title: Role of plasma kallikrein-kinin system activation in synovial recruitment of endothelial progenitor cells in experimental arthritis.
abstract: OBJECTIVE
  To examine whether activation of the plasma kallikrein-kinin system (KKS) mediates synovial recruitment of endothelial progenitor cells (EPCs) in arthritis.
  
  
  METHODS
  EPCs 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 a plasma kallikrein inhibitor (EPI-KAL2) and an antikallikrein antibody (13G11). A transendothelial migration assay was used to determine the role of bradykinin and its receptor in EPC mobilization.
  
  
  RESULTS
  EPCs 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 by EPI-KAL2 and 13G11 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.
  
  
  CONCLUSIONS
  These 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.
authors: Temple University School of Medicine, Philadelphia, Pennsylvania, USA.
authors: Jihong
authors: J
authors: Dai
authors: Alexis
authors: A
authors: Agelan
authors: Aizhen
authors: A
authors: Yang
authors: Viviana
authors: V
authors: Zuluaga
authors: Daniel
authors: D
authors: Sexton
authors: Robert W
authors: RW
authors: Colman
authors: Yi
authors: Y
authors: Wu
mesh_terms: D000208:Acute Disease; D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology* / Q000473:pathology; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology; D001920:Bradykinin / Q000276:immunology; D002465:Cell Movement / Q000276:immunology; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000276:immunology*; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000276:immunology*; D016234:Kallikrein-Kinin System / Q000276:immunology*; D007610:Kallikreins / Q000097:blood / Q000276:immunology; D009389:Neovascularization, Pathologic / Q000276:immunology / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D055647:Rats, Transgenic; D043782:Receptor, Bradykinin B2 / Q000276:immunology*; D019718:Receptors, CXCR4 / Q000235:genetics / Q000276:immunology; D013583:Synovial Membrane / Q000098:blood supply / Q000276:immunology* / Q000473:pathology
chemical_list: C486264:Cxcr4 protein, rat; D012333:RNA, Messenger; D043782:Receptor, Bradykinin B2; D019718:Receptors, CXCR4; D007610:Kallikreins; D001920:Bradykinin