title: Toll-like receptor 2/6 agonist macrophage-activating lipopeptide-2 promotes reendothelialization and inhibits neointima formation after vascular injury.
abstract: OBJECTIVE
  Reendothelialization after vascular injury (ie, balloon angioplasty or stent implantation) is clinically extremely relevant to promote vascular healing. We here investigated the therapeutic potential of the toll-like receptor 2/6 agonist macrophage-activating lipopeptide (MALP)-2 on reendothelialization and neointima formation in a murine model of vascular injury.
  
  
  RESULTS
  The left common carotid artery was electrically injured, and reendothelialization was quantified by Evans blue staining after 3 days. A single injection of MALP-2 (1 or 10 µg, IV) after vascular injury accelerated reendothelialization (P<0.001). Proliferation of endothelial cells at the wound margins determined by 5-ethynyl-2'-deoxyuridine incorporation was significantly higher in MALP-2-treated animals (P<0.05). Furthermore, wire injury-induced neointima formation of the left common carotid artery was completely prevented by a single injection of MALP-2 (10 µg, IV). In vitro, MALP-2 induced proliferation (BrdU incorporation) and closure of an artificial wound of endothelial cells (P<0.05) but not of smooth muscle cells. Protein array and ELISA analysis of isolated primary endothelial cells and ex vivo stimulated carotid segments revealed that MALP-2 stimulated the release of multiple growth factors and cytokines predominantly from endothelial cells. MALP-2 induced a strong activation of the mitogen-activated protein kinase cascade in endothelial cells, which was attenuated in smooth muscle cells. Furthermore, MALP-2 significantly enhanced circulating monocytes and hematopoietic progenitor cells.
  
  
  CONCLUSIONS
  The toll-like receptor 2/6 agonist MALP-2 promotes reendothelialization and inhibits neointima formation after experimental vascular injury via enhanced proliferation and migration of endothelial cells. Thus, MALP-2 represents a novel therapeutic option to accelerate reendothelialization after vascular injury.
authors.affiliation: Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany. grote.karsten@mh-hannover.de
authors.forename: Karsten
authors.initials: K
authors.lastname: Grote
authors.forename: Kristina
authors.initials: K
authors.lastname: Sonnenschein
authors.forename: Piyushkumar R
authors.initials: PR
authors.lastname: Kapopara
authors.forename: Anja
authors.initials: A
authors.lastname: Hillmer
authors.forename: Christina
authors.initials: C
authors.lastname: Grothusen
authors.forename: Gustavo
authors.initials: G
authors.lastname: Salguero
authors.forename: Daniel
authors.initials: D
authors.lastname: Kotlarz
authors.forename: Harald
authors.initials: H
authors.lastname: Schuett
authors.forename: Udo
authors.initials: U
authors.lastname: Bavendiek
authors.forename: Bernhard
authors.initials: B
authors.lastname: Schieffer
mesh_terms: D000818:Animals; D020212:Carotid Artery Injuries / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D017536:Carotid Artery, Common / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D055666:Lipopeptides / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D058426:Neointima; D010974:Platelet Aggregation / Q000187:drug effects; D040081:Protein Array Analysis; D013997:Time Factors; D051195:Toll-Like Receptor 2 / Q000819:agonists* / Q000378:metabolism; D051216:Toll-Like Receptor 6 / Q000819:agonists* / Q000378:metabolism; D057772:Vascular System Injuries / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D014945:Wound Healing / Q000187:drug effects
chemical_list: D016207:Cytokines; D055666:Lipopeptides; C493486:Tlr2 protein, mouse; C495369:Tlr6 protein, mouse; D051195:Toll-Like Receptor 2; D051216:Toll-Like Receptor 6; C106335:macrophage stimulatory lipopeptide 2; D020928:Mitogen-Activated Protein Kinases
keywords: cytokines; endothelial growth factors; neointima formation; toll-like receptors; vascular system injuries