Endothelial Progenitor Cells in Coronary Artery Disease: From Bench to Bedside

Abstract

Endothelial progenitor cells (EPCs) are a heterogeneous group of cells present in peripheral blood at various stages of endothelial differentiation. EPCs have been extensively investigated in patients with coronary artery disease (CAD), with controversial findings both on their role in atherosclerosis progression and in the process of neointimal growth after a percutaneous coronary intervention (PCI). Despite nearly 2 decades of experimental and clinical investigations, however, the significance of EPCs in clinical practice remains unclear and poorly understood. This review provides an update on the role of EPCs in the most common clinical scenarios that are experienced by cardiologists managing patients with CAD. We here summarize the main findings on the association of EPCs with cardiovascular risk factors, coronary atherosclerosis, and myocardial ischemia. We then discuss the potential effects of EPCs in post-PCI in-stent restenosis, as well as most recent findings with EPC-coated stents. Based on the mounting evidence of the relationship between levels of EPCs and several different adverse cardiovascular events, EPCs are emerging as novel predictive biomarkers of long-term outcomes in patients with CAD.

Keywords: coronary artery disease; endothelial progenitor cells; percutaneous coronary intervention; prognosis.

Endothelial progenitor cells (EPCs) can be differentiated based on surface antigens, are affected by several cardiovascular risk factors, and play a role in vascular repair. After percutaneous coronary intervention, EPCs are involved in the process of in-stent restenosis and might predict the outcome. EPCs-coated drug-eluting stents induce accelerated re- endothelialization but can favor excessive neointima growth.

Figure 1.

Expression of surface markers during the differentiation of the EPCs. There is a continuous shift in expression of stem and endothelial surface markers during the differentiation of EPCs. ‘Early’ EPCs are generally identified by expression of CD133 (an early hematopoietic stem cell marker) and KDR (an endothelial marker). Circulating “late” EPCs are more mature cells and are characterized by high expression of CD34 and KDR but decreased expression of CD133. Mature endothelial cells are terminally differentiated cells characterized by negative expression of CD34, CD133, and CD45, and positive expression of KDR, CD14, CD31, CD146, VE-cadherin, eNOS, and vWF. eNOS, endothelial nitric oxide synthase; EPCs, endothelial progenitor cells; KDR, kinase insert domain receptor; vWF, von Willebrand factor.

Figure 2.

Representative flow cytograms of major subtypes of EPCs. After identifying peripheral blood progenitor cells, CD34⁺ cells and CD133⁺ cells are gated in the mononuclear cell fraction (left panels A and D). After separate gating to exclude hematopoietic cells expressing the CD45 antigen (middle panels B and E), CD34⁺/KDR⁺/CD45⁻ cells are identified as CD34⁺/CD45⁻ cells positive for KDR (C), and CD133⁺/KDR⁺/CD45⁻ cells are identified as CD133⁺/CD45⁻ cells positive for KDR (F). EPCs, endothelial progenitor cells; KDR, kinase insert domain receptor.

Figure 3.

Paracrine activity of EPCs at the site of endothelial damage. When the endothelial layer is damaged, circulating EPCs are stimulated to act through paracrine mechanisms leading to the secretion of various cytokines and pro-angiogenic growth factors, such as VEGF, SDF-1, and NO. The paracrine signaling mediated by EPCs results in the production of an angiogenic microenvironment that stimulates the nearby endothelium to proliferate. EPCs, endothelial progenitor cells; SDF-1, stromal-derived factor-1; VEGF, vascular endothelial growth factor.

Figure 4.

Endothelial progenitor cells and restenosis. Endothelial progenitor cells at the time of PCI in patients who had evidence at follow-up angiography of in-stent restenosis, progression of coronary atherosclerosis in non-stented segments, or unchanged coronary anatomy. Data are expressed as n, mean ± SD, or n (%). *P < .05 for comparison between restenosis versus progression and stable groups. †P < .05 for comparison between restenosis group versus stable group. Modified from Pelliccia 
et al. PCI, percutaneous coronary intervention.

Figure 5.

Survival curves at 10 years in patients with high versus low EPCs counts. Kaplan-Meier 5-year survival curves (MACCE-free) of patients stratified according to (A) quantity of CD34⁺/KDR⁺/CD45⁻ cells lower or higher than the median value and (B) quantity of CD133⁺/KDR⁺/CD45⁻ cells lower or higher than the median value. Modified from Pelliccia et al. EPCs, endothelial progenitor cells; KDR, kinase insert domain receptor.