The role of the β2 adrenergic receptor on endothelial progenitor cells dysfunction of proliferation and migration in chronic obstructive pulmonary disease patients

Background: Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD), with > 44% of these patients presenting with generalized atherosclerosis at autopsy. It is accepted that endothelial progenitor cells (EPCs) participate in the repair of dysfunctional endothelium, thereby, protecting against atherosclerosis. The beta 2 adrenergic receptor (beta 2AR) expressed on mononuclear cells in peripheral blood and CD34(+) cells in bone has been shown to regulate T-cell traffic and proliferation. At present, there have been few systematic studies evaluating beta 2AR expression on EPCs in the peripheral blood of COPD patients and its role in EPCs migration and proliferation. Therefore, the objective of this study was to determine the role of beta 2ARs in EPCs function and, if this role is altered, in the COPD population. Methods: EPCs from 25 COPD and 16 control patients were isolated by Ficoll density-gradient centrifugation and identified using fluorescence-activated cell sorting. beta 2AR expression on EPCs was determined by western blotting and real-time PCR. The transwell migration assay was performed to determine the migration capacity of EPCs treated with a beta 2AR agonist, antagonist and beta 2AR monoclonal antibody. EPCs proliferation was assayed throughout the cell cycle. Following arterial damage in NOD/SCID mice, the number of EPCs treated with siRNA-beta 2AR incorporated at the injured vascular site was determined by fluorescence microscopy. Results: Data showed a significant increase in the total number of beta 2AR in addition to an increased expression on early EPCs in COPD patients. COPD EPCs treated with beta 2AR antagonist (ICI 118551) increased migration to SDF-1 alpha when compared to treatment with the b2AR agonist, norepinephrine. These changes were directly correlated to increase CXCR4 on EPCs. The proliferation of early EPCs treated with beta 2AR antagonist was improved and was correlated to an intercellular decrease in reactive oxygen species. Conclusion: Changes in beta 2AR in COPD patients alter EPCs migration and proliferation, contributing to altered EPC repair capacity in this patient population.