Novel Insights into the Critical Role of Bradykinin and the Kinin B2 Receptor for Vascular Recruitment of Circulating Endothelial Repair-Promoting Mononuclear Cell Subsets: Alterations in Patients with Coronary Disease
Background—Endothelial injury is considered critical for progression of atherosclerosis and its complications, in coronary artery disease (CAD). The endothelial-supportive effects of bradykinin have mainly been attributed to activation of the resident endothelium. Here we newly investigate the role of bradykinin and its B2 receptor for the recruitment and functional activation of circulating mononuclear cell subsets with endothelial-repair promoting capacity, such as CD34+CXCR4+cells, at sites of arterial injury.
Methods and Results—Bradykinin-B2-receptor (B2R) blockade by icatibant substantially impaired recruitment of circulating CD34+CXCR4+ mononuclear cells (expressing high levels of B2R) to endothelial cells in vitro and to injured arterial wall in vivo, while recruitment of CD14hi monocytes (expressing low levels of B2R) was unchanged. Moreover, the capacity of genetically B2R-deficient bone marrow cells (BMCs) to promote endothelial repair in vivo was markedly impaired as compared to wild-type BMCs. B2R-expression was reduced on CD34+CXCR4+ mononuclear cells and endothelial repair-promoting 'early outgrowth cells' (EOCs), but not on CD14hi monocytes, from CAD patients as compared to healthy subjects. B2R stimulation induced CD18 activation in EOCs of healthy subjects, but not in EOCs of CAD patients. Adenoviral B2R-overexpression enhanced in vivo vascular recruitment and rescued impaired endothelial repair capacity of EOCs from CAD patients.
Conclusions—We newly report that bradykinin/B2R signaling may promote endothelial repair after arterial injury by selective recruitment and functional activation of B2R-expressing circulating mononuclear cell subsets. In CAD patients, B2R downregulation on endothelial repair-promoting circulating MNCs substantially impairs the bradykinin-dependent endothelial repair, representing a novel mechanism promoting endothelial injury in CAD patients.
- Received May 11, 2012.
- Accepted December 14, 2012.
- Copyright © 2012, American Heart Association, Inc. All rights reserved. Unauthorized use prohibited