Number and function of endothelial progenitor cells as a marker of severity for diabetic vasculopathy

Department of Clinical and Experimental Medicine, Division of Metabolic Diseases, University of Padova, School of Medicine, Italy.
Arteriosclerosis Thrombosis and Vascular Biology (Impact Factor: 5.53). 10/2006; 26(9):2140-6. DOI: 10.1161/01.ATV.0000237750.44469.88
Source: PubMed

ABSTRACT Peripheral arterial disease (PAD) is a threatening complication of diabetes. As endothelial progenitor cells (EPCs) are involved in neovasculogenesis and maintenance of vascular homeostasis, their impairment may have a role in the pathogenesis of diabetic vasculopathy. This study aimed to establish whether number and function of EPCs correlate with PAD severity in type 2 diabetic patients.
EPCs were defined by the expression of CD34, CD133 and KDR, and quantified by flow cytometry in 127 diabetic patients with and without PAD. PAD severity has been assessed as carotid atherosclerosis and clinical stage of leg atherosclerosis obliterans. Diabetic patients with PAD displayed a significant 53% reduction in circulating EPCs versus non-PAD patients, and EPC levels were negatively correlated with the degree of carotid stenosis and the stage of leg claudication. Moreover, the clonogenic and adhesion capacity of cultured EPCs were significantly lower in diabetic patients with PAD versus patients without.
This study demonstrates that EPC decrease is related to PAD severity and that EPC function is altered in diabetic subjects with PAD, strengthening the pathogenetic role of EPC dysregulation in diabetic vasculopathy. EPC count may be considered a novel biological marker of peripheral atherosclerosis in diabetes.

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Available from: Carlo Agostini, Aug 02, 2015
    • "The numbers of EPCs could be altered additionally by diabetes complications. Fadini et al. [121] demonstrated that the number of EPCs described as CD34+/CD133+/KDR+ is significantly decreased in diabetic patients with PAD compared to diabetic patients without complications. Additionally, Nowak et al. [117] measured progenitor cells in diabetic patients with or without complications (different forms of diabetic foot ulcer (DFU)). "
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    ABSTRACT: Endothelial progenitor cells (EPCs) have been extensively studied for almost 19 years now and were considered as a potential marker for endothelial regeneration ability. On the other hand, circulating endothelial cells (CEC) were studied as biomarker for endothelial injury. Yet, in the literature, there is also huge incoherency in regards to terminology and protocols used. This results in misleading conclusions on the role of so called “EPCs”, especially in the clinical field. The discrepancies are mainly due to strong phenotypic overlap between EPCs and circulating angiogenic cells (CAC), therefore changes in “EPC” terminology have been suggested. Other factors leading to inconsistent results are varied definitions of the studied populations and the lack of universal data reporting, which could strongly affect data interpretation. The current review is focused on controversies concerning the use of “EPCs”/CAC and CEC as putative endothelial diagnostic markers.
    Pharmacological reports: PR 06/2015; DOI:10.1016/j.pharep.2015.05.017 · 2.17 Impact Factor
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    • "PGC-1a was similarly induced in ECs in two genetic models of type 2 diabetes (ob/ob and db/db) and in streptozotocin-induced type 1 diabetes (Figure 1A, right panels; Table S1). Human circulating CD34 + cells, which contain significant numbers of endothelial progenitor cells (EPCs) (Asahara et al., 1997; Fadini et al., 2006), isolated from patients with type 2 diabetes (see Table S2) as well as cultured EPCs established from the peripheral blood of diabetic patients also revealed elevated expression levels of PGC-1a, compared with control subjects (Figure 1B). Diabetes thus induces expression of PGC-1a in ECs in vivo in mice, and likely in humans as well. "
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    ABSTRACT: Endothelial dysfunction is a central hallmark of diabetes. The transcriptional coactivator PGC-1α is a powerful regulator of metabolism, but its role in endothelial cells remains poorly understood. We show here that endothelial PGC-1α expression is high in diabetic rodents and humans and that PGC-1α powerfully blocks endothelial migration in cell culture and vasculogenesis in vivo. Mechanistically, PGC-1α induces Notch signaling, blunts activation of Rac/Akt/eNOS signaling, and renders endothelial cells unresponsive to established angiogenic factors. Transgenic overexpression of PGC-1α in the endothelium mimics multiple diabetic phenotypes, including aberrant re-endothelialization after carotid injury, blunted wound healing, and reduced blood flow recovery after hindlimb ischemia. Conversely, deletion of endothelial PGC-1α rescues the blunted wound healing and recovery from hindlimb ischemia seen in type 1 and type 2 diabetes. Endothelial PGC-1α thus potently inhibits endothelial function and angiogenesis, and induction of endothelial PGC-1α contributes to multiple aspects of vascular dysfunction in diabetes.
    Cell metabolism 02/2014; 19(2):246-58. DOI:10.1016/j.cmet.2013.12.014 · 16.75 Impact Factor
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    • "Under normal conditions, ischemia promotes release of progenitor cells into the peripheral circulation and homing of these cells to ischemic sites [13] [14] [18] [19]. However, patients with PAD have fewer circulating progenitor cells than people without PAD [22] [23]. Based on this evidence, that both walking-related ischemia and GM-CSF can mobilize progenitor cells in people with PAD [10] [11] [12], we propose that the combination of walking exercise and GM-CSF may be a more potent stimulus of progenitor cell release and homing to ischemic tissue than either intervention alone (Fig. 1). "
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    ABSTRACT: Functional impairment, functional decline, and mobility loss are major public health problems in people with lower extremity peripheral artery disease (PAD). Few medical therapies significantly improve walking performance in PAD. We describe methods for the PROgenitor cell release Plus Exercise to improve functionaL performance in PAD (PROPEL) Study, a randomized controlled clinical trial designed to determine whether granulocyte-macrophage colony stimulating factor (GM-CSF) combined with supervised treadmill walking exercise improves six-minute walk distance more than GM-CSF alone, more than supervised treadmill exercise alone, and more than placebo plus attention control in participants with PAD, respectively. PROPEL Study participants are randomized to one of four arms in a 2 by 2 factorial design. The four study arms are GM-CSF plus supervised treadmill exercise, GM-CSF plus attention control, placebo plus supervised exercise therapy, or placebo plus attention control. The primary outcome is change in six-minute walk distance at 12-week follow-up. Secondary outcomes include change in brachial artery flow-mediated dilation (FMD), change in maximal treadmill walking time, and change in circulating CD34+ cells at 12-week follow-up. Outcomes are also measured at six-week and six-month follow-up. Results of the PROPEL Study will have important implications for understanding mechanisms of improving walking performance and preventing mobility loss in the large and growing number of men and women with PAD.
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