Activation of plasma kallikrein‐kinin system mediates synovial recruitment of endothelial progenitor cells in arthritis

Abstract

OBJECTIVEThis study aimed at determining whether activation of the plasma kallikrein‐kinin system (KKS) mediates synovial recruitment of endothelial progenitor cells (EPCs) in arthritis.METHODSEPCs were isolated from Lewis rat bone marrow, and expression of progenitor cell‐lineage markers and functional properties were characterized. EPCs were injected intravenously into Lewis rats with arthritis, and their recruitment and formation of de novo blood vessels in inflamed synovium were evaluated. The role of plasma KKS was examined using plasma kallikrein inhibitors. A transendothelial migration assay was used to determine the role of bradykinin and its receptor in EPC mobilization.RESULTSEPCs from Lewis rats exhibited a strong capacity to form tubes and vacuoles and expressed increased levels of bradykinin type 2 receptor (B2R) and progenitor cell markers CD34 and Sca‐1. In Lewis rats with arthritis, EPCs were recruited into inflamed synovium at the acute phase of disease and formed de novo blood vessels. Inhibition of plasma kallikrein significantly suppressed synovial recruitment of EPCs and hyperproliferation of synovial cells. Bradykinin stimulated transendothelial migration of EPCs in a concentration‐dependent manner. This was mediated by B2R, as demonstrated by the finding that knockdown of B2R with silencing RNA completely blocked bradykinin‐stimulated transendothelial migration. Moreover, bradykinin selectively up‐regulated expression of the homing receptor CXCR4 in EPCs.CONCLUSIONThese observations demonstrate a novel role of plasma KKS activation in the synovial recruitment of EPCs in arthritis, acting via kallikrein activation and B2R‐dependent mechanisms. B2R might be involved in the mobilization of EPCs via up‐regulation of CXCR4.