Published online before print October 16, 2008, doi: 10.1161/CIRCRESAHA.108.179952
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Submitted on August 30, 2007
Revised on September 17, 2008
Accepted on October 6, 2008
Role of Kinin B2 Receptor Signaling in the Recruitment of Circulating Progenitor Cells With Neovascularization Potential
Nicolle Kränkel ;
From Experimental Cardiovascular Medicine (N.K., R.G.K., M.S., L.S.B., P.C., G.M., R.A., G.A., C.E., P.M.), Bristol Heart Institute; and the Departments of Anaesthesia (N.T., K.Z.) and Cellular and Molecular Medicine (A.H.), University of Bristol, United Kingdom; IRCCS Multimedica (O.F., G.S.), Milan, Italy; Third Division of Cardiology (W.W., I.M.), Medical University of Silesia, Katowice, Poland; Department of Pharmacology (J.E.M.F., P.E.M.), University of Alberta, Edmonton, Canada; Institut National de la Santé et de la Recherche Médicale (J.P.S., J.L.B.), U858/I2MR, Department of Renal and Cardiac Remodeling, Team 5, Toulouse, France; and Université Toulouse III Paul Sabatier (J.P.S., J.L.B.), France.
* To whom correspondence should be addressed. E-mail: madeddu{at}yahoo.com.
Reduced migratory function of circulating angiogenic progenitor cells (CPCs) has been associated with impaired neovascularization in patients with cardiovascular disease (CVD). Previous findings underline the role of the kallikrein-kinin system in angiogenesis. We now demonstrate the involvement of the kinin B2 receptor (B2R) in the recruitment of CPCs to sites of ischemia and in their proangiogenic action. In healthy subjects, B2R was abundantly present on CD133+ and CD34+ CPCs as well as cultured endothelial progenitor cells (EPCs) derived from blood mononuclear cells (MNCs), whereas kinin B1 receptor expression was barely detectable. In transwell migration assays, bradykinin (BK) exerts a potent chemoattractant activity on CD133+ and CD34+ CPCs and EPCs via a B2R/phosphoinositide 3-kinase/eNOS-mediated mechanism. Migration toward BK was able to attract an MNC subpopulation enriched in CPCs with in vitro proangiogenic activity, as assessed by Matrigel assay. CPCs from cardiovascular disease patients showed low B2R levels and decreased migratory capacity toward BK. When injected systemically into wild-type mice with unilateral limb ischemia, bone marrow MNCs from syngenic B2R-deficient mice resulted in reduced homing of sca-1+ and cKit+flk1+ progenitors to ischemic muscles, impaired reparative neovascularization, and delayed perfusion recovery as compared with wild-type MNCs. Similarly, blockade of the B2R by systemic administration of icatibant prevented the beneficial effect of bone marrow MNC transplantation. BK-induced migration represents a novel mechanism mediating homing of circulating angiogenic progenitors. Reduction of BK sensitivity in progenitor cells from cardiovascular disease patients might contribute to impaired neovascularization after ischemic complications.
Key words: bradykinin • migration • progenitor recruitment • angiogenesis • therapeutic neovascularization
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