Endothelial progenitor cells: Novel players in the pathogenesis of rheumatic diseases

Cardiovascular disease is an integral part of most rheumatic diseases, and its impact on the outcome and prognosis of the rheumatic disease is a major research focus for rheumatologists and cardiologists. In patients with inflammatory rheumatic disorders, such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), the cardiovascular risk is highly increased, even if other cardiovascular risk factors known to promote and accelerate the progression of atherosclerotic lesions are absent. Patients with RA have a 2–5-fold increased risk of developing premature cardiovascular disease. The increased risk of myocardial infarction and stroke strongly contributes to the increased mortality risk and to the shortened (by 5–10 years) life expectancy of patients with RA (1,2). Other rheumatic disorders, such as systemic sclerosis (SSc), are characterized by a severe vasculopathy. Involvement of the microvascular circulation manifests as Raynaud’s syndrome and ischemic ulcers, and it has a profound impact on the quality of life (3,4). In addition, involvement of the pulmonary vasculature leads to pulmonary arterial hypertension (PAH) in 10–20% of patients with SSc. PAH is also known to be a major cause of death in SSc (5,6). As illustrated by these examples, rheumatic disorders are characterized by a profound cardiovascular disease and may therefore even serve as research models for studying the influence of systemic inflammatory processes on cardiovascular integrity. Over the last 13 years, endothelial progenitor cells (EPCs) have emerged as crucial regulators of cardiovascular integrity. Reduced numbers and altered functions of EPCs have been found to be involved in the pathogenesis of cardiovascular disease. The important role of vasculogenesis and EPCs in adults was discovered late. The formation of new vessels had long been believed to be mediated exclusively by the sprouting of fully differentiated endothelial cells (ECs) from preexisting vessels, a process called angiogenesis. This concept was first disproved by Asahara and colleagues (7) in 1997. In a landmark study, they demonstrated that new blood vessels can also be formed in adults by circulating progenitor cells, independently of the preexisting vasculature (7). They found that bone marrow–derived CD34 cells could acquire the characteristics of mature ECs, express endothelial markers, and incorporate into new vessels at sites of ischemia. Subsequent analyses revealed that these EPCs were not restricted to the bone marrow, but could also be detected in the peripheral circulation of adults (8). Since then, growing evidence has suggested that EPCs play an important role in the homeostasis of the physiologic vascular network. EPCs are not only involved in the formation of new vessels in ischemic tissues, thereby contributing to the vascular remodeling, but might also Supported by the Interdisciplinary Center of Clinical Research, Erlangen, Germany (grant A20), by a Career Support Award of Medicine from the Ernst Jung Foundation, and by the European Commission Seventh Framework Programme (integrated projects AutoCure and Masterswitch). Jörg H. W. Distler, MD, Christian Beyer, MD, Georg Schett, MD: University of Erlangen–Nuremberg, Erlangen, Germany; Thomas F. Lüscher, MD, FRCP, Steffen Gay, MD, Oliver Distler, MD: University Hospital Zurich, Zurich, Switzerland. Dr. J. H. W. Distler has received consulting fees, speaking fees, and/or honoraria from Pfizer and Actelion (less than $10,000 each). Dr. O. Distler has received consulting fees, speaking fees, and/or honoraria from Actelion, Pfizer, ErgoNex Pharma, FibroGen, and Biovitrum (less than $10,000 each). Address correspondence and reprint requests to Jörg H. W. Distler, MD, Department of Internal Medicine III and Institute for Clinical Immunology, University of Erlangen–Nuremberg, Universitätsstrasse 29, 91054 Erlangen, Germany. E-mail: joerg.distler@ukerlangen.de. Submitted for publication February 4, 2009; accepted in revised form July 27, 2009.