Endothelial JAM-A Guides Monocytes into Flow-Dependent Predilection Sites of Atherosclerosis
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 employed apolipoprotein E-deficient mice with a somatic or endothelium-specific deficiency in JAM-A and bone marrow chimeras with JAM-A-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 athero¬protective laminar flow through an up-regulation of 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.
- Received May 29, 2013.
- Revision received September 14, 2013.
- Accepted September 16, 2013.