Endothelial junctional adhesion molecule-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.


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 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 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.
Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Munich, Germany (M.M.N.S., R.T.A.M., K.B., R.R.K., C.W.); the Institute for Molecular Cardiovascular Research, RWTH Aachen University, Aachen, Germany (M.M.N.S., M.A.v.Z.); the Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands (M.M.N.S., R.T.A.M., N.M.v.d.A., T.R., M.A.v.Z., T.M.H., R.R.K., C.W.); the Division of Vascular Biology, Department of Vascular Surgery, Klinikum rechts der Isar, Technical University Munich, Germany (A.Z.); and the German Centre for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany (A.Z., C.W.).
Martin M N
MM
Schmitt
Remco T A
RT
Megens
Alma
A
Zernecke
Kiril
K
Bidzhekov
Nynke M
NM
van den Akker
Timo
T
Rademakers
Marc A
MA
van Zandvoort
Tilman M
TM
Hackeng
Rory R
RR
Koenen
Christian
C
Weber
D000818:Animals; D001011:Aorta / Q000166:cytology; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D015815:Cell Adhesion Molecules / Q000235:genetics*; D002461:Cell Line, Transformed; D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000166:cytology / Q000502:physiology*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000166:cytology / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000235:genetics*; D012039:Regional Blood Flow / Q000502:physiology; D014657:Vasculitis / Q000235:genetics / Q000473:pathology / Q000503:physiopathology
D001057:Apolipoproteins E; D015815:Cell Adhesion Molecules; C407243:F11R protein, human; C498686:F11r protein, mouse; D011956:Receptors, Cell Surface
atherosclerosis; cell adhesion molecules; endothelial cells; imaging, diagnostic; microRNAs