Foam cells were detected by Oil Red O staining for intracellular lipid droplets. We demonstrate that sub-endothelial monocytes can develop into foam cells within 48 h of TEM across TNF-α activated endothelium, in the absence of additional lipids. Our data indicate a role for both monocyte-endothelial interactions and soluble factors in the regulation of foam cell development, including oxidation of LDL in situ from lipid present in culture medium following TNF-α stimulation of the endothelial cells. Our study provides a simple model for investigating foam cell development in vitro that mimics cell migration in vivo, and demonstrates the critical role of inflammation in regulating early atherogenic events.
authors.affiliation: Centre for Virology, Burnet Institute for Medical Research and Public Health, Melbourne, VIC 3001, Australia. clare.westhorpe@monash.edu
authors.forename: Clare L V
authors.initials: CL
authors.lastname: Westhorpe
authors.forename: Eric M
authors.initials: EM
authors.lastname: Dufour
authors.forename: Anna
authors.initials: A
authors.lastname: Maisa
authors.forename: Anthony
authors.initials: A
authors.lastname: Jaworowski
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Crowe
authors.forename: William A
authors.initials: WA
authors.lastname: Muller
mesh_terms: D050197:Atherosclerosis / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D002465:Cell Movement; D002478:Cells, Cultured; D018920:Coculture Techniques; D005487:Foam Cells / Q000166:cytology* / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects; D008077:Lipoproteins, LDL / Q000378:metabolism; D009000:Monocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction; D057705:Transendothelial and Transepithelial Migration / Q000187:drug effects / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D008077:Lipoproteins, LDL; D014409:Tumor Necrosis Factor-alpha; C099252:oxidized low density lipoprotein