Impaired vascular function and repair in patients with premature coronary artery disease.
BACKGROUND
Endothelial dysfunction is central to the pathogenesis of coronary artery disease, but the role of local and circulating endothelial progenitor cells in maintaining vascular health is poorly understood. We hypothesised that impaired local and circulating vascular repair mechanisms predispose to endothelial dysfunction and the premature onset of coronary artery disease.


RESULTS
Patients with premature coronary artery disease (n = 16) and healthy age- and sex-matched controls (n = 16) underwent venous occlusion plethysmography with intra-arterial infusion of acetylcholine and sodium nitroprusside. Numbers of circulating endothelial progenitor cells were directly quantified in whole blood by flow cytometry. Endothelial cells were isolated from the blood vessel wall and from peripheral blood mononuclear cells, and expanded in vitro for phenotypic and functional characterisation and analysis of microRNA expression levels. A dose-dependent increase in forearm blood flow (p < 0.001) was attenuated in response to the endothelial-dependent vasodilator acetylcholine in patients compared with controls (p = 0.03). No differences in the number of circulating endothelial progenitor cells or in the phenotype, function or microRNA expression levels of endothelial outgrowth cells isolated from blood were observed in patients and controls. Conversely, local vessel wall endothelial cells from patients had significant impairments in proliferation, adhesion and migration, and significantly reduced expression levels of microRNAs known to regulate endothelial function (miRs -10 a, -let7b, -126 and -181 b) (p < 0.05 for all).


CONCLUSIONS
Local vessel wall derived endothelial cells, rather than circulating endothelial progenitor cells and their progeny, are impaired in patients with vascular dysfunction and premature coronary artery disease.
BHF/University Centre for Cardiovascular Science, University of Edinburgh, UK Scottish Centre for Regenerative Medicine, University of Edinburgh, UK mbrittan@staffmail.ed.ac.uk.
Mairi
M
Brittan
BHF/University Centre for Cardiovascular Science, University of Edinburgh, UK.
Amanda
A
Hunter
Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, UK.
Mounia
M
Boulberdaa
BHF/University Centre for Cardiovascular Science, University of Edinburgh, UK Scottish Centre for Regenerative Medicine, University of Edinburgh, UK.
Takeshi
T
Fujisawa
BHF/University Centre for Cardiovascular Science, University of Edinburgh, UK Scottish Centre for Regenerative Medicine, University of Edinburgh, UK.
Elizabeth M
EM
Skinner
BHF/University Centre for Cardiovascular Science, University of Edinburgh, UK.
Anoop Sv
AS
Shah
Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, UK.
Andrew H
AH
Baker
BHF/University Centre for Cardiovascular Science, University of Edinburgh, UK.
Nicholas L
NL
Mills
D000328:Adult; D017668:Age of Onset; D016022:Case-Control Studies; D002448:Cell Adhesion; D002452:Cell Count; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D003324:Coronary Artery Disease / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology / Q000628:therapy; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology*; D066026:Endothelial Progenitor Cells / Q000473:pathology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D010641:Phenotype; D010991:Plethysmography; D012038:Regeneration; D066253:Vascular Remodeling; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000008:administration & dosage
D035683:MicroRNAs; D014665:Vasodilator Agents
Endothelial progenitor cells; coronary disease; endothelium; vasodilation