The Use of Endothelial Progenitor Cells as a Marker of Cardiovascular Risk
By Nina Mikirova, Ph.D.
All blood vessels are lined with endothelial cells; the layer being called the endothelium. Both blood and lymphatic capillaries are composed of a single layer of endothelial cells. They form flat, pavement-like patterns on the inside of the vessels, and at the junctions between cells there are overlapping regions, which help to seal the vessel.
These extra ordinary cells were once considered to be simple lining cells with very few functional roles, other than to keep cells within the blood from leaking out of the vessels. However, for some years research on endothelial cells has revealed that they have an amazing array of functional and adaptive qualities. These cells reduce friction, allowing the blood to be pumped farther. Endothelial cells are selective filters, which regulate the passage of gases, fluid, and various molecules across their cell membranes.
Moreover, endothelial cells are the key determinants of health and disease in blood vessels and play a major role in arterial disease. Although the incidence of death from arterial disease is decreasing (due to better education, diet, smoking reduction, and life-style changes), it is still a major health problem. Endothelial cells play a crucial role in the initiation of this condition. It has long been realized that endothelial cells become “injured,” either physically by abrasion or toxic insult (such as from nicotine), and large molecules, which are normally confined to the blood, are allowed to escape through the endothelium and become lodged in the smooth muscle cells in the arterial wall. Macrophages also pass through and accumulate fat (lipid and cholesterol) deposits. The most common name for this disease is atherosclerosis. This process is very slow, but there is a gradual accumulation of this fatty and fibrous material, which not only makes the normally elastic artery hard (sclerotic), but the deposits, known as “plaques,” may encroach on the arterial lumen and cause turbulent blood flow.
Thus, the complete regeneration of injured blood vessels is of particular importance. This endothelial repair may occur by migration and proliferation of surrounding mature endothelial cells. However, the mature endothelial cells are terminally differentiated cells with a low proliferative potential, and their capacity to substitute damaged endothelial cells and to create new vessels is relatively limited.
Endothelial repair obviously needs the support of other cells. Accumulating evidence in past years indicates that peripheral blood of adults contains bone marrow-derived progenitor cells. These
precursor cells have the potential to differentiate into mature endothelial cells and were termed endothelial progenitor cells (EPCs).
As endothelial progenitor cells are originally derived from the bone marrow, it is thought that various growth factors and hormones cause them to be mobilized from the bone marrow and into the peripheral blood circulation, where they ultimately are recruited to regions where they are needed.
Circulating endothelial progenitor cells are involved in the repair process of the endothelium after endothelial-cell injury in myocardial ischemia, angina, and other stressful situations. Physiological variations in the number of EPCs have been recently described. For example, physical training enhances the number of circulating EPCs. Several studies have described the influence of various pathological conditions and some drugs and growth factors on the number of EPCs. The numbers of circulating EPCs and their activity have been reported to be reduced in patients with risk factors for ischemic cardiovascular disease. EPCs from patients with diabetes mellitus type II were characterized by a decreased proliferation capacity and reduction to form capillary tubes. In contrast, acute myocardial infarction was associated with a rapid increase of EPCs in the circulation. Vascular trauma also induces a rapid transient mobilization of EPCs.
Last year there were several clinical trials to use EPCs for the treatment of patients suffering from vascular diseases. These trials focused on the safety and efficiency of the administered EPCs in patients with cardiac disorder. Recent studies demonstrate that implantation of a patient’s progenitor cells after acute myocardial infarction appears to limit post-infarctional damage. For example, the study titled “The Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction” involved the delivery of circulating endothelial progenitor cells
or bone marrow cells directly into coronary arteries after the infarction in patients with acute myocardial infarction. At four months, transplantation of progenitor cells resulted in an improved
regional wall motion in the infarct zone. However, the exact mechanisms mediating the improvement of heart function, as well as the survival and distribution infused progenitor cells, remain open.
By the time heart problems are detected, the underlying cause, such as atherosclerosis, is usually quite advanced, having progressed for decades. Some biomarkers are thought to offer a more detailed risk of cardiovascular disease. Currently, biomarkers, which may reflect a high risk of cardiovascular disease, include high fibrinogen blood concentration, elevated homocysteine, elevated blood levels of asymmetric dimethylarginine, high inflammation as measured by C-reactive protein, and others.
As EPCs play an important role in the regeneration of ischemic and damaged tissue via repairing the endothelium in the injured vessels, it was demonstrated that a reduced number of EPCs predicts future cardiovascular events and proposed that a low number of these cells reflects the impaired repair capacity. Circulating EPCs are believed to be depleted by standard cardiovascular risk factors and unfavorable life-style.
Based on the assumption that the number and the functional characteristics of EPCs may be successfully used as a diagnostic tool and prognostic marker of vascular disease, here at The Center I developed a diagnostic tool for evaluation of the cardiovascular risk and severity of peripheral atherosclerosis based on the number and activity of circulating endothelial progenitor cells. In this study, the level of endothelial progenitor cells in the blood of people with low and high risk factors was measured to see if there is a relationship between these cells and cardiovascular risk factors such as smoking, high cholesterol level, high blood pressure, diabetes, and age. Results of our test were compared with the conventional risk factor score, Framingham-based scoring system, which is based on the same risk factors for atherosclerosis.
Our diagnostic procedure demonstrated a decreased number of repairing cells in circulation with the increasing of the level of cardiovascular risk factors. We hope that our research of endothelial cells will help with a more detailed understanding of their function, and in the future the estimation of the number and functional ability of endothelial progenitor cells will be used as a diagnostic tool for vascular diseases.