Aortic endothelial cells regulate proliferation of human monocytes in vitro via a mechanism synergistic with macrophage colony-stimulating factor: Convergence at the cyclin E/p27(Kip1) regulatory checkpoint

Alexander S. Antonov, David H. Munn, Frank D. Kolodgie, Renu Virmani, Ross G. Gerrity

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33 Scopus citations


Monocyte-derived macrophages (Mφs) are pivotal participants in the pathogenesis of atherosclerosis. Evidence from both animal and human plaques indicates that local proliferation may contribute to accumulation of lesion Mφs, and the major Mφ growth factor, macrophage colony stimulating factor (MCSF), is present in atherosclerotic plaques. However, most in vitro studies have failed to demonstrate that human monocytes/Mφs possess significant proliferative capacity. We now report that, although human monocytes cultured in isolation showed only limited MCSF-induced proliferation, monocytes cocultured with aortic endothelial cells at identical MCSF concentrations underwent enhanced (up to 40-fold) and prolonged (21 d) proliferation. In contrast with monocytes in isolation, this was optimal at low seeding densities, required endothelial cell contact, and could not be reproduced by coculture with smooth muscle cells. Intimal Mφ isolated from human aortas likewise showed endothelial cell contact-dependent, MCSF-induced proliferation. Consistent with a two-signal mechanism governing Mφ proliferation, the cell cycle regulatory protein, cyclin E, was rapidly upregulated by endothelial cell contact in an MCSF-independent fashion, but MCSF was required for successful downregulation of the cell cycle inhibitory protein p27(Kip1) before cell cycling. Thus endothelial cells and MCSF differentially and synergistically regulate two Mφ genes critical for progression through the cell cycle.

Original languageEnglish (US)
Pages (from-to)2867-2876
Number of pages10
JournalJournal of Clinical Investigation
Issue number12
Publication statusPublished - Jun 15 1997



  • Atherosclerosis
  • Cell cycle regulation
  • Macrophage

ASJC Scopus subject areas

  • Medicine(all)

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