Bone marrow-derived MCP1 required for experimental aortic aneurysm formation and smooth muscle phenotypic modulation

Christopher W. Moehle, Castigliano M. Bhamidipati, Matthew R. Alexander, Gaurav S. Mehta, James N. Irvine, Morgan Salmon, Gilbert R. Upchurch, Irving L. Kron, Gary K. Owens, Gorav Ailawadi

Research output: Contribution to journalArticle

40 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1567-1574
Number of pages8
JournalJournal of Thoracic and Cardiovascular Surgery
Volume142
Issue number6
DOIs
StatePublished - Dec 2011

ASJC Scopus subject areas

  • Surgery
  • Pulmonary and Respiratory Medicine
  • Cardiology and Cardiovascular Medicine

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    Moehle, C. W., Bhamidipati, C. M., Alexander, M. R., Mehta, G. S., Irvine, J. N., Salmon, M., Upchurch, G. R., Kron, I. L., Owens, G. K., & Ailawadi, G. (2011). Bone marrow-derived MCP1 required for experimental aortic aneurysm formation and smooth muscle phenotypic modulation. Journal of Thoracic and Cardiovascular Surgery, 142(6), 1567-1574. https://doi.org/10.1016/j.jtcvs.2011.07.053