The Role of Endothelial Progenitor Cells in Inflammation

Rheumatoid arthritis (RA) is the most common inflammatory rheumatic disease in the Western world. If untreated or insufficiently treated RA is a crippling disease that causes disability by inflammatory destruction of joints, cartilage and bone. RA is also characterized by an increased propensity to develop of atherosclerosis and cardiovascular morbidity. While much progress has been made in understanding mechanisms of chronic immune stimulation leading to joint destruction, much less is known about the pathomechanisms of RA-associated atherosclerosis. Endothelial progenitor cells (EPC) have been implicated in vascular repair and formation of new blood vessels. It has been proposed that insufficient supply of EPC aggravates atherosclerosis. On the other hand, EPC have been implicated in driving the vasculogenesis supporting synovitis. How these progenitor cells contribute to the disease manifestations in the joint and the vessel walls, however, remains unresolved. Our prior work shows that EPC are depleted in the blood of RA patients. Here, we hypothesize that chronic synovitis leads to EPC consumption that impairs vascular repair in atherosclerotic lesions and renders RA patients susceptible to premature complications of atherosclerosis. We propose that therapeutic interventions abrogating EPC recruitment to the inflamed joint would suppress synovitis and at the same time, improve vascular repair mechanisms. Dr. Cornelia Weyand and her co-workers at the Lowance Center for Human Immunology and Rheumatology at the Emory University have had a long-standing interest in immunopathways sustaining atherosclerosis. Our group at the Medical University of Vienna has performed various studies on EPC in RA. In this project we want to bring together the expertise of both groups and investigate, on a molecular level, how EPC contribute to synovitis as well as accelerated cardiovascular disease in RA. The studies will be performed in a mouse model which combines RA-like synovitis and atherosclerotic disease. Specifically, we will induce arthritis (by immunizing with collagen type II) in atherosclerosis-prone mice. By combining both disease pathways we will be able to study the contribution of EPC to each of the disease components. We hypothesize that EPC not only migrate into the inflamed synovium but also into the atherosclerotic vessel wall. We will investigate to what extent EPC contribute to synovial inflammation and whether integrin linked kinase (ILK), an enzyme critically involved in EPC recruitment, is a potential therapeutic target whose inhibition might redirect EPC away from the joint. Finally, we will study how immunosuppressants utilized in the care of RA patients, statins, ACE inhibitors and erythropoietin affect EPC biology and their involvement in joint inflammation and atherosclerosis.