Endothelial Progenitor Cells Novel Players in the Pathogenesis of Rheumatic Diseases

Vasculogenesis is not restricted to embryonic development, but contributes to the vascular homeostasis and integrity in adults. EPCs induce neovascularization of ischemic tissues and stimulate the repair of damaged vessels by the release of angiogenic factors, integration into the vessel wall, and differentiation into mature ECs. In fact, several cardiovascular risk factors are associated with a reduced number of circulating EPCs, and EPC counts are inversely correlated with the risk of major cardiovascular events, such as myocardial infarction and stroke. Thus far, EPCs have been implicated in the vascular pathogenesis of several rheumatic diseases. Reduced levels of circulating EPCs have been found in patients with RA and SLE. In SSc, however, EPC counts are still unresolved. In addition, altered EPC functions with increased apoptosis, decreased production of angiogenic factors, reduced adhesion, and impaired differentiation capacity have been described in patients with RA, SLE, and SSc. Together, these findings suggest that defects in vasculogenesis might contribute to the increased cardiovascular risk in patients with RA and SLE and might play a critical role in the vasculopathy observed in patients with SSc. However, a major problem in EPC research is the lack of clear definitions and common protocols for the isolation and identification of EPCs (83). Because of this, comparison of the results of different studies is often difficult, since different EPC isolation procedures might yield different subpopulations and maturation steps of EPCs. The lack of clear definitions and protocols might also explain the differences in EPC counts observed in SSc. Guidelines for the isolation, identification, quantification, and culturing of EPCs, such as those compiled by the EUSTAR group (83), will help to unify research within the field and allow better comparison between studies. Large amounts of blood are needed for the isolation of sufficient numbers of EPCs, and the protocols for the culture and propagation of EPCs are complicated. Consequently, evidence of altered EPC functions in patients with rheumatic diseases is still limited. Despite great progress in EPC research, many questions remain open. Do different subpopulations of EPCs have distinct functions during vasculogenesis? What is the physiologic relevance of mesenchymal stem cells and tissue-resident stem cells that can differentiate into EPCs? Although key molecules have been identified, the molecular mechanisms that lead to the formation of new vessels and the repair of preexisting vessels are only incompletely understood. In the field of rheumatology, the levels and function of EPCs have been investigated in SSc, RA, SLE, and the vasculitides. However, a number of research questions are still pending: What are the reasons for the observed functional defects of EPCs? Do patients benefit from injections of autologous EPCs or from treatment with drugs that increase the number of circulating EPCs (e.g., HMG-CoA reductase inhibitors) despite functional defects? Are there any long-term side effects of therapeutic injection of EPCs, such as enhanced plaque formation or an increased risk of cancer due to uncontrolled neoangiogenesis? These issues need to be addressed in further studies and might help to improve our understanding about the vascular pathogenesis of rheumatic diseases. © 2009, American College of Rheumatology.