title: MAP-Kinase Activated Protein Kinase 2 Links Endothelial Activation and Monocyte/macrophage Recruitment in Arteriogenesis.
abstract: Arteriogenesis, the growth of natural bypass arteries, is triggered by hemodynamic forces within vessels and requires a balanced inflammatory response, involving induction of the chemokine MCP-1 and recruitment of leukocytes. However, little is known how these processes are coordinated. The MAP-kinase-activated-proteinkinase-2 (MK2) is a critical regulator of inflammatory processes and might represent an important link between cytokine production and cell recruitment during postnatal arteriogenesis. Therefore, the present study investigated the functional role of MK2 during postnatal arteriogenesis. In a mouse model of hindlimb ischemia (HLI) MK2-deficiency (MK2KO) significantly impaired ischemic blood flow recovery and growth of collateral arteries as well as perivascular recruitment of mononuclear cells and macrophages. This was accompanied by induction of endothelial MCP-1 expression in wildtype (WT) but not in MK2KO collateral arteries. Following HLI, MK2 activation rapidly occured in the endothelium of growing WT arteries in vivo. In vitro, inflammatory cytokines and cyclic stretch activated MK2 in endothelial cells, which was required for stretch- and cytokine-induced release of MCP-1. In addition, a monocyte cell autonomous function of MK2 was uncovered potentially regulating MCP-1-dependent monocyte recruitment to vessels: MCP-1 stimulation of WT monocytes induced MK2 activation and monocyte migration in vitro. The latter was reduced in MK2KO monocytes, while in vivo MK2 was activated in monocytes recruited to collateral arteries. In conclusion, MK2 regulates postnatal arteriogenesis by controlling vascular recruitment of monocytes/macrophages in a dual manner: regulation of endothelial MCP-1 expression in response to hemodynamic and inflammatory forces as well as MCP-1 dependent monocyte migration.
authors.affiliation: Vascular Medicine Research, Dept. of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany; Integriertes Forschungs- und Behandlungszentrum Transplantation (IFB-Tx), Hannover Medical School, Hannover, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Limbourg
authors.affiliation: Dept. of Cardiology & Angiology, Hannover Medical School, Hannover, Germany.
authors.forename: Johann
authors.initials: J
authors.lastname: von Felden
authors.affiliation: Dept. of Cardiology & Angiology, Hannover Medical School, Hannover, Germany.
authors.forename: Kumaravelu
authors.initials: K
authors.lastname: Jagavelu
authors.affiliation: Vascular Medicine Research, Dept. of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany.
authors.forename: Kashyap
authors.initials: K
authors.lastname: Krishnasamy
authors.affiliation: Dept. of Cardiology & Angiology, Hannover Medical School, Hannover, Germany.
authors.forename: L Christian
authors.initials: LC
authors.lastname: Napp
authors.affiliation: Dept. of Cardiology & Angiology, Hannover Medical School, Hannover, Germany.
authors.forename: Piyushkumar R
authors.initials: PR
authors.lastname: Kapopara
authors.affiliation: Dept. of Biochemistry, Hannover Medical School, Hannover, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Gaestel
authors.affiliation: Dept. of Cardiology & Angiology, Hannover Medical School, Hannover, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Schieffer
authors.affiliation: Dept. of Cardiology & Angiology, Hannover Medical School, Hannover, Germany.
authors.forename: Johann
authors.initials: J
authors.lastname: Bauersachs
authors.affiliation: Vascular Medicine Research, Dept. of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany; Integriertes Forschungs- und Behandlungszentrum Transplantation (IFB-Tx), Hannover Medical School, Hannover, Germany.
authors.forename: Florian P
authors.initials: FP
authors.lastname: Limbourg
authors.affiliation: Dept. of Cardiology & Angiology, Hannover Medical School, Hannover, Germany.
authors.forename: Udo
authors.initials: U
authors.lastname: Bavendiek
mesh_terms: D000818:Animals; D001158:Arteries / Q000166:cytology / Q000254:growth & development*; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000502:physiology; D002633:Chemotaxis / Q000502:physiology; D004730:Endothelium, Vascular / Q000166:cytology* / Q000201:enzymology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology*; D051379:Mice; D009000:Monocytes / Q000166:cytology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D018932:Chemokine CCL2; D047908:Intracellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; D000099190:MAP-Kinase-Activated Kinase 2