MAP-Kinase Activated Protein Kinase 2 Links Endothelial Activation and Monocyte/macrophage Recruitment in Arteriogenesis |
| |
| Authors: | Anne Limbourg Johann von Felden Kumaravelu Jagavelu Kashyap Krishnasamy L Christian Napp Piyushkumar R Kapopara Matthias Gaestel Bernhard Schieffer Johann Bauersachs Florian P Limbourg Udo Bavendiek |
| |
| Institution: | 1. Vascular Medicine Research, Dept. of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany.; 2. Integriertes Forschungs- und Behandlungszentrum Transplantation (IFB-Tx), Hannover Medical School, Hannover, Germany.; 3. Dept. of Cardiology & Angiology, Hannover Medical School, Hannover, Germany.; 4. Dept. of Biochemistry, Hannover Medical School, Hannover, Germany.; University of Amsterdam Academic Medical Center, NETHERLANDS, |
| |
| 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. |
| |
| Keywords: | |
|
|
