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.

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 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: Karsten Grote, Kristina Sonnenschein, Piyushkumar R Kapopara, Anja Hillmer, Christina Grothusen, Gustavo Salguero, Daniel Kotlarz, Harald Schuett, Udo Bavendiek, Bernhard Schieffer
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 33 Issue 9 Pg. 2097-104 (Sep 2013) ISSN: 1524-4636 [Electronic] United States
• PMID: 23868938 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• Lipopeptides
• Tlr2 protein, mouse
• Tlr6 protein, mouse
• Toll-Like Receptor 2
• Toll-Like Receptor 6
• macrophage stimulatory lipopeptide 2
• Mitogen-Activated Protein Kinases

Topics

• Animals
• Carotid Artery Injuries (drug therapy, immunology, metabolism, pathology)
• Carotid Artery, Common (drug effects, immunology, metabolism, pathology)
• Cell Proliferation (drug effects)
• Cells, Cultured
• Cytokines (metabolism)
• Disease Models, Animal
• Endothelial Cells (drug effects, immunology, metabolism, pathology)
• Enzyme-Linked Immunosorbent Assay
• Humans
• Lipopeptides (pharmacology)
• MAP Kinase Signaling System (drug effects)
• Male
• Mice
• Mice, Inbred C57BL
• Mitogen-Activated Protein Kinases (metabolism)
• Myocytes, Smooth Muscle (drug effects, immunology, metabolism, pathology)
• Neointima
• Platelet Aggregation (drug effects)
• Protein Array Analysis
• Time Factors
• Toll-Like Receptor 2 (agonists, metabolism)
• Toll-Like Receptor 6 (agonists, metabolism)
• Vascular System Injuries (drug therapy, immunology, metabolism, pathology)
• Wound Healing (drug effects)