Monocyte Chemotactic Protein-1 Promotes Inflammatory Vascular Repair of Murine Carotid Aneurysms via a Macrophage Inflammatory Protein-1 alpha and Macrophage Inflammatory Protein-2-Dependent Pathway

Article

关键词: CC-CHEMOKINE RECEPTOR-2;    E-DEFICIENT MICE;    EXPERIMENTAL MYOCARDIAL-INFARCTION;    UNRUPTURED INTRACRANIAL ANEURYSMS;    HUMAN ENDOTHELIAL-CELLS;    SMOOTH-MUSCLE-CELLS;    CHEMOATTRACTANT PROTEIN-1;    NEOINTIMAL HYPERPLASIA;    ATHEROSCLEROTIC LESIONS;    SUBARACHNOID HEMORRHAGE;   

DOI  :  10.1161/CIRCULATIONAHA.111.036061

来源: SCIE

【 摘 要 】

Background-Up to 5% of the population may have a brain aneurysm. If the brain aneurysm ruptures, there is >50% mortality, and more than one third of survivors are dependent. Brain aneurysms detected before rupture can be treated to prevent rupture, or ruptured aneurysms can be treated to prevent rerupture. Endovascular coiling of brain aneurysms is the treatment of choice for some aneurysms; however, up to one quarter of aneurysms may recur. The coiled aneurysms that do not recur are characterized by inflammatory intra-aneurysmal tissue healing; therefore, we studied the biology of this process, specifically the role of monocyte chemotactic protein-1 (MCP-1), a cytokine known for tissue healing. Methods and Results-We created coils with a 50:50 poly-DL-lactic glycolic acid (PLGA) coating that released MCP-1 at 3 different doses (100 mu g/mL, 1 mg/mL, and 10 mg/mL) and performed a dose-response study for effect on intra-aneurysmal tissue healing in a murine carotid aneurysm model. We then demonstrated that MCP-1 (100 mu g/mL)-releasing coils promote significantly greater aneurysm tissue in-growth than bare platinum or PLGA-only coils. We show that MCP-1 recruits the migration of fibroblasts, macrophages, smooth muscle cells, and endothelial cells in vitro in cell migration assays and in vivo in murine carotid aneurysms. Using gfp(+) bone marrow-transplant chimeric mice, we demonstrate that the MCP-1-recruited fibroblasts and macrophages are derived from the bone marrow. We demonstrate that this MCP-1-mediated vascular inflammatory repair occurs via a macrophage inflammatory protein (MIP)-1 alpha- and MIP-2-dependent pathway. MCP-1 released from coiled murine aneurysms causes significant upregulation of MIP-1 alpha and MIP-2 expression by cytokine array assay. Blocking MIP-1 alpha and MIP-2 with antagonist antibody causes a significant decrease in MCP-1-mediated intra-aneurysmal tissue healing. Conclusion-Our findings suggest that MCP-1 has a critical role in promoting inflammatory intra-aneurysmal tissue healing in an MIP-1 alpha- and MIP-2-dependent pathway. (Circulation. 2011;124:2243-2252.)

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