title: Bone marrow-derived MCP1 required for experimental aortic aneurysm formation and smooth muscle phenotypic modulation.
abstract: OBJECTIVE
  This study tested the hypothesis that monocyte chemotactic protein 1 (MCP1) is required for abdominal aortic aneurysm (AAA) and smooth muscle phenotypic modulation in a mouse elastase perfusion model.
  
  
  METHODS
  Infrarenal aortas of C57BL/6 (wild type [WT]) and MCP1 knockout (KO) mice were analyzed at 14 days after perfusion. Key cellular sources of MCP1 were identified using bone marrow transplantation. Cultured aortic smooth muscle cells (SMCs) were treated with MCP1 to assess its potential to directly regulate SMC contractile protein expression and matrix metalloproteinases (MMPs).
  
  
  RESULTS
  Elastase perfused WT aortas had a mean dilation of 102% (n = 9) versus 53.7% for MCP1KO aortas (n = 9, P < .0001) and 56.3% for WT saline-perfused controls (n = 8). Cells positive for MMP9 and Mac-2 were nearly absent in the KO aortas. Complimentarily, the media of the KO vessels had abundant differentiated smooth muscle and intact elastic fibers and markedly less MMP2. Experiments in cultured SMCs showed MCP1 can directly repress smooth muscle markers and induce MMP2 and MMP9. Bone marrow transplantation studies showed that KO of MCP1 in bone marrow-derived cells protects from AAA formation. Moreover, KO in the bone was significantly more protective than global KO, suggesting an unexpected benefit to selectively depleting MCP1 in bone marrow-derived cells.
  
  
  CONCLUSIONS
  These results have shown that MCP1 derived from bone marrow cells is required for experimental AAA formation and that retention of nonbone marrow MCP1 limits AAA compared with global depletion. This protein contributes to macrophage infiltration into the AAA and can act directly on SMCs to reduce contractile proteins and induce MMPs.
authors: Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA, USA.
authors: Christopher W
authors: CW
authors: Moehle
authors: Castigliano M
authors: CM
authors: Bhamidipati
authors: Matthew R
authors: MR
authors: Alexander
authors: Gaurav S
authors: GS
authors: Mehta
authors: James N
authors: JN
authors: Irvine
authors: Morgan
authors: M
authors: Salmon
authors: Gilbert R
authors: GR
authors: Upchurch
authors: Irving L
authors: IL
authors: Kron
authors: Gary K
authors: GK
authors: Owens
authors: Gorav
authors: G
authors: Ailawadi
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism* / Q000473:pathology; D017544:Aortic Aneurysm, Abdominal / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D001854:Bone Marrow Cells / Q000378:metabolism*; D016026:Bone Marrow Transplantation; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology / Q000502:physiology*; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D010196:Pancreatic Elastase / Q000494:pharmacology
chemical_list: D018932:Chemokine CCL2; D010196:Pancreatic Elastase; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9