title: Aberrant phenotype in human endothelial cells of diabetic origin: implications for saphenous vein graft failure?
abstract: Type 2 diabetes (T2DM) confers increased risk of endothelial dysfunction, coronary heart disease, and vulnerability to vein graft failure after bypass grafting, despite glycaemic control. This study explored the concept that endothelial cells (EC) cultured from T2DM and nondiabetic (ND) patients are phenotypically and functionally distinct. Cultured human saphenous vein- (SV-) EC were compared between T2DM and ND patients in parallel. Proliferation, migration, and in vitro angiogenesis assays were performed; western blotting was used to quantify phosphorylation of Akt, ERK, and eNOS. The ability of diabetic stimuli (hyperglycaemia, TNF-α, and palmitate) to modulate angiogenic potential of ND-EC was also explored. T2DM-EC displayed reduced migration (~30%) and angiogenesis (~40%) compared with ND-EC and a modest, nonsignificant trend to reduced proliferation. Significant inhibition of Akt and eNOS, but not ERK phosphorylation, was observed in T2DM cells. Hyperglycaemia did not modify ND-EC function, but TNF-α and palmitate significantly reduced angiogenic capacity (by 27% and 43%, resp.), effects mimicked by Akt inhibition. Aberrancies of EC function may help to explain the increased risk of SV graft failure in T2DM patients. This study highlights the importance of other potentially contributing factors in addition to hyperglycaemia that may inflict injury and long-term dysfunction to the homeostatic capacity of the endothelium.
authors.affiliation: Division of Cardiovascular and Diabetes Research, Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: Anna C
authors.initials: AC
authors.lastname: Roberts
authors.affiliation: Division of Cardiovascular and Diabetes Research, Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: Jai
authors.initials: J
authors.lastname: Gohil
authors.affiliation: Division of Cardiovascular and Diabetes Research, Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: Laura
authors.initials: L
authors.lastname: Hudson
authors.affiliation: School of Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: Kyle
authors.initials: K
authors.lastname: Connolly
authors.affiliation: Division of Cardiovascular and Diabetes Research, Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds LS2 9JT, UK ; Multidisciplinary Cardiovascular Research Centre (MCRC), University of Leeds, Leeds LS2 9JT, UK.
authors.forename: Philip
authors.initials: P
authors.lastname: Warburton
authors.affiliation: Department of Biology, University of York, York YO10 5DD, UK.
authors.forename: Rakesh
authors.initials: R
authors.lastname: Suman
authors.affiliation: Department of Biology, University of York, York YO10 5DD, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: O'Toole
authors.affiliation: Multidisciplinary Cardiovascular Research Centre (MCRC), University of Leeds, Leeds LS2 9JT, UK ; Department of Cardiac Surgery, The Yorkshire Heart Centre, Leeds General Infirmary, Leeds LS1 3EX, UK.
authors.forename: David J
authors.initials: DJ
authors.lastname: O'Regan
authors.affiliation: Division of Cardiovascular and Diabetes Research, Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds LS2 9JT, UK ; Multidisciplinary Cardiovascular Research Centre (MCRC), University of Leeds, Leeds LS2 9JT, UK.
authors.forename: Neil A
authors.initials: NA
authors.lastname: Turner
authors.affiliation: Division of Cardiovascular and Diabetes Research, Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds LS2 9JT, UK ; Multidisciplinary Cardiovascular Research Centre (MCRC), University of Leeds, Leeds LS2 9JT, UK.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Riches
authors.affiliation: Division of Cardiovascular and Diabetes Research, Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds LS2 9JT, UK ; Multidisciplinary Cardiovascular Research Centre (MCRC), University of Leeds, Leeds LS2 9JT, UK.
authors.forename: Karen E
authors.initials: KE
authors.lastname: Porter
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000473:pathology*; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology*; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology*; D005260:Female; D006084:Graft Rejection; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D008875:Middle Aged; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010641:Phenotype; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012501:Saphenous Vein / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D052250:Nitric Oxide Synthase Type III; D051057:Proto-Oncogene Proteins c-akt