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J Am Coll Cardiol, 2005; 45:1441-1448, doi:10.1016/j.jacc.2004.12.074
© 2005 by the American College of Cardiology Foundation
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CLINICAL RESEARCH: PROGENITOR CELLS

Impaired Progenitor Cell Activity in Age-Related Endothelial Dysfunction

Christian Heiss, MD, Stefanie Keymel, MS, Ulrike Niesler, MS, Jutta Ziemann, BS, Malte Kelm, MD and Christoph Kalka, MD*

Department of Cardiology, Pneumology, and Vascular Medicine, Heinrich-Heine-University, Düsseldorf, Germany

Manuscript received July 12, 2004; revised manuscript received November 29, 2004, accepted December 6, 2004.

* Reprint requests and correspondence: Dr. Christoph Kalka, Department of Cardiology, Pneumology and Vascular Medicine, Heinrich-Heine-University, Moorenstr. 5, 40225 Düsseldorf, Germany (Email: kalka-moll{at}web.de).

OBJECTIVES: We investigated whether human age-related endothelial dysfunction is accompanied by quantitative and qualitative alterations of the endothelial progenitor cell (EPC) pool.

BACKGROUND: Circulating progenitor cells with an endothelial phenotype contribute to the regeneration and repair of the vessel wall. An association between the loss of endothelial integrity and EPC modification may provide a background to study the mechanistic nature of such age-related vascular changes.

METHODS: In 20 old and young healthy individuals (61 ± 2 years and 25 ± 1 year, respectively) without major cardiovascular risk factors, endothelial function, defined by flow-mediated dilation of the brachial artery via ultrasound, as well as the number and function of EPCs isolated from peripheral blood, were determined.

RESULTS: Older subjects had significantly impaired endothelium-dependent dilation of brachial artery (flow-mediated dilation [FMD] 5.2 ± 0.5% vs. 7.1 ± 0.6%; p < 0.05). Endothelium-independent dilation after glycerol trinitrate (GTN) was not different, but the FMD/GTN ratio was significantly lower in old subjects (49 ± 4% vs. 37 ± 3%; p < 0.05), suggesting endothelial dysfunction. There were no differences in the numbers of circulating EPCs, defined as CD34/KDR or CD133/KDR double-positive cells in peripheral blood. In contrast, lower survival (39 ± 6 cells/mm2 vs. 65 ± 11 cells/mm2; p < 0.05), migration (80 ± 12 vs. 157 ± 16 cells/mm2; p < 0.01), and proliferation (0.20 ± 0.04 cpm vs. 0.44 ± 0.07 cpm; p < 0.05) implicate functional impairment of EPCs from old subjects. The FMD correlated univariately with EPC migration (r = 0.52, p < 0.05) and EPC proliferation (r = 0.49, p < 0.05). Multivariate analysis showed that both functional features represent independent predictors of endothelial function.

CONCLUSIONS: Maintenance of vascular homeostasis by EPCs may be attenuated with age based on functional deficits rather than depletion of CD34/KDR or CD133/KDR cells.

Abbreviations and Acronyms
  EPC = endothelial progenitor cell
  FACS = fluorescence-activated cell sorting
  FBS = fetal bovine serum
  FMD = flow-mediated dilation
  GTN = glycerol trinitrate
  KDR = kinase insert domain-containing receptor (human VEGF receptor-2)
  MNC = peripheral blood mononuclear cell
  UEA-1 = Ulex europaeus agglutinin I
  VEGF = vascular endothelial growth factor


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