Antioxidant protection: yet another function of endothelial progenitor cells?

Abstract

Previously considered purely as a mechanical monolayer barrier, the modern view of the endothelium is of an extremely active ‘biochemical laboratory’ acting in both an endocrine and paracrine manner to maintain and regulate vascular health. The strong association between endothelial damage/dysfunction and cardiovascular disease has been the subject of intense research. Indeed, the endothelium is believed to play a pivotal role in many cardiovascular disease states, including hypertension. However, the concept of ‘endothelial dysfunction’ should not be limited purely to endothelial abnormalities, but should include consideration of a host of anomalies that occur in the conduit vessel wall, within the blood and perhaps even extended to alterations in the number and/or function of endothelial progenitor cells (EPCs) within the bone marrow. In all individuals, the vascular wall and the endothelium undergo a constant process of injury and repair in response to both mechanical and chemical injury. Accumulating evidence suggests that circulating EPCs derived from the bone marrow play an important role in the maintenance of vascular integrity by augmentation of neovascularization, endothelial repair and promotion of endothelial function. Both physiological (e.g. aging) and pathological (e.g. hypercholesterolemia, diabetes mellitus and coronary artery disease) conditions are associated with decreased number of circulating EPCs. Transplantation of EPCs from healthy individuals has suggested that these cells have capacity for potent angiogenic properties and may promote preservation of ischemic tissue. However, some disparity exists between the pronounced angiogenic effects of EPCs on animal models and the rather modest effects seen in clinical trials on human subjects. Importantly, the data would appear to imply that the number of available progenitors is not the primary factor for successful cellular revascularization, but instead the functional capacity of human EPCs is of paramount importance. Impaired EPC functionality in patients with cardiovascular risk factors is well documented. Of note, an inverse correlation is found between the number and functional activity of EPCs and cardiovascular risk factors among apparently healthy persons and also in patients with coronary artery disease. Furthermore, the number of EPCs has been demonstrated to correlate with endothelial function and is a better predictor for future cardiovascular risk than the combined Framingham risk factor score. The intimate mechanisms responsible for restoration of endothelial function remain unclear and this has prompted researchers to study different aspects of EPC biology and function. Among the large number of vasoactive substances produced by endothelial cells, nitric oxide (NO) appears to be of crucial importance. Some have speculated that endothelial NO activity is the hallmark of endothelial function, and the release of NO plays a critical role in the control of vascular tone. Potent antiaggregatory and proangiogenic properties of NO are also well determined. The clinical implications of endothelial dysfunction and the association between reduced NO bioavailability, cardiovascular risk factors (including hypertension) and cardiac events is well established. Moreover, NO production by EPCs has been shown to be not only marker of cellular maturation but also a factor which has a strong impact on their proangiogenic properties. How can we improve endothelial function? Apart from pharmacological methods, physical exercise has been associated with a significant reduction in cardiovascular morbidity and mortality, and this may be mediated through exercise-related improvements in endothelial function. Shear stress is one of the most effective endothelial stimulators, and results in an upregulation of the endothelial NO synthase activity and NO production, at least in an experimental model. The beneficial effect of exercise training on endothelium-dependent vasodilatation observed in several Correspondence: Professor GYH Lip, Haemostasis Thrombosis and Vascular Biology Unit, University Department of Medicine, City Hospital, Dudley Road, Birmingham B18 7QH, UK. E-mail: g.y.h.lip@bham.ac.uk Published online 22 February 2007 Journal of Human Hypertension (2007) 21, 343–346 & 2007 Nature Publishing Group All rights reserved 0950-9240/07 $30.00