PMID- 21996300 OWN - NLM STAT- MEDLINE DCOM- 20120110 LR - 20211020 IS - 1097-685X (Electronic) IS - 0022-5223 (Print) IS - 0022-5223 (Linking) VI - 142 IP - 6 DP - 2011 Dec TI - Bone marrow-derived MCP1 required for experimental aortic aneurysm formation and smooth muscle phenotypic modulation. PG - 1567-74 LID - 10.1016/j.jtcvs.2011.07.053 [doi] AB - OBJECTIVES: 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. CI - Copyright (c) 2011. Published by Mosby, Inc. FAU - Moehle, Christopher W AU - Moehle CW AD - Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA, USA. FAU - Bhamidipati, Castigliano M AU - Bhamidipati CM FAU - Alexander, Matthew R AU - Alexander MR FAU - Mehta, Gaurav S AU - Mehta GS FAU - Irvine, James N AU - Irvine JN FAU - Salmon, Morgan AU - Salmon M FAU - Upchurch, Gilbert R Jr AU - Upchurch GR Jr FAU - Kron, Irving L AU - Kron IL FAU - Owens, Gary K AU - Owens GK FAU - Ailawadi, Gorav AU - Ailawadi G LA - eng GR - T32 HL007849/HL/NHLBI NIH HHS/United States GR - T32/HL007849/HL/NHLBI NIH HHS/United States GR - T32/HL007284/HL/NHLBI NIH HHS/United States GR - R01 HL081629/HL/NHLBI NIH HHS/United States GR - T32 HL007284/HL/NHLBI NIH HHS/United States GR - K08 HL098560/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20111011 PL - United States TA - J Thorac Cardiovasc Surg JT - The Journal of thoracic and cardiovascular surgery JID - 0376343 RN - 0 (Chemokine CCL2) RN - EC 3.4.21.36 (Pancreatic Elastase) RN - EC 3.4.24.24 (Matrix Metalloproteinase 2) RN - EC 3.4.24.35 (Matrix Metalloproteinase 9) SB - IM MH - Animals MH - Aorta/*metabolism/pathology MH - Aortic Aneurysm, Abdominal/metabolism/pathology/*physiopathology MH - Bone Marrow Cells/*metabolism MH - Bone Marrow Transplantation MH - Cells, Cultured MH - Chemokine CCL2/genetics/*metabolism/pharmacology/*physiology MH - Humans MH - Matrix Metalloproteinase 2/metabolism MH - Matrix Metalloproteinase 9/metabolism MH - Mice MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Muscle, Smooth, Vascular/drug effects/metabolism/pathology/physiopathology MH - Pancreatic Elastase/pharmacology PMC - PMC3627218 MID - NIHMS450868 EDAT- 2011/10/15 06:00 MHDA- 2012/01/11 06:00 PMCR- 2013/04/16 CRDT- 2011/10/15 06:00 PHST- 2011/05/27 00:00 [received] PHST- 2011/07/01 00:00 [revised] PHST- 2011/07/25 00:00 [accepted] PHST- 2011/10/15 06:00 [entrez] PHST- 2011/10/15 06:00 [pubmed] PHST- 2012/01/11 06:00 [medline] PHST- 2013/04/16 00:00 [pmc-release] AID - S0022-5223(11)00829-4 [pii] AID - 10.1016/j.jtcvs.2011.07.053 [doi] PST - ppublish SO - J Thorac Cardiovasc Surg. 2011 Dec;142(6):1567-74. doi: 10.1016/j.jtcvs.2011.07.053. Epub 2011 Oct 11.