Endothelial Junctional Adhesion Molecule-A Guides Monocytes Into Flow-Dependent Predilection Sites of Atherosclerosis

Martin M. N. Schmitt, Remco T. A. Megens, Alma Zernecke, Kiril Bidzhekov, Nynke M. van den Akker, Timo Rademakers, Marc A. van Zandvoort, Tilman M. Hackeng, Rory R. Koenen, Christian Weber*

*Corresponding author for this work

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Abstract

Background-Junctional adhesion molecule (JAM)-A expressed in endothelial, epithelial, and blood cells can regulate permeability and leukocyte extravasation. Atherosclerosis develops at sites of disturbed flow in large arteries, but the mechanisms guiding inflammatory cells into these predilection sites remain unknown. Methods and Results-To characterize cell-specific functions of JAM-A in atherosclerosis, we used apolipoprotein E-deficient mice with a somatic or endothelium-specific deficiency in JAM-A and bone marrow chimeras with JAMA-deficient leukocytes. We show that impaired JAM-A expression in endothelial cells reduced mononuclear cell recruitment into the arterial wall and limited atherosclerotic lesion formation in hyperlipidemic mice. In contrast, JAM-A deficiency in bone marrow cells impeded monocyte de-adhesion, thereby increasing vascular permeability and lesion formation, whereas somatic JAM-A deletion revealed no significant effects. Regions with disturbed flow displayed a focal enrichment and luminal redistribution of endothelial JAM-A and were preferentially protected by its deficiency. The functional expression and redistribution of endothelial JAM-A was increased by oxidized low-density lipoprotein, but confined by atheroprotective laminar flow through an upregulation of microRNA (miR)-145, which repressed JAM-A. Conclusions-Our data identify endothelial JAM-A as an important effector molecule integrating atherogenic conditions to direct inflammatory cell entry at predilection sites of atherosclerosis.
Original languageEnglish
Pages (from-to)66-+
JournalCirculation
Volume129
Issue number1
DOIs
Publication statusPublished - 7 Jan 2014

Keywords

  • atherosclerosis
  • cell adhesion molecules
  • endothelial cells
  • imaging, diagnostic
  • microRNAs

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