Toll-Like Receptor 2/6 Agonist Macrophage-Activating Lipopeptide-2 Promotes Reendothelialization and Inhibits Neointima Formation After Vascular Injury

作者：Grote Karsten^*; Sonnenschein Kristina; Kapopara Piyushkumar R; Hillmer Anja; Grothusen Christina; Salguero Gustavo; Kotlarz Daniel; Schuett Harald; Bavendiek Udo; Schieffer Bernhard

来源：Arteriosclerosis, Thrombosis, and Vascular Biology, 2013, 33(9): 2097-2104.

DOI：10.1161/ATVBAHA.113.301799

• cytokines
• endothelial growth factors
• neointima formation
• toll-like receptors
• vascular system injuries

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. %26lt;br%26gt;Approach and 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 mu g, IV) after vascular injury accelerated reendothelialization (P%26lt;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%26lt;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 mu g, IV). In vitro, MALP-2 induced proliferation (BrdU incorporation) and closure of an artificial wound of endothelial cells (P%26lt;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. %26lt;br%26gt;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.

• 出版日期2013-9